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Entry
- #105400 - AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
- OMIM
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<span class="h4">#105400</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/105400"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS105400"> <strong>Phenotypic Series</strong> </a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(AMYOTROPHIC LATERAL SCLEROSIS) OR (NEFH OR SOD1 OR DCTN1 OR PRPH)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060193" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/105400" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/results?search_type=advanced&omia_id=000263,001165,002322,002491" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0060193" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:105400" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 1201863001<br />
<strong>ORPHA:</strong> 803<br />
<strong>DO:</strong> 0060193<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
105400
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL; FALS<br />
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL DOMINANT
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
AMYOTROPHIC LATERAL SCLEROSIS, SPORADIC, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/377?start=-3&limit=10&highlight=377">
2p13.1
</a>
</span>
</td>
<td>
<span class="mim-font">
{Amyotrophic lateral sclerosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
DCTN1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601143"> 601143 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/353?start=-3&limit=10&highlight=353">
12q13.12
</a>
</span>
</td>
<td>
<span class="mim-font">
{Amyotrophic lateral sclerosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
PRPH
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/170710"> 170710 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/21/54?start=-3&limit=10&highlight=54">
21q22.11
</a>
</span>
</td>
<td>
<span class="mim-font">
Amyotrophic lateral sclerosis 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
SOD1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147450"> 147450 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/152?start=-3&limit=10&highlight=152">
22q12.2
</a>
</span>
</td>
<td>
<span class="mim-font">
{?Amyotrophic lateral sclerosis, susceptibility to}
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
</span>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
NEFH
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162230"> 162230 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/105400" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS105400" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/105400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/105400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Muscle weakness and atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805345&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805345</a>]</span><br /> -
Fasciculations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82470000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82470000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015644&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015644</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002380</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002380" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002380</a>]</span><br /> -
Muscle cramps <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45352006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45352006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55300003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55300003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.83</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/728.85" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">728.85</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037763</a>, <a href="https://bioportal.bioontology.org/search?q=C0026821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026821</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003394</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
Hyperreflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
Ocular motility spared <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862943&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862943</a>]</span><br /> -
Upper and lower neuron manifestations <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862944&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862944</a>]</span><br /> -
Bulbar dysfunction (e.g. dysarthria and dysphagia) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862945&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862945</a>]</span><br /> -
Sleep apnea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73430006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73430006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.3</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.30</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.57" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.57</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3496180&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3496180</a>, <a href="https://bioportal.bioontology.org/search?q=C0037315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037315</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010535" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010535</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010535" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010535</a>]</span><br /> -
Pseudobulbar palsy (e.g. involuntary weeping or laughter) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862946</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7379000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7379000</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/335.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">335.23</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007024</a>]</span><br /> -
Pathologic changes in anterior horn cells and lateral corticospinal tracts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862947&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862947</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Reduced cytosolic superoxide dismutase-1 (SOD1) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862948&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862948</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Approximately 10% of ALS cases are familial<br /> -
Genetic heterogeneity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the superoxide dismutase-1 gene (SOD-1, <a href="/entry/147450#0001">147450.0001</a>) Susceptibility conferred by mutation in the neurofilament, heavy polypeptide gene (NEFH, <a href="/entry/162230#0001">162230.0001</a>)<br /> -
Susceptibility conferred by mutation in the peripherin gene (PRPH, <a href="/entry/170710#0001">170710.0001</a>)<br /> -
Susceptibility conferred by mutation in the dynactin 1 gene (DCTN1, <a href="/entry/601143#0002">601143.0002</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Amyotrophic lateral sclerosis
- <a href="/phenotypicSeries/PS105400">PS105400</a>
- 40 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/143?start=-3&limit=10&highlight=143"> 1p36.22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612069"> Amyotrophic lateral sclerosis 10, with or without FTD </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612069"> 612069 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605078"> TARDBP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605078"> 605078 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/143?start=-3&limit=10&highlight=143"> 1p36.22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612069"> Frontotemporal lobar degeneration, TARDBP-related </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612069"> 612069 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605078"> TARDBP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605078"> 605078 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/333?start=-3&limit=10&highlight=333"> 2p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619133"> Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619133"> 619133 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603518"> TIA1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603518"> 603518 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/377?start=-3&limit=10&highlight=377"> 2p13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> {Amyotrophic lateral sclerosis, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601143"> DCTN1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601143"> 601143 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/921?start=-3&limit=10&highlight=921"> 2q33.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/205100"> Amyotrophic lateral sclerosis 2, juvenile </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/205100"> 205100 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606352"> ALS2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606352"> 606352 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/976?start=-3&limit=10&highlight=976"> 2q34 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615515"> Amyotrophic lateral sclerosis 19 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615515"> 615515 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600543"> ERBB4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600543"> 600543 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1035?start=-3&limit=10&highlight=1035"> 2q35 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616208"> Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616208"> 616208 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191110"> TUBA4A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191110"> 191110 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/475?start=-3&limit=10&highlight=475"> 3p11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600795"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600795"> 600795 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609512"> CHMP2B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609512"> 609512 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/666?start=-3&limit=10&highlight=666"> 4q33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617892"> {Amyotrophic lateral sclerosis, susceptibility to, 24} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617892"> 617892 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604588"> NEK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604588"> 604588 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/516?start=-3&limit=10&highlight=516"> 5q31.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606070"> Amyotrophic lateral sclerosis 21 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606070"> 606070 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164015"> MATR3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164015"> 164015 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/837?start=-3&limit=10&highlight=837"> 5q35.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616437"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616437"> 616437 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601530"> SQSTM1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601530"> 601530 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/769?start=-3&limit=10&highlight=769"> 6q21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612577"> Amyotrophic lateral sclerosis 11 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612577"> 612577 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609390"> FIG4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609390"> 609390 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/466?start=-3&limit=10&highlight=466"> 8q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620452"> Amyotrophic lateral sclerosis 28 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620452"> 620452 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618299"> LRP12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618299"> 618299 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/117?start=-3&limit=10&highlight=117"> 9p21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105550"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105550"> 105550 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614260"> C9orf72 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614260"> 614260 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/152?start=-3&limit=10&highlight=152"> 9p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614373"> ?Amyotrophic lateral sclerosis 16, juvenile </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614373"> 614373 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601978"> SIGMAR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601978"> 601978 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/160?start=-3&limit=10&highlight=160"> 9p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613954"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613954"> 613954 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601023"> VCP </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601023"> 601023 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/301?start=-3&limit=10&highlight=301"> 9q22.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620285"> Amyotrophic lateral sclerosis 27, juvenile </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620285"> 620285 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605712"> SPTLC1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605712"> 605712 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/594?start=-3&limit=10&highlight=594"> 9q34.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602433"> Amyotrophic lateral sclerosis 4, juvenile </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602433"> 602433 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608465"> SETX </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608465"> 608465 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/61?start=-3&limit=10&highlight=61"> 10p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613435"> Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613435"> 613435 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602432"> OPTN </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602432"> 602432 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/336?start=-3&limit=10&highlight=336"> 10q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617839"> Amyotrophic lateral sclerosis 23 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617839"> 617839 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602572"> ANXA11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602572"> 602572 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/353?start=-3&limit=10&highlight=353"> 12q13.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> {Amyotrophic lateral sclerosis, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/170710"> PRPH </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/170710"> 170710 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/462?start=-3&limit=10&highlight=462"> 12q13.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615426"> Amyotrophic lateral sclerosis 20 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615426"> 615426 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164017"> HNRNPA1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164017"> 164017 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/547?start=-3&limit=10&highlight=547"> 12q13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617921"> {Amyotrophic lateral sclerosis, susceptibility to, 25} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617921"> 617921 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602821"> KIF5A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602821"> 602821 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/581?start=-3&limit=10&highlight=581"> 12q14.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616439"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616439"> 616439 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604834"> TBK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604834"> 604834 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/813?start=-3&limit=10&highlight=813"> 12q24.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> Spinocerebellar ataxia 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> 183090 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> ATXN2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> 601517 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/813?start=-3&limit=10&highlight=813"> 12q24.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> {Amyotrophic lateral sclerosis, susceptibility to, 13} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/183090"> 183090 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> ATXN2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601517"> 601517 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/35?start=-3&limit=10&highlight=35"> 14q11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611895"> Amyotrophic lateral sclerosis 9 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611895"> 611895 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105850"> ANG </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105850"> 105850 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/168?start=-3&limit=10&highlight=168"> 15q21.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602099"> Amyotrophic lateral sclerosis 5, juvenile </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602099"> 602099 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610844"> SPG11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610844"> 610844 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/106?start=-3&limit=10&highlight=106"> 16p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619141"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 5 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619141"> 619141 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600227"> CCNF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600227"> 600227 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/384?start=-3&limit=10&highlight=384"> 16p11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608030"> Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608030"> 608030 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/137070"> FUS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/137070"> 137070 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/430?start=-3&limit=10&highlight=430"> 16q12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619132"> ?Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619132"> 619132 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605018"> CYLD </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605018"> 605018 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/95?start=-3&limit=10&highlight=95"> 17p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614808"> Amyotrophic lateral sclerosis 18 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614808"> 614808 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176610"> PFN1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176610"> 176610 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/18/155?start=-3&limit=10&highlight=155"> 18q21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606640"> Amyotrophic lateral sclerosis 3 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606640"> 606640 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606640"> ALS3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606640"> 606640 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/2?start=-3&limit=10&highlight=2"> 20p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608031"> Amyotrophic lateral sclerosis 7 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608031"> 608031 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608031"> ALS7 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608031"> 608031 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/421?start=-3&limit=10&highlight=421"> 20q13.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608627"> Amyotrophic lateral sclerosis 8 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608627"> 608627 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605704"> VAPBC </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605704"> 605704 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/21/54?start=-3&limit=10&highlight=54"> 21q22.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> Amyotrophic lateral sclerosis 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> 105400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147450"> SOD1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147450"> 147450 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/101?start=-3&limit=10&highlight=101"> 22q11.23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615911"> Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615911"> 615911 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615903"> CHCHD10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615903"> 615903 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/152?start=-3&limit=10&highlight=152"> 22q12.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/105400"> {?Amyotrophic lateral sclerosis, susceptibility to} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
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<a href="/entry/300857"> Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia </a>
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<a href="/entry/300264"> 300264 </a>
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<a href="/entry/205200"> Amyotrophic lateral sclerosis, juvenile, with dementia </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/205200"> 205200 </a>
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<a href="/entry/205200"> ALSDC </a>
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<a href="/entry/205200"> 205200 </a>
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<p>A number sign (#) is used with this entry because 15 to 20% of cases of familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1, are associated with mutations in the superoxide dismutase-1 gene (SOD1; <a href="/entry/147450">147450</a>) on chromosome 21q22. Although most cases of SOD1-related familial ALS follow autosomal dominant inheritance, rare cases of autosomal recessive inheritance have been reported.</p>
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<p>Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (<a href="#106" class="mim-tip-reference" title="Siddique, T., Deng, H.-X. &lt;strong&gt;Genetics of amyotrophic lateral sclerosis.&lt;/strong&gt; Hum. Molec. Genet. 5: 1465-1470, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8875253/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8875253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/5.supplement_1.1465&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8875253">Siddique and Deng, 1996</a>). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8875253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#100" class="mim-tip-reference" title="Rowland, L. P., Shneider, N. A. &lt;strong&gt;Amyotrophic lateral sclerosis.&lt;/strong&gt; New Eng. J. Med. 344: 1688-1700, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11386269/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11386269&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200105313442207&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11386269">Rowland and Shneider (2001)</a> and <a href="#62" class="mim-tip-reference" title="Kunst, C. B. &lt;strong&gt;Complex genetics of amyotrophic lateral sclerosis.&lt;/strong&gt; Am. J. Hum. Genet. 75: 933-947, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15478096/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15478096&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/426001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15478096">Kunst (2004)</a> provided extensive reviews of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11386269+15478096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Some forms of ALS occur with frontotemporal dementia (FTD); see <a href="/entry/105500">105500</a>. <a href="#93" class="mim-tip-reference" title="Ranganathan, R., Haque, S., Coley, K., Shepheard, S., Cooper=Knock, J., Kirby, J. &lt;strong&gt;Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia.&lt;/strong&gt; Front. Neurosci. 14: 684, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32733193/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32733193&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32733193[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3389/fnins.2020.00684&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32733193">Ranganathan et al. (2020)</a> provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32733193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (<a href="/entry/105500">105500</a>) (<a href="#35" class="mim-tip-reference" title="Espinosa, R. E., Okihiro, M. M., Mulder, D. W., Sayre, G. P. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis: a clinical and pathologic report with comments on classification.&lt;/strong&gt; Neurology 12: 1-7, 1962."None>Espinosa et al., 1962</a>; <a href="#54" class="mim-tip-reference" title="Husquinet, H., Franck, G. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis transmitted for five generations.&lt;/strong&gt; Clin. Genet. 18: 109-115, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7438491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7438491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1980.tb01020.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7438491">Husquinet and Franck, 1980</a>), in which the histology is different and dementia and parkinsonism complicate the clinical picture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7438491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Amyotrophic Lateral Sclerosis</em></strong></p><p>
ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci.</p><p>ALS6 (<a href="/entry/608030">608030</a>) is caused by mutation in the FUS gene (<a href="/entry/137070">137070</a>) on chromosome 16p11; ALS8 (<a href="/entry/608627">608627</a>) is caused by mutation in the VAPB gene (<a href="/entry/605704">605704</a>) on chromosome 13; ALS9 (<a href="/entry/611895">611895</a>) is caused by mutation in the ANG gene (<a href="/entry/105850">105850</a>) on chromosome 14q11; ALS10 (<a href="/entry/612069">612069</a>) is caused by mutation in the TARDBP gene (<a href="/entry/605078">605078</a>) on 1p36; ALS11 (<a href="/entry/612577">612577</a>) is caused by mutation in the FIG4 gene (<a href="/entry/609390">609390</a>) on chromosome 6q21; ALS12 (<a href="/entry/613435">613435</a>) is caused by mutation in the OPTN gene (<a href="/entry/602432">602432</a>) on chromosome 10p13; ALS15 (<a href="/entry/300857">300857</a>) is caused by mutation in the UBQLN2 gene (<a href="/entry/300264">300264</a>) on chromosome Xp11; ALS18 (<a href="/entry/614808">614808</a>) is caused by mutation in the PFN1 gene (<a href="/entry/176610">176610</a>) on chromosome 17p13; ALS19 (<a href="/entry/615515">615515</a>) is caused by mutation in the ERBB4 gene (<a href="/entry/600543">600543</a>) on chromosome 2q34; ALS20 (<a href="/entry/615426">615426</a>) is caused by mutation in the HNRNPA1 gene (<a href="/entry/164017">164017</a>) on chromosome 12q13; ALS21 (<a href="/entry/606070">606070</a>) is caused by mutation in the MATR3 gene (<a href="/entry/164015">164015</a>) on chromosome 5q31; ALS22 (<a href="/entry/616208">616208</a>) is caused by mutation in the TUBA4A gene (<a href="/entry/191110">191110</a>) on chromosome 2q35; ALS23 (<a href="/entry/617839">617839</a>) is caused by mutation in the ANXA11 gene (<a href="/entry/602572">602572</a>) on chromosome 10q23; ALS26 (<a href="/entry/619133">619133</a>) is caused by mutation in the TIA1 gene (<a href="/entry/603518">603518</a>) on chromosome 2p13; ALS27 (<a href="/entry/620285">620285</a>) is caused by mutation in the SPTLC1 gene (<a href="/entry/605712">605712</a>) on chromosome 9q22; and ALS28 (<a href="/entry/620452">620452</a>) is caused by mutation in the LRP12 gene (<a href="/entry/618299">618299</a>) on chromosome 8q22.</p><p>Loci associated with ALS have been found on chromosomes 18q21 (ALS3; <a href="/entry/606640">606640</a>) and 20p13 (ALS7; <a href="/entry/608031">608031</a>).</p><p>Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (<a href="/entry/601517">601517</a>) contribute to susceptibility to ALS (ALS13; <a href="/entry/183090">183090</a>). Susceptibility to ALS24 (<a href="/entry/617892">617892</a>) is conferred by mutation in the NEK1 gene (<a href="/entry/604588">604588</a>) on chromosome 4q33, and susceptibility to ALS25 (<a href="/entry/617921">617921</a>) is conferred by mutation in the KIF5A gene (<a href="/entry/602821">602821</a>) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; <a href="/entry/162230">162230</a>); deletions in the gene encoding peripherin (PRPH; <a href="/entry/170710">170710</a>); and mutations in the dynactin gene (DCTN1; <a href="/entry/601143">601143</a>).</p><p>Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (<a href="/entry/205100">205100</a>), caused by mutation in the alsin (<a href="/entry/606352">606352</a>) gene on 2q33; ALS4 (<a href="/entry/602433">602433</a>), caused by mutation in the senataxin gene (SETX; <a href="/entry/608465">608465</a>) on 9q34; ALS5 (<a href="/entry/602099">602099</a>), caused by mutation in the SPG11 gene (<a href="/entry/610844">610844</a>) on 15q21; and ALS16 (<a href="/entry/614373">614373</a>), caused by mutation in the SIGMAR1 gene (<a href="/entry/601978">601978</a>) on 9p13.</p>
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<p><a href="#52" class="mim-tip-reference" title="Horton, W. A., Eldridge, R., Brody, J. A. &lt;strong&gt;Familial motor neuron disease: evidence for at least three different types.&lt;/strong&gt; Neurology 26: 460-465, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/944398/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;944398&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.26.5.460&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="944398">Horton et al. (1976)</a> suggested that there are 3 phenotypic forms of familial ALS, each inherited as an autosomal dominant disorder. The first form they delineated is characterized by rapidly progressive loss of motor function with predominantly lower motor neuron manifestations and a course of less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second form is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke column, and spinocerebellar tracts. The third form is similar to the second except for a much longer survival, usually beyond 10 and often 20 years. Examples of type 1 include the families of <a href="#44" class="mim-tip-reference" title="Green, J. B. &lt;strong&gt;Familial amyotrophic lateral sclerosis occurring in 4 generations.&lt;/strong&gt; Neurology 10: 960-962, 1960.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13708181/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13708181&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.10.11.960&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13708181">Green (1960)</a>, <a href="#87" class="mim-tip-reference" title="Poser, C. M., Johnson, M., Bunch, L. D. &lt;strong&gt;Familial amyotrophic lateral sclerosis.&lt;/strong&gt; Dis. Nerv. Syst. 26: 697-702, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5843014/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5843014&lt;/a&gt;]" pmid="5843014">Poser et al. (1965)</a> and <a href="#120" class="mim-tip-reference" title="Thomson, A. F., Alvarez, F. A. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis.&lt;/strong&gt; J. Neurol. Sci. 8: 101-110, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5790363/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5790363&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(69)90044-6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5790363">Thomson and Alvarez (1969)</a>. Examples of type 2 include the families of <a href="#63" class="mim-tip-reference" title="Kurland, L. T., Mulder, D. W. &lt;strong&gt;Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance.&lt;/strong&gt; Neurology 5: 182-196 and 249-268, 1955.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14356347/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14356347&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.5.3.182&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14356347">Kurland and Mulder (1955)</a> and <a href="#33" class="mim-tip-reference" title="Engel, W. K., Kurland, L. T., Klatzo, I. &lt;strong&gt;An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement: an intermediate form?&lt;/strong&gt; Brain 82: 203-220, 1959.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13849712/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13849712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/82.2.203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13849712">Engel et al. (1959)</a>. <a href="#33" class="mim-tip-reference" title="Engel, W. K., Kurland, L. T., Klatzo, I. &lt;strong&gt;An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement: an intermediate form?&lt;/strong&gt; Brain 82: 203-220, 1959.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13849712/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13849712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/82.2.203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13849712">Engel et al. (1959)</a> described 2 American families, 1 of which was of Pennsylvania Dutch stock with at least 11 members of 4 generations affected with what was locally and popularly termed 'Pecks disease.' Examples of type 3 include the families of <a href="#5" class="mim-tip-reference" title="Amick, L. D., Nelson, J. W., Zellweger, H. &lt;strong&gt;Familial motor neuron disease, non-Chamorro type: report of kinship.&lt;/strong&gt; Acta Neurol. Scand. 47: 341-349, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5096760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5096760&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-0404.1971.tb07488.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5096760">Amick et al. (1971)</a> and <a href="#2" class="mim-tip-reference" title="Alberca, R., Castilla, J. M., Gil-Peralta, A. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis.&lt;/strong&gt; J. Neurol. Sci. 50: 201-206, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7229665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7229665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(81)90166-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7229665">Alberca et al. (1981)</a>. In the Spanish kindred reported by <a href="#2" class="mim-tip-reference" title="Alberca, R., Castilla, J. M., Gil-Peralta, A. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis.&lt;/strong&gt; J. Neurol. Sci. 50: 201-206, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7229665/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7229665&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(81)90166-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7229665">Alberca et al. (1981)</a>, early onset and persistence of muscle cramps, unilateral proximal segmental myoclonus, and early abolition of ankle jerks were conspicuous clinical features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5096760+944398+5843014+13849712+5790363+14356347+13708181+7229665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Brown (<a href="#19" class="mim-tip-reference" title="Brown, M. R. &lt;strong&gt;&#x27;Wetherbee ail&#x27;: the inheritance of progressive muscular atrophy as a dominant trait in two New England families.&lt;/strong&gt; New Eng. J. Med. 245: 645-647, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14875225/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14875225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM195110252451704&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14875225">1951</a>, <a href="#20" class="mim-tip-reference" title="Brown, M. R. &lt;strong&gt;The inheritance of progressive muscular atrophy as a dominant trait in two New England families.&lt;/strong&gt; New Eng. J. Med. 262: 1280-1282, 1960.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13804989/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13804989&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM196006232622508&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13804989">1960</a>) described 2 New England families, Wetherbee and Farr by name, with autosomal dominant inheritance of a rapidly progressive neurodegenerative disorder with loss of anterior horn cells of the spinal cord and bulbar palsy. (See also <a href="#49" class="mim-tip-reference" title="Hammond, W. A. &lt;strong&gt;A Treatise on the Diseases of the Nervous System. (7th ed.)&lt;/strong&gt; Philadelphia: Blakiston, Son, &amp; Co. (pub.) 1888. P. 351."None>Hammond, 1888</a> and <a href="#79" class="mim-tip-reference" title="Myrianthopoulos, N. C., Brown, I. A. &lt;strong&gt;A genetic study of progressive spinal muscular atrophy.&lt;/strong&gt; Am. J. Hum. Genet. 6: 387-411, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14349945/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14349945&lt;/a&gt;]" pmid="14349945">Myrianthopoulos and Brown, 1954</a>). Neuropathology showed a classic 'middle-root zone' pattern of posterior column demyelination in addition to involvement of the anteriolateral columns and ventral horn cells. Although the disorder was clinically indistinguishable from ALS, the pattern of posterior column demyelinations was unexpected. <a href="#83" class="mim-tip-reference" title="Osler, W. &lt;strong&gt;On heredity in progressive muscular atrophy as illustrated in the Farr family of Vermont.&lt;/strong&gt; Arch. Med. 4: 316-320, 1880."None>Osler (1880)</a> had described the Farr family earlier (<a href="#72" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Osler as medical geneticist.&lt;/strong&gt; Johns Hopkins Med. J. 139: 163-174, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/824491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;824491&lt;/a&gt;]" pmid="824491">McKusick, 1976</a>). Variability in disease severity in the Farr family was indicated by the case of a 78-year-old woman with relatively minor findings who had buried a son and whose mother had been affected (<a href="#112" class="mim-tip-reference" title="Siddique, T. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Chicago, Ill. 11/17/1993."None>Siddique, 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14349945+14875225+13804989+824491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#88" class="mim-tip-reference" title="Powers, J. M., Horoupian, D. S., Schaumburg, H. H. &lt;strong&gt;Wetherbee ail: documentation of a neurological disease in a Vermont family 90 years later.&lt;/strong&gt; Canad. J. Sci. Neurol. 1: 139-140, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4434271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4434271&lt;/a&gt;]" pmid="4434271">Powers et al. (1974)</a> reported the first autopsy in a member of the Wetherbee family from Vermont. The patient was a 35-year-old woman who began to experience weakness in the left leg 1 year before her terminal admission. She then gradually developed weakness and atrophy of the left hand, right lower limb, and right hand. One month before admission she developed dyspnea which steadily worsened, and she was admitted to hospital because of severe ventilatory insufficiency secondary to muscle weakness. She showed atrophy of all extremities, areflexia, and, except for slight movement of the left shoulder and right foot, quadriplegia. The patient died on the second hospital day. Autopsy showed severe demyelination type of atrophy of all muscles. Gray atrophy of the lumbar and cervical anterior roots was evident grossly. Microscopic neuronal changes included a moderate loss of neurons from the hypoglossal nuclei and dorsal motor vagal nuclei, severe neuronal loss from the anterior horns of the cervical and lumbar cord with reactive gliosis, eosinophilic intracytoplasmic inclusions in many of the remaining lumbar anterior horn cells, and a moderately symmetric loss of neurons from the Clarke column. A severe asymmetric loss of axons and myelin was demonstrated throughout the cervical dorsal spinocerebellar tracts and lumbar posterior columns, with moderate loss in the lumbar lateral corticospinal tracts. <a href="#88" class="mim-tip-reference" title="Powers, J. M., Horoupian, D. S., Schaumburg, H. H. &lt;strong&gt;Wetherbee ail: documentation of a neurological disease in a Vermont family 90 years later.&lt;/strong&gt; Canad. J. Sci. Neurol. 1: 139-140, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4434271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4434271&lt;/a&gt;]" pmid="4434271">Powers et al. (1974)</a> concluded that the disorder corresponded exactly to a subgroup of familial ALS described by <a href="#51" class="mim-tip-reference" title="Hirano, A., Kurland, L. T., Sayre, G. P. &lt;strong&gt;Familial amyotrophic lateral sclerosis: a subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells.&lt;/strong&gt; Arch. Neurol. 16: 232-243, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6018874/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6018874&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1967.00470210008002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6018874">Hirano et al. (1967)</a>. <a href="#34" class="mim-tip-reference" title="Engel, W. K. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Bethesda, Md. 1976."None>Engel (1976)</a> concluded that the 'Wetherbee ail' and the Farr family disease were consistent with ALS (<a href="#33" class="mim-tip-reference" title="Engel, W. K., Kurland, L. T., Klatzo, I. &lt;strong&gt;An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement: an intermediate form?&lt;/strong&gt; Brain 82: 203-220, 1959.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13849712/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13849712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/82.2.203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13849712">Engel et al., 1959</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6018874+4434271+13849712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Alter, M., Schaumann, B. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis: a report of two families.&lt;/strong&gt; Europ. Neurol. 14: 250-265, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/954772/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;954772&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000114747&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="954772">Alter and Schaumann (1976)</a> reported 14 cases in 2 families and attempted a refinement of the classification of hereditary ALS. <a href="#53" class="mim-tip-reference" title="Hudson, A. J. &lt;strong&gt;Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review.&lt;/strong&gt; Brain 104: 217-247, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7016254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7016254&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/104.2.217&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7016254">Hudson (1981)</a> stated that posterior column disease is found in association with ALS in 80% of familial cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=954772+7016254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a kindred with an apparently 'new' microcephaly-cataract syndrome (<a href="/entry/212540">212540</a>), reported by <a href="#104" class="mim-tip-reference" title="Scott-Emuakpor, A. B., Heffelfinger, J., Higgins, J. V. &lt;strong&gt;A syndrome of microcephaly and cataracts in four siblings: a new genetic syndrome?&lt;/strong&gt; Am. J. Dis. Child. 131: 167-169, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/835533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;835533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1977.02120150049010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="835533">Scott-Emuakpor et al. (1977)</a>, 10 persons had died of a seemingly unrelated genetic defect--amyotrophic lateral sclerosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=835533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#125" class="mim-tip-reference" title="Veltema, A. N., Roos, R. A. C., Bruyn, G. W. &lt;strong&gt;Autosomal dominant adult amyotrophic lateral sclerosis: a six generation Dutch family.&lt;/strong&gt; J. Neurol. Sci. 97: 93-115, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2370562/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2370562&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(90)90101-r&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2370562">Veltema et al. (1990)</a> described adult ALS in 18 individuals from 6 generations of a Dutch family. Onset occurred between ages 19 and 46; duration of disease averaged 1.7 years. The clinical symptoms were predominantly those of initial shoulder girdle and ultimate partial bulbar muscle involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2370562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Iwasaki, Y., Kinoshita, M., Ikeda, K. &lt;strong&gt;Concurrence of familial amyotrophic lateral sclerosis with Ribbing&#x27;s disease.&lt;/strong&gt; Int. J. Neurosci. 58: 289-292, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1365052/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1365052&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/00207459108985445&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1365052">Iwasaki et al. (1991)</a> reported a Japanese family in which members in at least 3 generations had ALS. At least 2 individuals in the family also had Ribbing disease (<a href="/entry/601477">601477</a>), a skeletal dysplasia that was presumably unrelated to the ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1365052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<p>Familial ALS caused by mutations in the SOD1 gene usually causes autosomal dominant disease, but can also cause autosomal recessive ALS.</p><p>In Germany, <a href="#48" class="mim-tip-reference" title="Haberlandt, W. F. &lt;strong&gt;Ergebnisse einer neurologisch-genetischen Studie im nordwestdeutschen Raum. In: Gedda, L. (ed.): Proceedings of the Second International Congress of Human Genetics, Rome, Sept. 6-12, 1961. Vol. 3.&lt;/strong&gt; Rome: Instituo G. Mendel 1963. Pp. 1645-1651."None>Haberlandt (1963)</a> concluded that ALS is an 'irregular' autosomal dominant disorder in many instances. <a href="#41" class="mim-tip-reference" title="Gardner, J. H., Feldmahn, A. &lt;strong&gt;Hereditary adult motor neuron disease.&lt;/strong&gt; Trans. Am. Neurol. Assoc. 91: 239-241, 1966."None>Gardner and Feldmahn (1966)</a> described adult-onset ALS in a family in which 15 members spanning 7 generations were affected.</p><p><a href="#54" class="mim-tip-reference" title="Husquinet, H., Franck, G. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis transmitted for five generations.&lt;/strong&gt; Clin. Genet. 18: 109-115, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7438491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7438491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1980.tb01020.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7438491">Husquinet and Franck (1980)</a> reported a family with ALS suggesting autosomal dominant inheritance with incomplete penetrance. Twelve men and 6 women were affected; 4 unaffected members of the family transmitted the disease. The first signs of the disease, which ran its course in 5 to 6 years, were in either the arms or the legs. As in most cases of ALS, death was caused by bulbar paralysis. Mean age at death was about 57 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7438491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of a familial ALS, <a href="#28" class="mim-tip-reference" title="de Belleroche, J., Orrell, R., King, A. &lt;strong&gt;Familial amyotrophic lateral sclerosis/motor neurone disease (FALS): a review of current developments.&lt;/strong&gt; J. Med. Genet. 32: 841-847, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8592323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8592323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.11.841&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8592323">de Belleroche et al. (1995)</a> found autosomal dominant inheritance with incomplete penetrance; by age 85 years, about 80% of carriers had manifested the disorder, and it was not uncommon to see obligate carriers in a family who died without manifesting the disease. Phenotypic heterogeneity was also common within families: for example, age of onset varying over 30 years within a family and duration of illness varying from 6 months to 5 years. Signs at onset were variable, but the disease usually began with focal and asymmetric wasting of hand muscles. Lower motor neuron involvement was usually conspicuous, whereas involvement of upper motor neurons was less marked. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8592323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Bradley, M., Bradley, L., de Belleroche, J., Orrell, R. W. &lt;strong&gt;Patterns of inheritance in familial ALS.&lt;/strong&gt; Neurology 64: 1628-1631, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15883330/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15883330&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.WNL.0000160395.43761.AC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15883330">Bradley et al. (2005)</a> found no evidence for preferential maternal or paternal transmission among 185 families in which at least 2 individuals were diagnosed with ALS. Initial evidence suggesting anticipation was rejected following further analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15883330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of a Swedish multigeneration registry spanning from 1961 to 2005, <a href="#36" class="mim-tip-reference" title="Fang, F., Kamel, F., Lichtenstein, P., Bellocco, R., Sparen, P., Sandler, D. P., Ye, W. &lt;strong&gt;Familial aggregation of amyotrophic lateral sclerosis.&lt;/strong&gt; Ann. Neurol. 66: 94-99, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19670447/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19670447&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21580&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19670447">Fang et al. (2009)</a> identified 6,671 probands with ALS. There was a 17-fold increased risk for development of ALS among sibs, and a 9-fold increased risk among children of probands. Sibs and children had a greater risk if the proband was diagnosed at a younger age, and the risk decreased with increasing age at diagnosis of the proband. Two cases were identified among the cotwins of ALS probands, yielding a relative risk of 32 for monozygotic twins. Spouses of probands had no significantly increased risk compared to controls. The findings indicated that there is a major genetic role in the development of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19670447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Possible X-linked Inheritance</em></strong></p><p>
In a family with ALS reported by <a href="#126" class="mim-tip-reference" title="Wilkins, L. E., Winter, R. M., Myer, E. C., Nance, W. E. &lt;strong&gt;Dominantly inherited amyotrophic lateral sclerosis (motor neuron disease).&lt;/strong&gt; Med. Coll. Va. Quart. 13(4): 182-186, 1977."None>Wilkins et al. (1977)</a>, X-linked dominant inheritance was suggested by the late onset in females and the lack of male-to-male transmission.</p><p><a href="#109" class="mim-tip-reference" title="Siddique, T., Pericak-Vance, M. A., Brooks, B. R., Bias, W., Walker, N., Siddique, N., Hung, W.-Y., Roses, A. D. &lt;strong&gt;Linkage in familial amyotrophic lateral sclerosis (ALS). (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 46: 692, 1987."None>Siddique et al. (1987)</a> did linkage studies in a family with 13 affected persons in 4 generations. There was no instance of male-to-male transmission. <a href="#62" class="mim-tip-reference" title="Kunst, C. B. &lt;strong&gt;Complex genetics of amyotrophic lateral sclerosis.&lt;/strong&gt; Am. J. Hum. Genet. 75: 933-947, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15478096/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15478096&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/426001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15478096">Kunst (2004)</a> referenced an X-linked dominant, late-onset form linked to Xp11-q12 but reported only in abstract (<a href="#108" class="mim-tip-reference" title="Siddique, T., Hong, S.-T., Brooks, B. R., Hung, W. Y., Siddique, N. A., Rimmler, J., Kaplan, J. P., Haines, J. L., Brown, R. H., Jr., Pericak-Vance, M. A. &lt;strong&gt;X-linked dominant locus for late-onset familial amyotrophic lateral sclerosis. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 63 (suppl.): A308 only, 1998."None>Siddique et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15478096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#110" class="mim-tip-reference" title="Siddique, T., Pericak-Vance, M. A., Brooks, B. R., Roos, R. P., Tandan, R., Nicholson, G., Noore, F., Antel, J. P., Munsat, T. L., Phillips, K. L., Hung, W.-Y., Warner, K. L., Bebout, J., Bias, W., Roses, A. D. &lt;strong&gt;Genetic linkage analysis in familial amyotrophic lateral sclerosis. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1080, 1989."None>Siddique et al. (1989)</a> presented preliminary data from genetic linkage analysis in 150 families with familial ALS. Two regions of possible linkage were identified on chromosomes 11 and 21. The highest lod score observed was 1.46, obtained with D21S13 at theta = 0.20. The next highest lod score was observed with marker D11S21 (lod score = 1.05 at maximum theta of 0.001).</p><p><a href="#107" class="mim-tip-reference" title="Siddique, T., Figlewicz, D. A., Pericak-Vance, M. A., Haines, J. L., Rouleau, G., Jeffers, A. J., Sapp, P., Hung, W.-Y., Bebout, J., McKenna-Yasek, D., Deng, G., Horvitz, H. R., and 25 others. &lt;strong&gt;Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity.&lt;/strong&gt; New Eng. J. Med. 324: 1381-1384, 1991. Note: Erratum: New Eng. J. Med. 325: 71 only, 1991; Erratum: New Eng. J. Med. 325: 524 only, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2020294/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2020294&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199105163242001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2020294">Siddique et al. (1991)</a> presented evidence for linkage of familial ALS, termed ALS1, to markers on chromosome 21q22.1-q22.2 (maximum lod score of 5.03 10 cM telomeric to marker D21S58). Tests for heterogeneity in these families yielded a probability of less than 0.0001 that of genetic-locus heterogeneity, i.e., a low probability of homogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2020294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity</em></strong></p><p>
<a href="#60" class="mim-tip-reference" title="King, A., Houlden, H., Hardy, J., Lane, R., Chancellor, A., de Belleroche, J. &lt;strong&gt;Absence of linkage between chromosome 21 loci and familial amyotrophic lateral sclerosis.&lt;/strong&gt; J. Med. Genet. 30: 318, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8487280/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8487280&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.4.318&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8487280">King et al. (1993)</a> failed to find linkage to loci on chromosome 21 in 8 U.K. families with ALS, indicating genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8487280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
In a genomewide association study (GWAS) of 1,014 deceased patients with sporadic ALS and 2,258 controls from the U.S. and Europe, <a href="#66" class="mim-tip-reference" title="Landers, J. E., Melki, J., Meininger, V., Glass, J. D., van den Berg, L. H., van Es, M. A., Sapp, P. C., van Vught, P. W. J., McKenna-Yasek, D. M., Blauw, H. M., Cho, T.-J., Polak, M., and 34 others. &lt;strong&gt;Reduced expression of the kinesin-associated protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 106: 9004-9009, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19451621/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19451621&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19451621[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0812937106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19451621">Landers et al. (2009)</a> found a significant association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1541160;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1541160</a> in intron 8 of the KIFAP3 gene (<a href="/entry/601836">601836</a>) on chromosome 1q24 and survival (p = 1.84 x 10(-8), p = 0.021 after Bonferroni correction). Homozygosity for the favorable allele, CC, conferred a 14-month survival advantage compared to TT. There was linkage disequilibrium between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1541160;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1541160</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs522444;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs522444</a> within the KIFAP3 promoter, and the favorable alleles of both SNPs correlated with decreased KIFAP3 expression in brain. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. The findings suggested that genetic factors may modify phenotypes in ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19451621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#123" class="mim-tip-reference" title="van Es, M. A., Veldink, J. H., Saris, C. G. J., Blauw, H. M., van Vught, P. W. J., Birve, A., Lemmens, R., Schelhaas, H. J., Groen, E. J. N., Huisman, M. H. B., van der Kooi, A. J., de Visser, M. &lt;strong&gt;{and 42 others}: Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Nature Genet. 41: 1083-1087, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19734901/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19734901&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19734901">Van Es et al. (2009)</a> conducted a genomewide association study among 2,323 individuals with sporadic ALS and 9,013 control subjects and evaluated all SNPs with P less than 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genomewide data revealed genomewide significance for 1 SNP, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12608932;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12608932</a>, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort, and a combined analysis over the 2 stages yielded P = 2.53 x 10(-14). The <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12608932;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12608932</a> SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A (<a href="/entry/609894">609894</a>), which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19734901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Exclusion Studies</em></strong></p><p>
<a href="#128" class="mim-tip-reference" title="Wills, A.-M., Cronin, S., Slowik, A., Kasperaviciute, D., Van Es, M. A., Morahan, J. M., Valdmanis, P. N., Meininger, V., Melki, J., Shaw, C. E., Rouleau, G. A., Fisher, E. M. C., and 11 others. &lt;strong&gt;A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.&lt;/strong&gt; Neurology 73: 16-24, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19321847/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19321847&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19321847[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181a18674&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19321847">Wills et al. (2009)</a> conducted a metaanalysis of 10 published studies, including 4 GWAS, and 1 unpublished study that had reported findings on association of sporadic ALS and paraoxonase (see PON1; <a href="/entry/168820">168820</a>) SNPs on chromosome 7q21.3. The metaanalysis found no association between sporadic ALS and the PON locus and encompassed 4,037 ALS patients and 4,609 controls, including GWAS data from 2,018 ALS cases and 2,425 controls. The authors stated that this was the largest metaanalysis of a candidate gene in ALS to date and the first ALS metaanalysis to include data from GWAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19321847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#17" class="mim-tip-reference" title="Bradley, W. G., Krasin, F. &lt;strong&gt;A new hypothesis of the etiology of amyotrophic lateral sclerosis: the DNA hypothesis.&lt;/strong&gt; Arch. Neurol. 39: 677-680, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6181766/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6181766&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1982.00510230003001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6181766">Bradley and Krasin (1982)</a> suggested that a defect in DNA repair may underlie ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6181766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Rothstein, J. D., Martin, L. J., Kuncl, R. W. &lt;strong&gt;Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis.&lt;/strong&gt; New Eng. J. Med. 326: 1464-1468, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1349424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1349424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199205283262204&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1349424">Rothstein et al. (1992)</a> found in in vitro studies that synaptosomes in neural tissue obtained from 13 ALS patients showed a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in spinal cord, motor cortex, and somatosensory cortex compared to controls. The decrease in glutamate uptake was not observed in tissue from visual cortex, striatum, or hippocampus. Neural tissue from patients with other neurodegenerative disorders did not show this defect. In ALS tissue, there was no defect in affinity of the transporter for glutamate and no decrease in the transport of other molecules (gamma-aminobutyric acid and phenylalanine). <a href="#99" class="mim-tip-reference" title="Rothstein, J. D., Martin, L. J., Kuncl, R. W. &lt;strong&gt;Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis.&lt;/strong&gt; New Eng. J. Med. 326: 1464-1468, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1349424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1349424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199205283262204&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1349424">Rothstein et al. (1992)</a> suggested that defects in a high-affinity glutamate transporter (see, e.g., SLC1A1, <a href="/entry/133550">133550</a>) could lead to neurotoxic levels of extracellular glutamate, contributing to neurodegeneration in ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1349424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Liu, R., Althaus, J. S., Ellerbrock, B. R., Becker, D. A., Gurney, M. E. &lt;strong&gt;Enhanced oxygen radical production in a transgenic mouse model of familial amyotrophic lateral sclerosis.&lt;/strong&gt; Ann. Neurol. 44: 763-770, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9818932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9818932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410440510&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9818932">Liu et al. (1998)</a> demonstrated increased free radical production in the spinal cord but not the brain of transgenic mice expressing mutant human SOD1 (G93A; <a href="/entry/147450#0008">147450.0008</a>), which preceded the degeneration of motor neurons. They hypothesized that in situ production of free radicals initiates oxidative injury and that antioxidants that penetrate into the central nervous system may be of therapeutic benefit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9818932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Li, M., Ona, V. O., Guegan, C., Chen, M., Jackson-Lewis, V., Andrews, L. J., Olszewski, A. J., Stieg, P. E., Lee, J.-P., Przedborski, S., Friedlander, R. M. &lt;strong&gt;Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.&lt;/strong&gt; Science 288: 335-339, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10764647/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10764647&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.288.5464.335&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10764647">Li et al. (2000)</a> demonstrated an 81.5% elevation of caspase-1 (CASP1; <a href="/entry/147678">147678</a>) activity in the spinal cord of humans with ALS when compared with normal controls, and, using an animal model, suggested that caspases play an instrumental role in the neurodegenerative processing of ALS. Caspase inhibition using zVAD-fmk delayed disease onset and mortality in the mouse model of ALS. Moreover, zVAD-fmk was found to inhibit caspase-1 activity as well as caspase-1 and caspase-3 (<a href="/entry/600636">600636</a>) mRNA upregulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. The findings also showed that zVAD-fmk decreased IL1-beta (<a href="/entry/147720">147720</a>), an indication that caspase-1 activity was inhibited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10764647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#82" class="mim-tip-reference" title="Okado-Matsumoto, A., Fridovich, I. &lt;strong&gt;Amyotrophic lateral sclerosis: a proposed mechanism.&lt;/strong&gt; Proc. Nat. Acad. Sci. 99: 9010-9014, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12060716/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12060716&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12060716[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.132260399&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12060716">Okado-Matsumoto and Fridovich (2002)</a> proposed a mechanism by which missense mutations in SOD1 lead to ALS. They suggested that the binding of mutant SOD1 to heat-shock proteins leads to formation of sedimentable aggregates, making the heat shock proteins unavailable for their antiapoptotic functions and leading ultimately to motor neuron death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12060716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., Kwak, S. &lt;strong&gt;RNA editing and death of motor neurons: there is a glutamate-receptor defect in patients with amyotrophic lateral sclerosis. (Letter)&lt;/strong&gt; Nature 427: 801 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14985749/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14985749&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/427801a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14985749">Kawahara et al. (2004)</a> extracted RNA from single motor neurons isolated with a laser microdissector from 5 individuals with sporadic ALS and 5 normal control subjects. GluR2 (GRIA2; <a href="/entry/138247">138247</a>) RNA editing was 100% efficient in the control samples, but the editing efficiency varied between 0 and 100% in the motor neurons from each individual with ALS and was incomplete in 44 (56%) of them. Mice transgenic for GluR2 made artificially permeable to calcium ions developed motor neuron disease late in life (<a href="#37" class="mim-tip-reference" title="Feldmeyer, D., Kask, K., Brusa, R., Kornau, H.-C., Kolhekar, R., Rozov, A., Burnashev, N., Jensen, V., Hvalby, O., Sprengel, R., Seeburg, P. H. &lt;strong&gt;Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B.&lt;/strong&gt; Nature Neurosci. 2: 57-64, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10195181/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10195181&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/4561&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10195181">Feldmeyer et al., 1999</a>), indicating that motor neurons may be specifically vulnerable to defective RNA editing. <a href="#58" class="mim-tip-reference" title="Kawahara, Y., Ito, K., Sun, H., Aizawa, H., Kanazawa, I., Kwak, S. &lt;strong&gt;RNA editing and death of motor neurons: there is a glutamate-receptor defect in patients with amyotrophic lateral sclerosis. (Letter)&lt;/strong&gt; Nature 427: 801 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14985749/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14985749&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/427801a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14985749">Kawahara et al. (2004)</a> suggested that defective GluR2 RNA editing at the Q/R site may be relevant to ALS etiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14985749+10195181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#105" class="mim-tip-reference" title="Shibata, N., Hirano, A., Kobayashi, M., Sasaki, S., Kato, T., Matsumoto, S., Shiozawa, Z., Komori, T., Ikemoto, A., Umahara, T., Asayama, K. &lt;strong&gt;Cu/Zn superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Neurosci. Lett. 179: 149-152, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7845611/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7845611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0304-3940(94)90956-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7845611">Shibata et al. (1994)</a> found SOD1-like immunoreactivity within Lewy body-like inclusions in the spinal cords of 10 of 20 patients with sporadic ALS. Skein-like inclusions and Bunina bodies, which were found in all 20 ALS cases, showed no SOD1-like immunoreactivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7845611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="He, C. Z., Hays, A. P. &lt;strong&gt;Expression of peripherin in ubiquinated (sic) inclusions of amyotrophic lateral sclerosis.&lt;/strong&gt; J. Neurol. Sci. 217: 47-54, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14675609/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14675609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jns.2003.08.016&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14675609">He and Hays (2004)</a> identified Lewy body-like ubiquitinated (see UBB; <a href="/entry/191339">191339</a>) inclusions in motor neurons from 9 of 40 ALS patients; all of the inclusions expressed peripherin. Similar inclusions were not identified in 39 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14675609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.&lt;/strong&gt; Science 314: 130-133, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17023659/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17023659&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1134108&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17023659">Neumann et al. (2006)</a> identified TDP43 (<a href="/entry/605078">605078</a>) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration (see <a href="/entry/607485">607485</a>) and ALS. Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected CNS regions, including hippocampus, neocortex, and spinal cord. <a href="#80" class="mim-tip-reference" title="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.&lt;/strong&gt; Science 314: 130-133, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17023659/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17023659&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1134108&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17023659">Neumann et al. (2006)</a> concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17023659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#76" class="mim-tip-reference" title="Miller, T. M., Kim, S. H., Yamanaka, K., Hester, M., Umapathi, P., Arnson, H., Rizo, L., Mendell, J. R., Gage, F. H., Cleveland, D. W., Kaspar, B. K. &lt;strong&gt;Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 19546-19551, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17164329/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17164329&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17164329[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0609411103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17164329">Miller et al. (2006)</a> demonstrated that human SOD1 mutant-mediated damage within muscles was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17164329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#89" class="mim-tip-reference" title="Pradat, P.-F., Bruneteau, G., Gonzalez de Aguilar, J.-L., Dupuis, L., Jokic, N., Salachas, F., Le Forestier, N., Echaniz-Laguna, A., Dubourg, O., Hauw, J.-J., Tranchant, C., Loeffler, J.-P., Meininger, V. &lt;strong&gt;Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes.&lt;/strong&gt; Ann. Neurol. 62: 15-20, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17455292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17455292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21122&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17455292">Pradat et al. (2007)</a> found muscle NOGOA (<a href="/entry/604475">604475</a>) expression in 17 of 33 patients with spinal lower motor neuron syndrome observed for 12 months. NOGOA expression correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was detected as early as 3 months after symptom onset in patients who later developed typical ALS. <a href="#89" class="mim-tip-reference" title="Pradat, P.-F., Bruneteau, G., Gonzalez de Aguilar, J.-L., Dupuis, L., Jokic, N., Salachas, F., Le Forestier, N., Echaniz-Laguna, A., Dubourg, O., Hauw, J.-J., Tranchant, C., Loeffler, J.-P., Meininger, V. &lt;strong&gt;Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes.&lt;/strong&gt; Ann. Neurol. 62: 15-20, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17455292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17455292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21122&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17455292">Pradat et al. (2007)</a> suggested that muscle NOGOA may be a prognostic marker for ALS in lower motor neuron syndromes. <a href="#116" class="mim-tip-reference" title="Tagerud, S., Libelius, R., Magnusson, C. &lt;strong&gt;Muscle Nogo-A: a marker for amyotrophic lateral sclerosis or for denervation? (Letter)&lt;/strong&gt; Ann. Neurol. 62: 676 only, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17702029/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17702029&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21187&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17702029">Tagerud et al. (2007)</a> and <a href="#8" class="mim-tip-reference" title="Askanas, V., Wojcik, S., Engel, W. K. &lt;strong&gt;Expression of Nogo-A in human muscle fibers is not specific for amyotrophic lateral sclerosis. (Letter)&lt;/strong&gt; Ann. Neurol. 62: 676-677, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17894379/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17894379&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21245&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17894379">Askanas et al. (2007)</a> both commented that studies have demonstrated that NOGOA expression is increased in denervated muscles in mouse models and in other human neuropathies and myopathies. Both groups suggested that it may be premature to consider NOGOA muscle expression as a specific biomarker for ALS, as suggested by <a href="#89" class="mim-tip-reference" title="Pradat, P.-F., Bruneteau, G., Gonzalez de Aguilar, J.-L., Dupuis, L., Jokic, N., Salachas, F., Le Forestier, N., Echaniz-Laguna, A., Dubourg, O., Hauw, J.-J., Tranchant, C., Loeffler, J.-P., Meininger, V. &lt;strong&gt;Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes.&lt;/strong&gt; Ann. Neurol. 62: 15-20, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17455292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17455292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21122&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17455292">Pradat et al. (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17894379+17702029+17455292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a specific antibody to monomer or misfolded forms of SOD1 (<a href="#92" class="mim-tip-reference" title="Rakhit, R., Robertson, J., Vande Velde, C., Horne, P., Ruth, D. M., Griffin, J., Cleveland, D. W., Cashman, N. R., Chakrabartty, A. &lt;strong&gt;An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.&lt;/strong&gt; Nature Med. 13: 754-759, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17486090/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17486090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1559&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17486090">Rakhit et al., 2007</a>), <a href="#69" class="mim-tip-reference" title="Liu, H.-N., Sanelli, T., Horne, P., Pioro, E. P., Strong, M. J., Rogaeva, E., Bilbao, J., Zinman, L., Robertson, J. &lt;strong&gt;Lack of evidence of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Ann. Neurol. 66: 75-80, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19670443/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19670443&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21704&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19670443">Liu et al. (2009)</a> detected monomer/misfolded SOD1 in spinal cord sections of all 5 patients with familial ALS due to mutations in the SOD1 gene. The antibody localized primarily to hyaline conglomerate inclusions in motor neuron perikarya and occasionally to neuritic processes. In contrast, no immunostaining was observed in spinal cord tissue from ALS patients without SOD1 mutations, including 13 with sporadic disease and 1 with non-SOD1 familial ALS. The findings indicated a distinct difference between familial ALS1 and sporadic ALS, and supported the idea that monomer or misfolded SOD1 is not a common disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17486090+19670443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#91" class="mim-tip-reference" title="Rabin, S. J., Kim, J. M. H., Baughn, M., Libby, R. T., Kim, Y. J., Fan, Y., Libby, R. T., La Spada, A., Stone, B., Ravits, J. &lt;strong&gt;Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology.&lt;/strong&gt; Hum. Molec. Genet. 19: 313-328, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19864493/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19864493&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19864493[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp498&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19864493">Rabin et al. (2010)</a> studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. Whole-genome exon splicing was profiled from RNA pools collected from motor neurons and from the surrounding anterior horns. In the motor neuron-enriched mRNA pool, there were 2 distinct cohorts of mRNA signals, most of which were upregulated: 148 differentially expressed genes and 411 aberrantly spliced genes. The aberrantly spliced genes were highly enriched in cell adhesion, especially cell-matrix as opposed to cell-cell adhesion. Most of the enriching genes encoded transmembrane or secreted as opposed to nuclear or cytoplasmic proteins. The differentially expressed genes were not biologically enriched. In the anterior horn enriched mRNA pool, there were no clearly identified mRNA signals or biologic enrichment. <a href="#91" class="mim-tip-reference" title="Rabin, S. J., Kim, J. M. H., Baughn, M., Libby, R. T., Kim, Y. J., Fan, Y., Libby, R. T., La Spada, A., Stone, B., Ravits, J. &lt;strong&gt;Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology.&lt;/strong&gt; Hum. Molec. Genet. 19: 313-328, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19864493/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19864493&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19864493[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp498&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19864493">Rabin et al. (2010)</a> suggested possible mechanisms in cell adhesion for the contiguously progressive nature of motor neuron degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19864493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using unbiased transcript profiling in the SOD1G93A mouse model of ALS, <a href="#68" class="mim-tip-reference" title="Lincecum, J. M., Vieira, F. G., Wang, M. Z., Thompson, K., De Zutter, G. S., Kidd, J., Moreno, A., Sanchez, R., Carrion, I. J., Levine, B. A., Al-Nakhala, B. M., Sullivan, S. M., Gill, A., Perrin, S. &lt;strong&gt;From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis.&lt;/strong&gt; Nature Genet. 42: 392-399, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20348957/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20348957&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.557&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20348957">Lincecum et al. (2010)</a> identified a role for the costimulatory pathway, a key regulator of immune responses. Furthermore, <a href="#68" class="mim-tip-reference" title="Lincecum, J. M., Vieira, F. G., Wang, M. Z., Thompson, K., De Zutter, G. S., Kidd, J., Moreno, A., Sanchez, R., Carrion, I. J., Levine, B. A., Al-Nakhala, B. M., Sullivan, S. M., Gill, A., Perrin, S. &lt;strong&gt;From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis.&lt;/strong&gt; Nature Genet. 42: 392-399, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20348957/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20348957&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.557&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20348957">Lincecum et al. (2010)</a> observed that this pathway is upregulated in the blood of 56% of human patients with ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20348957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Kudo, L. C., Parfenova, L., Vi, N., Lau, K., Pomakian, J., Valdmanis, P., Rouleau, G. A., Vinters, H. V., Wiedau-Pazos, M., Karsten, S. L. &lt;strong&gt;Integrative gene-tissue microarray-based approach for identification of human disease biomarkers: application to amyotrophic lateral sclerosis.&lt;/strong&gt; Hum. Molec. Genet. 19: 3233-3253, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20530642/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20530642&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq232&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20530642">Kudo et al. (2010)</a> used laser capture microdissection coupled with microarrays to identify early transcriptome changes occurring in spinal cord motor neurons or surrounding glial cells in models of ALS. Two transgenic mouse models of familial motor neuron disease, Sod1G93A and TAUP301L (<a href="/entry/157140#0001">157140.0001</a>), were used at the presymptomatic stage. Identified gene expression changes were predominantly model-specific. However, several genes were regulated in both models. The relevance of identified genes as clinical biomarkers was tested in the peripheral blood transcriptome of presymptomatic Sod1G93A animals using custom-designed ALS microarray. To confirm the relevance of identified genes in human sporadic ALS (SALS), selected corresponding protein products were examined by high-throughput immunoassays using tissue microarrays constructed from human postmortem spinal cord tissues. Genes that were identified by these experiments and were located within a linkage region associated with familial ALS/frontotemporal dementia were sequenced in several families. This large-scale gene and protein expression study pointing to distinct molecular mechanisms of TAU- and SOD1-induced motor neuron degeneration identified several novel SALS-relevant proteins, including CNGA3 (<a href="/entry/600053">600053</a>), CRB1 (<a href="/entry/604210">604210</a>), OTUB2 (<a href="/entry/608338">608338</a>), MMP14 (<a href="/entry/600754">600754</a>), SLK (FYN; <a href="/entry/137025">137025</a>), DDX58 (<a href="/entry/609631">609631</a>), RSPO2 (<a href="/entry/610575">610575</a>) and the putative blood biomarker Mgll (<a href="/entry/609699">609699</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20530642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Pedrini, S., Sau, D., Guareschi, S., Bogush, M., Brown, R. H., Jr., Naniche, N., Kia, A., Trotti, D., Pasinelli, P. &lt;strong&gt;ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2.&lt;/strong&gt; Hum. Molec. Genet. 19: 2974-2986, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20460269/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20460269&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20460269[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq202&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20460269">Pedrini et al. (2010)</a> showed that the toxicity of mutant SOD1 (<a href="/entry/147450">147450</a>) relies on its spinal cord mitochondria-specific interaction with BCL2 (<a href="/entry/151430">151430</a>). Mutant SOD1 induced morphologic changes and compromised mitochondrial membrane integrity leading to the release of cytochrome c only in the presence of BCL2. In cells and in mouse and human spinal cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a conformational change in BCL2 that resulted in the exposure of its BH3 domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain failed to support mutant SOD1-mediated mitochondrial toxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20460269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Ferri, A., Fiorenzo, P., Nencini, M., Cozzolino, M., Pesaresi, M. G., Valle, C., Sepe, S., Moreno, S., Carri, M. T. &lt;strong&gt;Glutaredoxin 2 prevents aggregation of mutant SOD1 in mitochondria and abolishes its toxicity.&lt;/strong&gt; Hum. Molec. Genet. 19: 4529-4542, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20829229/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20829229&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20829229[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq383&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20829229">Ferri et al. (2010)</a> exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and IMS, where Grx1 (GLRX; <a href="/entry/600443">600443</a>) is localized, or in the mitochondrial matrix, where Grx2 (GLRX2; 606820) is localized, as a tool for restoring a correct redox environment and preventing aggregation of mutant SOD1 (G93A; <a href="/entry/147450#0008">147450.0008</a>). Overexpression of Grx1 increased the solubility of mutant SOD1 in the cytosol but did not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells or in immortalized motoneurons. Conversely, the overexpression of Grx2 increased the solubility of mutant SOD1 in mitochondria, interfered with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserved mitochondrial function and strongly protected neuronal cells from apoptosis. The authors concluded that the toxicity of mutant SOD1 primarily arises from mitochondrial dysfunction, and that rescue of mitochondrial damage may represent a therapeutic strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20829229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Meissner, F., Molawi, K., Zychlinsky, A. &lt;strong&gt;Mutant superoxide dismutase 1-induced IL-1-beta accelerates ALS pathogenesis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 107: 13046-13050, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20616033/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20616033&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20616033[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.1002396107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20616033">Meissner et al. (2010)</a> found that G93A mutant SOD1 activated caspase-1 (CASP1; <a href="/entry/147678">147678</a>) and CASP1-mediated secretion of mature IL1-beta (<a href="/entry/147720">147720</a>) in a dose-dependent manner in microglia and macrophages. In cells in which CASP1 was activated, there was rapid endocytosis of mutant SOD1 into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm dampened the proinflammatory response. Mutant SOD1 induced caspase activation through a gain of amyloid conformation, not through its enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the life span of mutant Sod1 mice and was associated with decreased microgliosis and astrogliosis; however, age at disease onset was not affected. Treatment of mutant mice with an IL1 receptor inhibitor also extended survival and improved motor performance. The findings suggested that IL1-beta contributes to neuroinflammation and disease progression in ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20616033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether increased SOD1 protects the heart from ischemia <a href="#7" class="mim-tip-reference" title="Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D. &lt;strong&gt;Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.&lt;/strong&gt; Nature Genet. 44: 1302-1309, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23104007/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23104007&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.2434&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23104007">Armakola et al. (2012)</a> reported results from 2 genomewide loss-of-function TDP43 (<a href="/entry/605078">605078</a>) toxicity suppressor screens in yeast. The strongest suppressor of TDP43 toxicity was deletion of DBR1 (<a href="/entry/607024">607024</a>), which encodes an RNA lariat debranching enzyme. <a href="#7" class="mim-tip-reference" title="Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D. &lt;strong&gt;Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.&lt;/strong&gt; Nature Genet. 44: 1302-1309, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23104007/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23104007&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.2434&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23104007">Armakola et al. (2012)</a> showed that, in the absence of DBR1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal cell line or in primary rat neurons was also sufficient to rescue TDP43 toxicity. <a href="#7" class="mim-tip-reference" title="Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D. &lt;strong&gt;Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.&lt;/strong&gt; Nature Genet. 44: 1302-1309, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23104007/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23104007&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.2434&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23104007">Armakola et al. (2012)</a> concluded that their findings provided insight into TDP43-mediated cytotoxicity and suggested that decreasing DBR1 activity could be a potential therapeutic approach for ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23104007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Autosomal Dominant Mutations</em></strong></p><p>
In affected members of 13 unrelated families with ALS, <a href="#98" class="mim-tip-reference" title="Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O&#x27;Regan, J. P., Deng, H.-X., Rahmani, Z., Krizus, A., and 21 others. &lt;strong&gt;Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.&lt;/strong&gt; Nature 362: 59-62, 1993. Note: Erratum: Nature: 364: 362 only, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8446170/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8446170&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/362059a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8446170">Rosen et al. (1993)</a> identified 11 different heterozygous mutations in exons 2 and 4 of the SOD1 gene (<a href="/entry/147450#0001">147450.0001</a>-<a href="/entry/147450#0011">147450.0011</a>). <a href="#29" class="mim-tip-reference" title="Deng, H.-X., Hentati, A., Tainer, J. A., Iqbal, Z., Cayabyab, A., Hung, W.-Y., Getzoff, E. D., Hu, P., Herzfeldt, B., Roos, R. P., Warner, C., Deng, G., Soriano, E., Smyth, C., Parge, H. E., Ahmed, A., Roses, A. D., Hallewell, R. A., Pericak-Vance, M. A., Siddique, T. &lt;strong&gt;Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.&lt;/strong&gt; Science 261: 1047-1051, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8351519/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8351519&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.8351519&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8351519">Deng et al. (1993)</a> identified 3 mutations in exons 1 and 5 of the SOD1 gene in affected members of ALS families. Eight families had the same mutation (A4V; <a href="/entry/147450#0012">147450.0012</a>). One of the families with the A4V mutation was the Farr family reported by Brown (<a href="#19" class="mim-tip-reference" title="Brown, M. R. &lt;strong&gt;&#x27;Wetherbee ail&#x27;: the inheritance of progressive muscular atrophy as a dominant trait in two New England families.&lt;/strong&gt; New Eng. J. Med. 245: 645-647, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14875225/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14875225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM195110252451704&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14875225">1951</a>, <a href="#20" class="mim-tip-reference" title="Brown, M. R. &lt;strong&gt;The inheritance of progressive muscular atrophy as a dominant trait in two New England families.&lt;/strong&gt; New Eng. J. Med. 262: 1280-1282, 1960.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13804989/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13804989&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM196006232622508&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13804989">1960</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8446170+14875225+8351519+13804989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Pramatarova, A., Figlewicz, D. A., Krizus, A., Han, F. Y., Ceballos-Picot, I., Nicole, A., Dib, M., Meininger, V., Brown, R. H., Rouleau, G. A. &lt;strong&gt;Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis.&lt;/strong&gt; Am. J. Hum. Genet. 56: 592-596, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7887412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7887412&lt;/a&gt;]" pmid="7887412">Pramatarova et al. (1995)</a> estimated that approximately 10% of ALS cases are inherited as an autosomal dominant and that SOD1 mutations are responsible for at least 13% of familial ALS cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7887412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Jones, C. T., Brock, D. J. H., Chancellor, A. M., Warlow, C. P., Swingler, R. J. &lt;strong&gt;Cu/Zn superoxide dismutase (SOD1) mutations and sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Lancet 342: 1050-1051, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8105280/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8105280&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(93)92905-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8105280">Jones et al. (1993)</a> demonstrated that mutation in the SOD1 gene can also be responsible for sporadic cases of ALS. They found the same mutation (I113T; <a href="/entry/147450#0011">147450.0011</a>) in 3 of 56 sporadic cases of ALS drawn from a population-based study in Scotland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8105280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 233 sporadic ALS patients, <a href="#18" class="mim-tip-reference" title="Broom, W. J., Parton, M. J., Vance, C. A., Russ, C., Andersen, P. M., Hansen, V., Leigh, P. N., Powell, J. F., Al-Chalabi, A., Shaw, C. E. &lt;strong&gt;No association of the SOD1 locus and disease susceptibility or phenotype in sporadic ALS.&lt;/strong&gt; Neurology 63: 2419-2422, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15623718/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15623718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000147264.60349.eb&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15623718">Broom et al. (2004)</a> found no association between disease susceptibility or phenotype and a deletion and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing against a major role for wildtype SOD1 in sporadic ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15623718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of familial ALS, <a href="#28" class="mim-tip-reference" title="de Belleroche, J., Orrell, R., King, A. &lt;strong&gt;Familial amyotrophic lateral sclerosis/motor neurone disease (FALS): a review of current developments.&lt;/strong&gt; J. Med. Genet. 32: 841-847, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8592323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8592323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.11.841&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8592323">de Belleroche et al. (1995)</a> listed 30 missense mutations and a 2-bp deletion in the SOD1 gene. <a href="#106" class="mim-tip-reference" title="Siddique, T., Deng, H.-X. &lt;strong&gt;Genetics of amyotrophic lateral sclerosis.&lt;/strong&gt; Hum. Molec. Genet. 5: 1465-1470, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8875253/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8875253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/5.supplement_1.1465&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8875253">Siddique and Deng (1996)</a> reviewed the genetics of ALS, including a tabulation of SOD1 mutations in familial ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8592323+8875253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others. &lt;strong&gt;SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.&lt;/strong&gt; J. Med. Genet. 47: 554-560, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20577002/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20577002&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2010.077180&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20577002">Millecamps et al. (2010)</a> identified 18 different SOD1 missense mutations in 20 (12.3%) of 162 French probands with familial ALS. Compared to those with ALS caused by mutations in other genes, those with SOD1 tended to have disease onset predominantly in the lower limbs. One-third of SOD1 patients survived for more than 7 years: these patients had an earlier disease onset compared to those presenting with a more rapid course. No patients with SOD1 mutations developed cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20577002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Recessive Mutations</em></strong></p><p>
<a href="#6" class="mim-tip-reference" title="Andersen, P. M., Nilsson, P., Ala-Hurula, V., Keranen, M.-L., Tarvainen, I., Haltia, T., Nilsson, L., Binzer, M., Forsgren, L., Marklund, S. L. &lt;strong&gt;Amyotrophic lateral sclerosis associated with homozygosity for an asp90-to-ala mutation in CuZn-superoxide dismutase.&lt;/strong&gt; Nature Genet. 10: 61-66, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7647793/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7647793&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0595-61&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7647793">Andersen et al. (1995)</a> found homozygosity for a mutation in the SOD1 gene (D90A; <a href="/entry/147450#0015">147450.0015</a>) in 14 ALS patients from 4 unrelated families and 4 apparently sporadic ALS patients from Sweden and Finland. Consanguinity was present in several of the families, consistent with autosomal recessive inheritance. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Age at onset ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1 to 4 years' disease duration in all patients, and none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype like that in the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Thus, familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms. <a href="#1" class="mim-tip-reference" title="Al-Chalabi, A., Andersen, P. M., Chioza, B., Shaw, C., Sham, P. C., Robberecht, W., Matthijs, G., Camu, W., Marklund, S. L., Forsgren, L., Rouleau, G., Laing, N. G., Hurse, P. V., Siddique, T., Leigh, P. N., Powell, J. F. &lt;strong&gt;Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.&lt;/strong&gt; Hum. Molec. Genet. 7: 2045-2050, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9817920/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9817920&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/7.13.2045&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9817920">Al-Chalabi et al. (1998)</a> concluded that a 'tightly linked protective factor' in some families modifies the toxic effect of the mutant SOD1, resulting in recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7647793+9817920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Susceptibility Genes and Association Studies</em></strong></p><p>
<a href="#111" class="mim-tip-reference" title="Siddique, T., Pericak-Vance, M. A., Caliendo, J., Hong, S.-T., Hung, W.-Y., Kaplan, J., McKenna-Yasek, D., Rimmler, J. B., Sapp, P., Saunders, A. M., Scott, W. K., Siddique, N., Haines, J. L., Brown, R. H. &lt;strong&gt;Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Neurogenetics 1: 213-216, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10737125/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10737125&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s100480050031&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10737125">Siddique et al. (1998)</a> could demonstrate no relationship between APOE genotype (<a href="/entry/107741">107741</a>) and sporadic ALS. Previous studies had resulted in contradictory results. <a href="#111" class="mim-tip-reference" title="Siddique, T., Pericak-Vance, M. A., Caliendo, J., Hong, S.-T., Hung, W.-Y., Kaplan, J., McKenna-Yasek, D., Rimmler, J. B., Sapp, P., Saunders, A. M., Scott, W. K., Siddique, N., Haines, J. L., Brown, R. H. &lt;strong&gt;Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Neurogenetics 1: 213-216, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10737125/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10737125&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s100480050031&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10737125">Siddique et al. (1998)</a> found no significant difference in age at onset between patients with 1, 2, or no APOE*4 alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 1 of 189 ALS patients, <a href="#45" class="mim-tip-reference" title="Gros-Louis, F., Lariviere, R., Gowing, G., Laurent, S., Camu, W., Bouchard, J.-P., Meininger, V., Rouleau, G. A., Julien, J.-P. &lt;strong&gt;A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis.&lt;/strong&gt; J. Biol. Chem. 279: 45951-45956, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15322088/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15322088&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M408139200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15322088">Gros-Louis et al. (2004)</a> identified a 1-bp deletion in the peripherin gene (<a href="/entry/170710#0001">170710.0001</a>), suggesting that the mutation conferred an increased susceptibility to development of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 250 patients with a putative diagnosis of ALS, <a href="#78" class="mim-tip-reference" title="Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G., Ludolph, A. C. &lt;strong&gt;Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.&lt;/strong&gt; Neurology 63: 724-726, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15326253/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15326253&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000134608.83927.b1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15326253">Munch et al. (2004)</a> identified 3 mutations in the DCTN1 gene (<a href="/entry/601143#0002">601143.0002</a>-<a href="/entry/601143#0004">601143.0004</a>) in 3 families. One of the mutations showed incomplete penetrance. The authors suggested that mutations in the DCTN1 gene may be a susceptibility risk factor for ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#124" class="mim-tip-reference" title="Veldink, J. H., Kalmijn, S., Van der Hout, A. H., Lemmink, H. H., Groeneveld, G. J., Lummen, C., Scheffer, H., Wokke, J. H. J., Van den Berg, L. H. &lt;strong&gt;SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.&lt;/strong&gt; Neurology 65: 820-825, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16093455/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16093455&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000174472.03292.dd&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16093455">Veldink et al. (2005)</a> presented evidence suggesting that SMN genotypes producing less SMN protein increased susceptibility to and severity of ALS. Among 242 ALS patients, the presence of 1 SMN1 (<a href="/entry/600354">600354</a>) copy, which represents spinal muscular atrophy (SMA; <a href="/entry/253300">253300</a>) carrier status, was significantly increased in patients (6.6%) compared to controls (1.7%). The presence of 1 copy of SMN2 (<a href="/entry/601627">601627</a>) was significantly increased in patients (58.7%) compared to controls (29.7%), whereas 2, 3, or 4 SMN2 copies were significantly decreased in patients compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16093455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 167 ALS patients and 167 matched controls, <a href="#23" class="mim-tip-reference" title="Corcia, P., Mayeux-Portas, V., Khoris, J., de Toffol, B., Autret, A., Muh, J.-P., Camu, W., Andres, C., the French ALS Research Group. &lt;strong&gt;Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis.&lt;/strong&gt; Ann. Neurol. 51: 243-246, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11835381/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11835381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11835381">Corcia et al. (2002)</a> found that 14% of ALS patients had an abnormal copy number of the SMN1 gene, either 1 or 3 copies, compared to 4% of controls. Among 600 patients with sporadic ALS, <a href="#22" class="mim-tip-reference" title="Corcia, P., Camu, W., Halimi, J.-M., Vourc&#x27;h, P., Antar, C., Vedrine, S., Giraudeau, B., de Toffol, B., Andres, C. R., the French ALS Research Group. &lt;strong&gt;SMN1 gene, but not SMN2, is a risk factor for sporadic ALS.&lt;/strong&gt; Neurology 67: 1147-1150, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16931506/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16931506&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000233830.85206.1e&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16931506">Corcia et al. (2006)</a> found an association between disease and 1 or 3 copies of the SMN1 gene (p less than 0.0001; odds ratio of 2.8). There was no disease association with SMN2 copy number. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11835381+16931506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Dunckley, T., Huentelman, M. J., Craig, D. W., Pearson, J. V., Szelinger, S., Joshipura, K., Halperin, R. F., Stamper, C., Jensen, R., Letizia, D., Hesterlee, S. E., Pestronk, A., and 23 others. &lt;strong&gt;Whole-genome analysis of amyotrophic lateral sclerosis.&lt;/strong&gt; New Eng. J. Med. 357: 775-788, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17671248/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17671248&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa070174&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17671248">Dunckley et al. (2007)</a> provided evidence suggestive of an association between the FLJ10986 gene (<a href="/entry/611370">611370</a>) on chromosome 1 and sporadic amyotrophic lateral sclerosis in 3 independent patient populations. The susceptibility allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6690993;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6690993</a> conferred an odds ratio of 1.35 (p = 3.0 x 10(-4)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17671248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#113" class="mim-tip-reference" title="Simpson, C. L., Lemmens, R., Miskiewicz, K., Broom, W. J., Hansen, V. K., van Vught, P. W. J., Landers, J. E., Sapp, P., Van Den Bosch, L., Knight, J., Neale, B. M., Turner, M. R., and 18 others. &lt;strong&gt;Variants of elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.&lt;/strong&gt; Hum. Molec. Genet. 18: 472-481, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18996918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18996918&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18996918[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn375&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18996918">Simpson et al. (2009)</a> performed a multistage association study using 1,884 microsatellite markers in 3 populations totaling 781 ALS patients and 702 control individuals. They identified a significant association (p = 1.96 x 10(-9)) with the 15-allele marker D8S1820 in intron 10 of the ELP3 gene (<a href="/entry/612722">612722</a>). Fine mapping with SNPs in and around the ELP3 gene identified a haplotype consisting of allele 6 of D8S1820 and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12682496;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12682496</a> strongly associated with ALS (p = 1.05 x 10(-6)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18996918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Lambrechts, D., Poesen, K., Fernandez-Santiago, R., Al-Chalabi, A., Del Bo, R., Van Vught, P. W. J., Khan, S., Marklund, S. L., Brockington, A., van Marion, I., Anneser, J., Shaw, C., and 12 others. &lt;strong&gt;Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.&lt;/strong&gt; J. Med. Genet. 46: 840-846, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18413368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18413368&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.058222&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18413368">Lambrechts et al. (2009)</a> performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene (<a href="/entry/192240">192240</a>) and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs699947;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs699947</a>; <a href="/entry/192240#0002">192240.0002</a>), which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#102" class="mim-tip-reference" title="Sabatelli, M., Eusebi, F., Al-Chalabi, A., Conte, A., Madia, F., Luigetti, M., Mancuso, I., Limatola, C., Trettel, F., Sobrero, F., Di Angelantonio, S., Grassi, F., and 11 others. &lt;strong&gt;Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Hum. Molec. Genet. 18: 3997-4006, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19628475/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19628475&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19628475">Sabatelli et al. (2009)</a> identified nonsynonymous variants in the CHRNA3 (<a href="/entry/118503">118503</a>) and CHRNB4 (<a href="/entry/118509">118509</a>) genes on chromosome 15q25.1 and the CHRNA4 gene (<a href="/entry/118504">118504</a>) on chromosome 20q13.2-q13.3, encoding neuronal nicotinic acetylcholine receptor (nAChR) subunits, in 19 sporadic ALS patients and in 14 controls. NAChRs formed by mutant alpha-3 and alpha-4 and wildtype beta-4 subunits exhibited altered affinity for nicotine (Nic), reduced use-dependent rundown of Nic-activated currents, and reduced desensitization leading to sustained intracellular calcium concentration, in comparison with wildtype nAChR. <a href="#102" class="mim-tip-reference" title="Sabatelli, M., Eusebi, F., Al-Chalabi, A., Conte, A., Madia, F., Luigetti, M., Mancuso, I., Limatola, C., Trettel, F., Sobrero, F., Di Angelantonio, S., Grassi, F., and 11 others. &lt;strong&gt;Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis.&lt;/strong&gt; Hum. Molec. Genet. 18: 3997-4006, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19628475/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19628475&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19628475">Sabatelli et al. (2009)</a> suggested that gain-of-function nAChR variants may contribute to disease susceptibility in a subset of ALS patients because calcium signals mediate the neuromodulatory effects of nAChRs, including regulation of glutamate release and control of cell survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19628475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-generation kindred with familial ALS, <a href="#77" class="mim-tip-reference" title="Mitchell, J., Paul, P., Chen, H.-J., Morris, A., Payling, M., Falchi, M., Habgood, J., Panoutsou, S., Winkler, S., Tisato, V., Hajitou, A., Smith, B., Vance, C., Shaw, C., Mazarakis, N. D., de Belleroche, J. &lt;strong&gt;Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase.&lt;/strong&gt; Proc. Nat. Acad. Sci. 107: 7556-7561, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20368421/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20368421&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20368421[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0914128107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20368421">Mitchell et al. (2010)</a> found linkage to markers D12S1646 and D12S354 on chromosome 12q24 (2-point lod score of 2.7). Screening of candidate genes identified a heterozygous arg199-to-trp (R199W) mutation in exon 7 of the DAO gene (<a href="/entry/124050">124050</a>) in 3 affected members and in 1 obligate carrier, who died at age 73 years of cardiac failure and reportedly had right-sided weakness and dysarthria. The proband had onset at age 40, and the mean age at death in 7 cases was 44 years (range, 42 to 55 years). The mutation was also present in 3 at-risk individuals of 33, 44, and 48 years of age, respectively. The R199W mutation was not found in 780 Caucasian controls. Postmortem examination of the obligate carrier showed some loss of motor neurons in the spinal cord and degeneration of 1 of the lateral corticospinal tracts. There was markedly decreased DAO enzyme activity in the spinal cord compared to controls. Coexpression of mutant protein with wildtype protein in COS-7 cells indicated a dominant-negative effect for the mutant protein. Rat neuronal cell lines expressing the R199W-mutant protein showed decreased viability and increased ubiquitinated aggregates compared to wildtype. <a href="#77" class="mim-tip-reference" title="Mitchell, J., Paul, P., Chen, H.-J., Morris, A., Payling, M., Falchi, M., Habgood, J., Panoutsou, S., Winkler, S., Tisato, V., Hajitou, A., Smith, B., Vance, C., Shaw, C., Mazarakis, N. D., de Belleroche, J. &lt;strong&gt;Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase.&lt;/strong&gt; Proc. Nat. Acad. Sci. 107: 7556-7561, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20368421/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20368421&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20368421[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0914128107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20368421">Mitchell et al. (2010)</a> suggested a role for the DAO gene in ALS, but noted that a causal role for the R199W-mutant protein remained to be unequivocally established. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20368421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 847 patients with ALS and 984 controls, <a href="#12" class="mim-tip-reference" title="Blauw, H. M., Barnes, C. P., van Vught, P. W. J., van Rheenen, W., Verheul, M., Cuppen, E., Veldink, J. H., van den Berg, L. H. &lt;strong&gt;SMN1 gene duplications are associated with sporadic ALS.&lt;/strong&gt; Neurology 78: 776-780, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22323753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22323753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e318249f697&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22323753">Blauw et al. (2012)</a> found that SMN1 duplications were associated with increased susceptibility to ALS (odds ratio (OR) of 2.07; p = 0.001). A metaanalysis with previous data including 3,469 individuals showed a similar effect, with an OR of 1.85 (p = 0.008). SMN1 deletions or point mutations and SMN2 copy number status were not associated with ALS, and SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For discussion of a possible association between variation in the SS18L1 gene and ALS, see <a href="/entry/606472#0001">606472.0001</a>-<a href="/entry/606472#0003">606472.0003</a>.</p><p>Among 376 individuals with sporadic ALS, <a href="#25" class="mim-tip-reference" title="Course, M. M., Gudsnuk, K., Smukowski, S. N., Winston, K., Desai, N., Ross, J. P., Sulovari, A., Bourassa, C. V., Spiegelman, D., Couthouis, J., Yu, C.-E., Tsuang, D. W., Jayadev, S., Kay, M. A., Gitler, A. D., Dupre, N., Eichler, E. E., Dion, P. A., Rouleau, G. A., Valdmanis, P. N. &lt;strong&gt;Evolution of a human-specific tandem repeat associated with ALS.&lt;/strong&gt; Am. J. Hum. Genet. 107: 445-460, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32750315/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32750315&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32750315[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2020.07.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32750315">Course et al. (2020)</a> identified a 69-bp variable number tandem repeat (VNTR) in the last intron of the WDR7 gene (<a href="/entry/613473#0001">613473.0001</a>) that was associated with the disease. For a more detailed discussion of the association and potential pathogenic mechanisms, see <a href="/entry/613473#0001">613473.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32750315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
<a href="#42" class="mim-tip-reference" title="Giess, R., Holtmann, B., Braga, M., Grimm, T., Muller-Myhsok, B., Toyka, K. V., Sendtner, M. &lt;strong&gt;Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1277-1286, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11951178/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11951178&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11951178[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340427&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11951178">Giess et al. (2002)</a> reported a 25-year-old man with ALS who died after a rapid disease course of only 11 months. Genetic analysis identified a heterozygous mutation in the SOD1 gene and a homozygous mutation in the ciliary neurotrophic factor gene (CNTF; <a href="/entry/118945#0001">118945.0001</a>). The patient's mother, who developed ALS at age 54, had the SOD1 mutation and was heterozygous for the CNTF mutation. His healthy 35-year-old sister had the SOD1 mutation, but did not have the CNTF mutation. Two maternal aunts had died from ALS at 56 and 43 years of age, and a maternal grandmother and a great-grandmother had died from progressive muscle weakness and atrophy at ages 62 and less than 50 years, respectively. <a href="#42" class="mim-tip-reference" title="Giess, R., Holtmann, B., Braga, M., Grimm, T., Muller-Myhsok, B., Toyka, K. V., Sendtner, M. &lt;strong&gt;Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1277-1286, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11951178/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11951178&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11951178[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340427&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11951178">Giess et al. (2002)</a> found that transgenic SOD1 mutant mice who were Cntf-deficient had a significantly earlier age at disease onset compared to in transgenic mice that were wildtype for CNTF. Although linkage analysis in mice revealed that the SOD1 gene was solely responsible for the disease, disease onset as a quantitative trait was regulated by the CNTF locus. In addition, patients with sporadic ALS who had a homozygous CNTF gene defect showed significantly earlier disease onset, but did not show a significant difference in disease duration. <a href="#42" class="mim-tip-reference" title="Giess, R., Holtmann, B., Braga, M., Grimm, T., Muller-Myhsok, B., Toyka, K. V., Sendtner, M. &lt;strong&gt;Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1277-1286, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11951178/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11951178&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11951178[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340427&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11951178">Giess et al. (2002)</a> concluded that CNTF acts as a modifier gene that leads to early onset of disease in patients with SOD1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11951178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between ALS and mutation in the PDIA3 gene, see <a href="/entry/602046">602046</a>.</p>
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<p><a href="#28" class="mim-tip-reference" title="de Belleroche, J., Orrell, R., King, A. &lt;strong&gt;Familial amyotrophic lateral sclerosis/motor neurone disease (FALS): a review of current developments.&lt;/strong&gt; J. Med. Genet. 32: 841-847, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8592323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8592323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.11.841&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8592323">De Belleroche et al. (1995)</a> noted that the SOD1 H46R mutation (<a href="/entry/147450#0013">147450.0013</a>) was associated with a more benign form of ALS with average duration of 17 years and only slightly reduced levels of SOD1 enzyme activity. The authors referred to a family with an I113T mutation (<a href="/entry/147450#0011">147450.0011</a>) in which 1 affected member of the family died after a short progression and another member survived more than 20 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8592323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Cudkowicz, M. E., McKenna-Yasek, D., Sapp, P. E., Chin, W., Geller, B., Hayden, D. L., Schoenfeld, D. A., Hosler, B. A., Horvitz, H. R., Brown, R. H. &lt;strong&gt;Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.&lt;/strong&gt; Ann. Neurol. 41: 210-221, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9029070/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9029070&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410410212&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9029070">Cudkowicz et al. (1997)</a> registered 366 families in a study of dominantly inherited ALS. They screened 290 families for mutations in the SOD1 gene and detected mutations in 68 families; the most common SOD1 mutation, A4V (<a href="/entry/147450#0012">147450.0012</a>), was present in 50% of the families. The presence of either of 2 SOD1 mutations, G37R (<a href="/entry/147450#0001">147450.0001</a>) or L38V (<a href="/entry/147450#0002">147450.0002</a>), predicted an earlier age at onset. Additionally, the presence of the A4V mutation correlated with shorter survival, whereas G37R, G41D (<a href="/entry/147450#0004">147450.0004</a>), and G93C (<a href="/entry/147450#0007">147450.0007</a>) mutations predicted longer survival. The clinical characteristics of patients with familial ALS arising from SOD1 mutations were similar to those without SOD1 defects. However, <a href="#26" class="mim-tip-reference" title="Cudkowicz, M. E., McKenna-Yasek, D., Sapp, P. E., Chin, W., Geller, B., Hayden, D. L., Schoenfeld, D. A., Hosler, B. A., Horvitz, H. R., Brown, R. H. &lt;strong&gt;Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.&lt;/strong&gt; Ann. Neurol. 41: 210-221, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9029070/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9029070&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410410212&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9029070">Cudkowicz et al. (1997)</a> reported that mean age at onset was earlier in the SOD1 group than in the non-SOD1 group, and Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9029070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#103" class="mim-tip-reference" title="Sato, T., Nakanishi, T., Yamamoto, Y., Andersen, P. M., Ogawa, Y., Fukada, K., Zhou, Z., Aoike, F., Sugai, F., Nagano, S., Hirata, S., Ogawa, M., Nakano, R., Ohi, T., Kato, T., Nakagawa, M., Hamasaki, T., Shimizu, A., Sakoda, S. &lt;strong&gt;Rapid disease progression correlates with instability of mutant SOD1 in familial ALS.&lt;/strong&gt; Neurology 65: 1954-1957, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16291929/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16291929&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000188760.53922.05&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16291929">Sato et al. (2005)</a> measured the ratio of mutant-to-normal SOD1 protein in 29 ALS patients with mutations in the SOD1 gene. Although there was no relation to age at onset, turnover of mutant SOD1 was correlated with a shorter disease survival time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16291929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Regal, L., Vanopdenbosch, L., Tilkin, P., Van Den Bosch, L., Thijs, V., Sciot, R., Robberecht, W. &lt;strong&gt;The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis.&lt;/strong&gt; Arch. Neurol. 63: 262-267, 2006. Note: Erratum: Arch Neurol. 63: 963 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16476815/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16476815&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.63.2.262&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16476815">Regal et al. (2006)</a> reported the clinical features of 20 ALS patients from 4 families with the SOD1 G93C mutation (<a href="/entry/147450#0007">147450.0007</a>). Mean age at onset was 45.9 years, and all patients had slowly progressive weakness and atrophy starting in the distal lower limbs. Although symptoms gradually spread proximally and to the upper extremities, bulbar function was preserved. None of the patients developed upper motor neuron signs. Postmortem findings of 1 patient showed severe loss of anterior horn cells and loss of myelinated fibers in the posterior column and spinocerebellar tracts, but only mild changes in the lateral corticospinal tracts. Lipofuscin and hyaline inclusions were observed in many neurons. Patients with the G93C mutation had significantly longer survival compared to patients with other SOD1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16476815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Amyotrophic lateral sclerosis is a disorder that has prominently been mentioned as justification for assisted suicide. <a href="#40" class="mim-tip-reference" title="Ganzini, L., Johnston, W. S., McFarland, B. H., Tolle, S. W., Lee, M. A. &lt;strong&gt;Attitudes of patients with amyotrophic lateral sclerosis and their care givers toward assisted suicide.&lt;/strong&gt; New Eng. J. Med. 339: 967-973, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753713/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753713&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199810013391406&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753713">Ganzini et al. (1998)</a> found that in the states of Oregon and Washington most patients with ALS whom they surveyed would consider assisted suicide. Many would request a prescription for a lethal dose of medication well before they intended to use it. <a href="#101" class="mim-tip-reference" title="Rowland, L. P. &lt;strong&gt;Assisted suicide and alternatives in amyotrophic lateral sclerosis. (Editorial)&lt;/strong&gt; New Eng. J. Med. 339: 987-989, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753716/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753716&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199810013391409&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753716">Rowland (1998)</a> reviewed the question of what it is about ALS that raised the question of suicide. The progressive paralysis leads to increase of loss of function, culminating in complete dependence on the help of others for all activities of daily living and, if life is sustained by assisted ventilation, loss of the ability to communicate or swallow. Ten percent of patients are under the age of 40 years. Some patients, wanting to live as long as possible, opted for tracheostomy and assisted ventilation at home. In a study of 92 patients receiving long-term assisted ventilation with tracheostomy, 20 lived for 8 to 17 years with the tracheostomy, and 9 became 'locked in' (they were conscious but severely paralyzed and unable to communicate except by eye movements). In the Oregon series, however, only 2 patients opted for tracheostomy with long-term mechanical ventilation, and among patients at the ALS Center at Columbia Presbyterian Medical Center, only 2.9% chose it (<a href="#101" class="mim-tip-reference" title="Rowland, L. P. &lt;strong&gt;Assisted suicide and alternatives in amyotrophic lateral sclerosis. (Editorial)&lt;/strong&gt; New Eng. J. Med. 339: 987-989, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753716/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753716&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199810013391409&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753716">Rowland, 1998</a>). The last year in the life of an ALS victim, Professor Morris Schwartz, was chronicled in a bestselling book written by <a href="#3" class="mim-tip-reference" title="Albom, M. &lt;strong&gt;Tuesdays with Morrie: an old man, a young man, and the last great lesson.&lt;/strong&gt; New York: Doubleday (pub) 1997. P. 162."None>Albom (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9753713+9753716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a prospective randomized control trial of 44 ALS patients, <a href="#39" class="mim-tip-reference" title="Fornai, F., Longone, P., Cafaro, L., Kastsiuchenka, O., Ferrucci, M., Manca, M. L., Lazzeri, G., Spalloni, A., Bellio, N., Lenzi, P., Modugno, N., Siciliano, G., Isidoro, C., Murri, L., Ruggieri, S., Paparelli, A. &lt;strong&gt;Lithium delays progression of amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 2052-2057, 2008. Note: Erratum: Proc. Nat. Acad. Sci. 105: 16404 only, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18250315/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18250315&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18250315[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0708022105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18250315">Fornai et al. (2008)</a> reported that treatment of 16 patients with lithium plus riluzole resulted in slower disease progression compared to 28 patients treated with riluzole alone. All 16 patients treated with lithium survived for 15 months; 29% of the patients receiving riluzole alone did not survive by this endpoint. Studies in transgenic ALS mice showed a similar delay in disease progression and longer survival. Mice treated with lithium showed delayed cell death in spinal cord motor neurons, increased numbers of normal mitochondria in motor neurons, decreased SOD1 aggregation, and decreased reactive astrogliosis. Studies of cultured mutant murine motor neurons suggested that lithium treatment increased endosomal autophagy of aggregated proteins or abnormal mitochondria, which may have contributed to the observed neuroprotective effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 regions of northwestern Italy with a total population of approximately 4.5 million, the <a href="#86" class="mim-tip-reference" title="Piemonte and Valle d&#x27;Aosta Register for Amyotrophic Lateral Sclerosis. &lt;strong&gt;Incidence of ALS in Italy: evidence for a uniform frequency in Western countries.&lt;/strong&gt; Neurology 56: 239-244, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11160962/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11160962&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.56.2.239&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11160962">Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (2001)</a> determined a mean annual incidence rate of 2.5 per 100,000 from 1995 to 1996. The data were comparable to similar studies in other Western countries, suggesting diffuse genetic or environmental factors in the pathogenesis of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11160962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Chio, A., Traynor, B. J., Lombardo, F., Fimognari, M., Calvo, A., Ghiglione, P., Mutani, R., Restagno, G. &lt;strong&gt;Prevalence of SOD1 mutations in the Italian ALS population.&lt;/strong&gt; Neurology 70: 533-537, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18268245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18268245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000299187.90432.3f&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18268245">Chio et al. (2008)</a> found that 5 of 325 patients with ALS in Turin province of the Piemonte region of Italy had mutations in the SOD1 gene. Mutations were identified in 3 (13.6%) of 22 patients with a family history of ALS, and 2 (0.7%) of 303 sporadic cases. <a href="#21" class="mim-tip-reference" title="Chio, A., Traynor, B. J., Lombardo, F., Fimognari, M., Calvo, A., Ghiglione, P., Mutani, R., Restagno, G. &lt;strong&gt;Prevalence of SOD1 mutations in the Italian ALS population.&lt;/strong&gt; Neurology 70: 533-537, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18268245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18268245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000299187.90432.3f&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18268245">Chio et al. (2008)</a> noted that the frequency of FALS (5.7%) was lower in this population-based series compared to series reported from ALS referral centers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18268245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>See also ANIMAL MODEL in <a href="/entry/147450">147450</a>.</p><p>The murine Mnd (motor neuron degeneration) mutation causes a late-onset, progressive degeneration of upper and lower motor neurons. Using endogenous retroviruses as markers, <a href="#74" class="mim-tip-reference" title="Messer, A., Plummer, J., Maskin, P., Coffin, J. M., Frankel, W. N. &lt;strong&gt;Mapping of the motor neuron degeneration (Mnd) gene, a mouse model of amyotrophic lateral sclerosis (ALS).&lt;/strong&gt; Genomics 13: 797-802, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1639406/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1639406&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(92)90155-l&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1639406">Messer et al. (1992)</a> mapped the Mnd gene in the mouse to proximal chromosome 8. <a href="#74" class="mim-tip-reference" title="Messer, A., Plummer, J., Maskin, P., Coffin, J. M., Frankel, W. N. &lt;strong&gt;Mapping of the motor neuron degeneration (Mnd) gene, a mouse model of amyotrophic lateral sclerosis (ALS).&lt;/strong&gt; Genomics 13: 797-802, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1639406/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1639406&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(92)90155-l&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1639406">Messer et al. (1992)</a> suggested that examination of human chromosome 8, which shows homology of synteny, in human kindreds with ALS as well as related hereditary neurologic diseases might be fruitful. They presented evidence suggesting that a combination of genetic and environmental modifiers can alter the time course of the phenotypic expression in the mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Gurney, M. E., Pu, H., Chiu, A. Y., Dal Canto, M. C., Polchow, C. Y., Alexander, D. D., Caliendo, J., Hentati, A., Kwon, Y. W., Deng, H.-X., Chen, W., Zhai, P., Sufit, R. L., Siddique, T. &lt;strong&gt;Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.&lt;/strong&gt; Science 264: 1772-1775, 1994. Note: Erratum: Science 269: 149 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8209258/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8209258&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.8209258&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8209258">Gurney et al. (1994)</a> found that expression of high levels of human SOD containing the gly93-to-ala mutation (G93A; <a href="/entry/147450#0008">147450.0008</a>), a change that had little effect on enzyme activity, resulted in motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. Ongoing reinnervation and remodeling of muscle innervation suggested that 'sprouting' probably compensates for the loss of motor neurons until late in the course of the disease. <a href="#46" class="mim-tip-reference" title="Gurney, M. E., Pu, H., Chiu, A. Y., Dal Canto, M. C., Polchow, C. Y., Alexander, D. D., Caliendo, J., Hentati, A., Kwon, Y. W., Deng, H.-X., Chen, W., Zhai, P., Sufit, R. L., Siddique, T. &lt;strong&gt;Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.&lt;/strong&gt; Science 264: 1772-1775, 1994. Note: Erratum: Science 269: 149 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8209258/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8209258&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.8209258&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8209258">Gurney et al. (1994)</a> suggested that the toxicity of SOD1 from motor neurons could involve the formation of the strong oxidant peroxynitrite from oxygen and nitric oxide free radicals, representing a dominant, gain-of-function role for SOD1 mutations in the pathogenesis of familial ALS. The fact that mice with the abnormal human SOD became paralyzed even though copies of the animals' own normal Sod gene remained intact supported the gain-of-function role. <a href="#46" class="mim-tip-reference" title="Gurney, M. E., Pu, H., Chiu, A. Y., Dal Canto, M. C., Polchow, C. Y., Alexander, D. D., Caliendo, J., Hentati, A., Kwon, Y. W., Deng, H.-X., Chen, W., Zhai, P., Sufit, R. L., Siddique, T. &lt;strong&gt;Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.&lt;/strong&gt; Science 264: 1772-1775, 1994. Note: Erratum: Science 269: 149 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8209258/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8209258&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.8209258&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8209258">Gurney et al. (1994)</a> and other groups studying transgenic mice found that animals making the highest amounts of mutant Sod proteins were the ones that become paralyzed, a finding that runs counter to the idea that decreased SOD activity is at fault in ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8209258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#129" class="mim-tip-reference" title="Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., Sisodia, S. S., Cleveland, D. W., Price, D. L. &lt;strong&gt;An adverse property of familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.&lt;/strong&gt; Neuron 14: 1105-1116, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7605627/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7605627&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0896-6273(95)90259-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7605627">Wong et al. (1995)</a> generated transgenic mice carrying a gly37-to-arg (G37R; <a href="/entry/147450#0001">147450.0001</a>) mutation in the SOD1 gene associated with a subset of familial ALS cases. The mice developed severe, progressive motor neuron disease and provided an animal model for ALS. <a href="#129" class="mim-tip-reference" title="Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., Sisodia, S. S., Cleveland, D. W., Price, D. L. &lt;strong&gt;An adverse property of familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.&lt;/strong&gt; Neuron 14: 1105-1116, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7605627/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7605627&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0896-6273(95)90259-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7605627">Wong et al. (1995)</a> observed that at lower levels of mutant accumulation, pathology was restricted to lower motor neurons, whereas higher levels caused more severe abnormalities and affected a variety of other neuronal populations. The authors noted that the most obvious cellular abnormality in the mutant mice was the presence in axons and dendrites of membrane-bound vacuoles, which they hypothesized were derived from degenerating mitochondria. <a href="#129" class="mim-tip-reference" title="Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., Sisodia, S. S., Cleveland, D. W., Price, D. L. &lt;strong&gt;An adverse property of familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.&lt;/strong&gt; Neuron 14: 1105-1116, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7605627/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7605627&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0896-6273(95)90259-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7605627">Wong et al. (1995)</a> concluded that the disease in mice expressing G37R arises from the acquisition of an adverse property by the mutant enzyme rather than elevation or loss of SOD1 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7605627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#97" class="mim-tip-reference" title="Ripps, M. E., Huntley, G. W., Hof, P. R., Morrison, J. H., Gordon, J. W. &lt;strong&gt;Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 92: 689-693, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7846037/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7846037&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.92.3.689&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7846037">Ripps et al. (1995)</a> produced a transgenic mouse model of familial ALS by introducing an SOD1 mutation (gly86-to-arg). In 2 lines of mice that produced high levels of transgene mRNA in the CNS, motor paralysis developed and was associated with degenerative changes of motor neurons within the spinal cord, brainstem, and neocortex. Biochemical measurements in these animals revealed no diminution of Sod activity, indicating a dominant gain-of-function mutation. <a href="#121" class="mim-tip-reference" title="Tu, P.-H., Raju, P., Robinson, K. A., Gurney, M. E., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.&lt;/strong&gt; Proc. Nat. Acad. Sci. 93: 3155-3160, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8610185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8610185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.93.7.3155&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8610185">Tu et al. (1996)</a> reported that transgenic mice expressing a human SOD1 gene containing the G92A mutation developed a motor neuron disease similar to familial ALS, but transgenic mice expressing a wildtype human SOD1 transgene did not. Neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of ALS. <a href="#121" class="mim-tip-reference" title="Tu, P.-H., Raju, P., Robinson, K. A., Gurney, M. E., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.&lt;/strong&gt; Proc. Nat. Acad. Sci. 93: 3155-3160, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8610185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8610185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.93.7.3155&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8610185">Tu et al. (1996)</a> found that such inclusions were detectable in spinal cord motor neurons of the mutant carrying transgenic mice at 82 days of age and about the time that the mice first showed clinical evidence of the disease. In contrast, NF inclusions were not seen in the mice with the wildtype transgene until they were 132 days old, and ubiquitin immunoreactivity, which likewise started at about 82 days in mutant-bearing mice, was not increased in wildtype mice even at 199 days of age. A striking similarity between the cytoskeletal pathology of the mutant transgenic mice and the patients with ALS was demonstrated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8610185+7846037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemistry and immunoblot experiments, <a href="#81" class="mim-tip-reference" title="Nguyen, M. D., Lariviere, R. C., Julien, J.-P. &lt;strong&gt;Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.&lt;/strong&gt; Neuron 30: 135-147, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(01)00268-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343650">Nguyen et al. (2001)</a> found that the p25/p35 (see <a href="/entry/603460">603460</a>) ratio and Cdk5 (<a href="/entry/123831">123831</a>) activity were abnormally elevated in the spinal cord of transgenic mice with the G37R mutation in SOD1 (<a href="#129" class="mim-tip-reference" title="Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., Sisodia, S. S., Cleveland, D. W., Price, D. L. &lt;strong&gt;An adverse property of familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.&lt;/strong&gt; Neuron 14: 1105-1116, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7605627/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7605627&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0896-6273(95)90259-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7605627">Wong et al., 1995</a>). This elevation was associated with the hyperphosphorylation of neurofilament and tau (<a href="/entry/157140">157140</a>) proteins. By analyzing transgenic mouse lines with differing G37R transgene expression levels, <a href="#81" class="mim-tip-reference" title="Nguyen, M. D., Lariviere, R. C., Julien, J.-P. &lt;strong&gt;Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.&lt;/strong&gt; Neuron 30: 135-147, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(01)00268-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343650">Nguyen et al. (2001)</a> observed a correlation between Cdk5 activity and the longevity of the mutant mice. <a href="#81" class="mim-tip-reference" title="Nguyen, M. D., Lariviere, R. C., Julien, J.-P. &lt;strong&gt;Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.&lt;/strong&gt; Neuron 30: 135-147, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(01)00268-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343650">Nguyen et al. (2001)</a> bred the G37R transgene onto neurofilament mutant backgrounds and observed that the absence of neurofilament light subunit (NEFL; <a href="/entry/162280">162280</a>) provoked an accumulation of unassembled neurofilament subunits in the perikaryon of motor neurons and extended the average life span of the mutant mice. Using double immunofluorescence microscopy, <a href="#81" class="mim-tip-reference" title="Nguyen, M. D., Lariviere, R. C., Julien, J.-P. &lt;strong&gt;Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.&lt;/strong&gt; Neuron 30: 135-147, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(01)00268-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343650">Nguyen et al. (2001)</a> confirmed that Cdk5 and p25 colocalized with perikaryal neurofilament accumulations in G37R mice on the neurofilament mutant background. Using immunoblotting, <a href="#81" class="mim-tip-reference" title="Nguyen, M. D., Lariviere, R. C., Julien, J.-P. &lt;strong&gt;Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.&lt;/strong&gt; Neuron 30: 135-147, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(01)00268-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343650">Nguyen et al. (2001)</a> observed that the occurrence of perikaryal neurofilament accumulations in the mutant mice was associated with a reduction in the elevated phosphorylation of tau, another p25/cdk5 substrate. <a href="#81" class="mim-tip-reference" title="Nguyen, M. D., Lariviere, R. C., Julien, J.-P. &lt;strong&gt;Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.&lt;/strong&gt; Neuron 30: 135-147, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11343650/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11343650&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(01)00268-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11343650">Nguyen et al. (2001)</a> hypothesized that perikaryal accumulations of neurofilament proteins in motor neurons may alleviate ALS pathogenesis in SOD1(G37R) mice by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7605627+11343650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascano, J., Tokito, M., Van Winkle, T., Howland, D. S., Holzbaur, E. L. F. &lt;strong&gt;Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.&lt;/strong&gt; Neuron 34: 715-727, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12062019/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12062019&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00696-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12062019">LaMonte et al. (2002)</a> generated a mouse model of ALS by overexpressing dynamitin (DCTN2; <a href="/entry/607376">607376</a>) in postnatal motor neurons of transgenic mice. They found that dynamitin overexpression disrupted the dynein-dynactin complex, resulting in an inhibition of retrograde axonal transport. The authors observed a late-onset, slowly progressive motor neuron degenerative disease characterized by muscle weakness, spontaneous trembling, abnormal posture and gaits, and deficits in strength and endurance. <a href="#65" class="mim-tip-reference" title="LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascano, J., Tokito, M., Van Winkle, T., Howland, D. S., Holzbaur, E. L. F. &lt;strong&gt;Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.&lt;/strong&gt; Neuron 34: 715-727, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12062019/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12062019&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00696-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12062019">LaMonte et al. (2002)</a> detected histologic changes in spinal cord motor neurons and skeletal muscle indicative of degeneration of motor neurons and denervation atrophy of muscle. The transgenic mice also displayed neurofilament accumulations. <a href="#65" class="mim-tip-reference" title="LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascano, J., Tokito, M., Van Winkle, T., Howland, D. S., Holzbaur, E. L. F. &lt;strong&gt;Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.&lt;/strong&gt; Neuron 34: 715-727, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12062019/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12062019&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00696-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12062019">LaMonte et al. (2002)</a> concluded that their mouse model confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12062019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#95" class="mim-tip-reference" title="Raoul, C., Estevez, A. G., Nishimune, H., Cleveland, D. W., deLapeyriere, O., Henderson, C. E., Hasse, G., Pettmann, B. &lt;strong&gt;Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations.&lt;/strong&gt; Neuron 35: 1067-1083, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12354397/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12354397&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00905-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12354397">Raoul et al. (2002)</a> showed that Fas (<a href="/entry/134637">134637</a>), a member of the death receptor family, triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; <a href="/entry/163731">163731</a>) mediated by p38 kinase (<a href="/entry/600289">600289</a>). ASK1 (<a href="/entry/602448">602448</a>) and Daxx (<a href="/entry/603186">603186</a>) act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (<a href="/entry/602457">602457</a>)/caspase-8 (<a href="/entry/601763">601763</a>) cell death pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing ALS-linked SOD1 mutations displayed increased susceptibility to activation of the Fas/NO pathway. <a href="#95" class="mim-tip-reference" title="Raoul, C., Estevez, A. G., Nishimune, H., Cleveland, D. W., deLapeyriere, O., Henderson, C. E., Hasse, G., Pettmann, B. &lt;strong&gt;Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations.&lt;/strong&gt; Neuron 35: 1067-1083, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12354397/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12354397&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00905-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12354397">Raoul et al. (2002)</a> emphasized that this signaling pathway was unique to motor neurons and suggested that these cell death pathways may contribute to motor neuron loss in ALS. <a href="#94" class="mim-tip-reference" title="Raoul, C., Buhler, E., Sadeghi, C., Jacquier, A., Aebischer, P., Pettmann, B., Henderson, C. E., Haase, G. &lt;strong&gt;Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 6007-6012, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16581901/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16581901&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16581901[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0508774103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16581901">Raoul et al. (2006)</a> reported that exogenous NO triggered expression of Fas ligand (FASL; <a href="/entry/134638">134638</a>) in cultured motoneurons. In motoneurons from ALS model mice with mutations in the SOD1 gene, this upregulation resulted in activation of Fas, leading through Daxx and p38 to further NO synthesis. The authors suggested that chronic low activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12354397+16581901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2 subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (see GLUR2, <a href="/entry/138247">138247</a>) to SOD1-related motoneuronal death, <a href="#119" class="mim-tip-reference" title="Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R.-M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., Takahashi, R. &lt;strong&gt;Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model.&lt;/strong&gt; Hum. Molec. Genet. 13: 2183-2196, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15294873/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15294873&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh246&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15294873">Tateno et al. (2004)</a> generated choline acetyltransferase (ChAT; <a href="/entry/118490">118490</a>)-GluR2 transgenic mice with significantly reduced Ca(2)+ permeability of these receptors in spinal motoneurons. Crossbreeding of the SOD1(G93A) transgenic mouse model of ALS with ChAT-GluR2 mice led to marked delay of disease onset, mortality, and the pathologic hallmarks such as release of cytochrome c from mitochondria, induction of cox2 (<a href="/entry/600262">600262</a>), and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species accumulated in 2 fractions (P1, composed of nuclei and certain kinds of cytoskeletons such as neurofilaments and glial fibrillary acidic protein (GFAP; <a href="/entry/137780">137780</a>), and P2, composed of mitochondria) long before disease onset and then extensively accumulated in the P1 fractions by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca(2+) influx through atypical motoneuronal AMPA receptors thus promoted a misfolding of mutant SOD1 protein and eventual death of these neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15294873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mice carrying a deletable mutant Sod1 gene, <a href="#13" class="mim-tip-reference" title="Boillee, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., Cleveland, D. W. &lt;strong&gt;Onset and progression in inherited ALS determined by motor neurons and microglia.&lt;/strong&gt; Science 312: 1389-1392, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16741123/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16741123&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1123511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16741123">Boillee et al. (2006)</a> demonstrated that expression within motor neurons is a primary determinant of ALS disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early phase but sharply slowed later disease progression. <a href="#13" class="mim-tip-reference" title="Boillee, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., Cleveland, D. W. &lt;strong&gt;Onset and progression in inherited ALS determined by motor neurons and microglia.&lt;/strong&gt; Science 312: 1389-1392, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16741123/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16741123&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1123511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16741123">Boillee et al. (2006)</a> concluded that onset and progression thus represent distinct ALS disease phases defined by mutant action within different cell types to generate non-cell autonomous killing of motor neurons; their findings validate therapies, including cell replacement, targeted to the nonneuronal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#76" class="mim-tip-reference" title="Miller, T. M., Kim, S. H., Yamanaka, K., Hester, M., Umapathi, P., Arnson, H., Rizo, L., Mendell, J. R., Gage, F. H., Cleveland, D. W., Kaspar, B. K. &lt;strong&gt;Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 19546-19551, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17164329/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17164329&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17164329[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0609411103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17164329">Miller et al. (2006)</a> demonstrated that human SOD1 mutant-mediated damage within muscles of mice was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17164329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Marden, J. J., Harraz, M. M., Williams, A. J., Nelson, K., Luo, M., Paulson, H., Engelhardt, J. F. &lt;strong&gt;Redox modifier genes in amyotrophic lateral sclerosis in mice.&lt;/strong&gt; J. Clin. Invest. 117: 2913-2919, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17853944/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17853944&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17853944[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI31265&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17853944">Marden et al. (2007)</a> evaluated the effects of NADPH oxidase-1 (NOX1; <a href="/entry/300225">300225</a>) or Nox2 (CYBB; <a href="/entry/300481">300481</a>) deletion on transgenic mice overexpressing human SOD1 with the G93A mutation by monitoring the onset and progression of disease using various indices. Disruption of either Nox1 or Nox2 significantly delayed progression of motor neuron disease in these mice. However, 50% survival rates were enhanced significantly more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased survival rates, suggesting that in the setting of random X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a substantial therapeutic benefit in ALS mice. <a href="#71" class="mim-tip-reference" title="Marden, J. J., Harraz, M. M., Williams, A. J., Nelson, K., Luo, M., Paulson, H., Engelhardt, J. F. &lt;strong&gt;Redox modifier genes in amyotrophic lateral sclerosis in mice.&lt;/strong&gt; J. Clin. Invest. 117: 2913-2919, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17853944/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17853944&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17853944[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI31265&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17853944">Marden et al. (2007)</a> concluded that NOX1 and NOX2 contribute to the progression of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Kieran, D., Woods, I., Villunger, A., Strasser, A., Prehn, J. H. M. &lt;strong&gt;Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 104: 20606-20611, 2007. Note: Erratum: Proc. Nat. Acad. Sci. 118: e2112400118, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18077368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18077368&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18077368[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0707906105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18077368">Kieran et al. (2007)</a> detected a significant upregulation of Puma (BBC3; <a href="/entry/605854">605854</a>), a proapoptotic protein, in motoneurons of G93A-mutant mice before symptom onset. Deletion of Puma in these mice improved motoneuron survival and delayed disease onset and motor dysfunction, but did not extend life span. The findings suggested that Puma may play a role in the early stages of neurodegeneration in ALS by increasing ER stress-mediated apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18077368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Awano, T., Johnson, G. S., Wade, C. M., Katz, M. L., Johnson, G. C., Taylor, J. F., Perloski, M., Biagi, T., Baranowska, I., Long, S., March, P. A., Olby, N. J., Shelton, G. D., Khan, S., O&#x27;Brien, D. P., Lindblad-Toh, K., Coates, J. R. &lt;strong&gt;Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 106: 2794-2799, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19188595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19188595&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19188595[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0812297106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19188595">Awano et al. (2009)</a> found that canine degenerative myelopathy, a spontaneously occurring adult-onset neurodegenerative disease, was highly associated with a homozygous glu40-to-lys (E40K) mutation in the canine Sod1 gene. The mutation was found in affected breeds including Pembroke Welsh corgi, boxer, Rhodesian ridgeback, Chesapeake Bay retriever, and German shepherd. The disorder was characterized clinically by adult onset of spasticity and proprioceptive ataxia, followed by weakness, paraplegia, and hyporeflexia. Histopathologic examination of the spinal cord of 46 affected dogs showed white matter degeneration with axonal and myelin loss and cytoplasmic Sod1-positive inclusions in surviving neurons. The disorder closely resembled human ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19188595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#118" class="mim-tip-reference" title="Tateno, M., Kato, S., Sakurai, T., Nukina, N., Takahashi, R., Araki, T. &lt;strong&gt;Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.&lt;/strong&gt; Hum. Molec. Genet. 18: 942-955, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19088126/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19088126&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19088126[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn422&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19088126">Tateno et al. (2009)</a> demonstrated that, starting from the pre-onset stage of ALS, misfolded SOD1 species associated specifically with Kap3 (KIFAP3; <a href="/entry/601836">601836</a>) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargoes including ChAT. Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. Using a purified hybrid mouse neuroblastoma/rat glioma cell line NG108-15 transfected with SOD1 mutations, the authors showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species and that impairment was normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in spinal motor neurons from human ALS patients as well. <a href="#118" class="mim-tip-reference" title="Tateno, M., Kato, S., Sakurai, T., Nukina, N., Takahashi, R., Araki, T. &lt;strong&gt;Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.&lt;/strong&gt; Hum. Molec. Genet. 18: 942-955, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19088126/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19088126&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19088126[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn422&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19088126">Tateno et al. (2009)</a> suggested that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the pathophysiology of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#130" class="mim-tip-reference" title="Wong, W., Martin, L. J. &lt;strong&gt;Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice.&lt;/strong&gt; Hum. Molec. Genet. 19: 2284-2302, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20223753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20223753&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20223753[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20223753">Wong and Martin (2010)</a> created transgenic mice expressing wildtype, G37R (<a href="/entry/147450#0001">147450.0001</a>), and G93A (<a href="/entry/147450#0008">147450.0008</a>) human SOD1 in only skeletal muscle. These mice developed age-related neurologic and pathologic phenotypes consistent with ALS. Affected mice showed limb weakness and paresis with motor deficits. Skeletal muscles developed severe pathology involving oxidative damage, protein nitration, myofiber cell death, and marked neuromuscular junction abnormalities. Spinal motor neurons developed distal axonopathy, formed ubiquitinated inclusions, and degenerated through an apoptotic-like pathway involving caspase-3 (<a href="/entry/600636">600636</a>). Mice expressing wildtype and mutant forms of SOD1 developed motor neuron pathology. The authors concluded that SOD1 in skeletal muscle has a causal role in ALS, and they proposed a nonautonomous mechanism to explain the degeneration and selective vulnerability of these motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20223753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Blacher, E., Bashiardes, S., Shapiro, H., Rothschild, D., Mor, U., Dori-Bachash, M., Kleimeyer, C., Moresi, C., Harnik, Y., Zur, M., Zabari, M., Brik, R. B.-Z., and 21 others. &lt;strong&gt;Potential roles of gut microbiome and metabolites in modulating ALS in mice.&lt;/strong&gt; Nature 572: 474-480, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31330533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31330533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1443-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31330533">Blacher et al. (2019)</a> showed that ALS-prone Sod1 transgenic mice have a presymptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. <a href="#11" class="mim-tip-reference" title="Blacher, E., Bashiardes, S., Shapiro, H., Rothschild, D., Mor, U., Dori-Bachash, M., Kleimeyer, C., Moresi, C., Harnik, Y., Zur, M., Zabari, M., Brik, R. B.-Z., and 21 others. &lt;strong&gt;Potential roles of gut microbiome and metabolites in modulating ALS in mice.&lt;/strong&gt; Nature 572: 474-480, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31330533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31330533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1443-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31330533">Blacher et al. (2019)</a> correlated 11 distinct commensal bacteria with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1 transgenic mice they demonstrated that Akkermansia muciniphila (AM) ameliorates, whereas Ruminococcus torques and Parabacteroides distasonis exacerbate, the symptoms of ALS. Furthermore, Sod1 transgenic mice that are administered AM accumulated AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improved motor symptoms and gene expression patterns in the spinal cord of Sod1 transgenic mice. In humans, <a href="#11" class="mim-tip-reference" title="Blacher, E., Bashiardes, S., Shapiro, H., Rothschild, D., Mor, U., Dori-Bachash, M., Kleimeyer, C., Moresi, C., Harnik, Y., Zur, M., Zabari, M., Brik, R. B.-Z., and 21 others. &lt;strong&gt;Potential roles of gut microbiome and metabolites in modulating ALS in mice.&lt;/strong&gt; Nature 572: 474-480, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31330533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31330533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1443-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31330533">Blacher et al. (2019)</a> identified distinct microbiome and metabolite configurations, including reduced levels of nicotinamide systemically and in the CSF, in a small preliminary study that compared patients with ALS with household controls. <a href="#11" class="mim-tip-reference" title="Blacher, E., Bashiardes, S., Shapiro, H., Rothschild, D., Mor, U., Dori-Bachash, M., Kleimeyer, C., Moresi, C., Harnik, Y., Zur, M., Zabari, M., Brik, R. B.-Z., and 21 others. &lt;strong&gt;Potential roles of gut microbiome and metabolites in modulating ALS in mice.&lt;/strong&gt; Nature 572: 474-480, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31330533/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31330533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1443-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31330533">Blacher et al. (2019)</a> suggested that environmentally driven microbiome-brain interactions may modulate ALS in mice, and called for similar investigations in the human form of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31330533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Therapeutic Strategies</em></strong></p><p>
Transgenic mice overexpressing a mutated form of human SOD1 with a gly93-to-ala substitution (G93A; <a href="/entry/147450#0008">147450.0008</a>) develop progressive muscle wasting and paralysis as a result of spinal motor neuron loss and die at 5 to 6 months. <a href="#14" class="mim-tip-reference" title="Bordet, T., Lesbordes, J.-C., Rouhani, S., Castelnau-Ptakhine, L., Schmalbruch, H., Haase, G., Kahn, A. &lt;strong&gt;Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice.&lt;/strong&gt; Hum. Molec. Genet. 10: 1925-1933, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11555629/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11555629&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.18.1925&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11555629">Bordet et al. (2001)</a> found that intramuscular injection of an adenoviral vector encoding CTF1 (<a href="/entry/600435">600435</a>) in SOD1(G93A) newborn mice delayed the onset of motor impairment as assessed in the rotarod test. By CTF1 treatment, axonal degeneration was slowed, skeletal muscle atrophy was largely reduced, and the time-course of motor impairment was significantly decreased. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a transgenic mouse model of ALS with the human G93A SOD1 mutation, <a href="#31" class="mim-tip-reference" title="Drachman, D. B., Frank, K., Dykes-Hoberg, M., Teismann, P., Almer, G., Przedborski, S., Rothstein, J. D. &lt;strong&gt;Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS.&lt;/strong&gt; Ann. Neurol. 52: 771-778, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12447931/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12447931&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10374&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12447931">Drachman et al. (2002)</a> demonstrated that treatment with the cyclooxygenase-2 (COX2; <a href="/entry/600262">600262</a>) inhibitor celecoxib resulted in significant delay of onset of weakness and weight loss, prolonged survival, preservation of ventral gray neurons in the spinal cord, and reduced spinal cord astroglial and microglial proliferation. The authors suggested that COX2 inhibition prevents prostaglandin-mediated release of glutamate from astrocytes and interrupts the inflammatory processes that result in the production of toxic reactive oxygen species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Adeno-associated virus (AAV) can be retrogradely transported efficiently from muscle to motor neurons of the spinal cord (<a href="#27" class="mim-tip-reference" title="Davidson, B. L., Stein, C. S., Heth, J. A., Martins, I., Kotin, R. M., Derksen, T. A., Zabner, J., Ghodsi, A., Chiorini, J. A. &lt;strong&gt;Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 3428-3432, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10688913/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10688913&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10688913[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.97.7.3428&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10688913">Davidson et al., 2000</a>; <a href="#15" class="mim-tip-reference" title="Boulis, N. M., Willmarth, N. E., Song, D. K., Feldman, E. L., Imperiale, M. J. &lt;strong&gt;Intraneural colchicine inhibition of adenoviral and adeno-associated viral vector remote spinal cord gene delivery.&lt;/strong&gt; Neurosurgery 52: 381-387, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12535368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12535368&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1227/01.neu.0000044459.24519.3e&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12535368">Boulis et al., 2003</a>). In the Sod1-overexpressing model of ALS in the mouse, <a href="#57" class="mim-tip-reference" title="Kaspar, B. K., Llado, J., Sherkat, N., Rothstein, J. D., Gage, F. H. &lt;strong&gt;Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model.&lt;/strong&gt; Science 301: 839-842, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12907804/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12907804&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1086137&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12907804">Kaspar et al. (2003)</a> found that IGF1 (<a href="/entry/147440">147440</a>) administered through an AAV vector by intramuscular injection into hindlimb quadriceps and intercostal muscles at 60 days of age, approximately 30 days prior to disease onset, delayed onset by 31 days, twice as long as that seen in mice given GDNF (<a href="/entry/600837">600837</a>) through an AAV vector. GDNF-treated animals showed a smaller, 11-day increase in median survival compared to GFP-treated controls. IGF1-treated animals showed a larger, significant improvement in life span, with a 37-day increase in median survival compared to controls. The maximal life span of IGF1-treated animals was 265 days, compared to 140 days in the control group. <a href="#57" class="mim-tip-reference" title="Kaspar, B. K., Llado, J., Sherkat, N., Rothstein, J. D., Gage, F. H. &lt;strong&gt;Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model.&lt;/strong&gt; Science 301: 839-842, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12907804/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12907804&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1086137&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12907804">Kaspar et al. (2003)</a> concluded that injection of IGF1 not only delayed the onset of disease but also slowed the rate of disease progression. In contrast, GDNF appeared only to have delayed the onset of symptoms. IGF1 treatment was even able to expand life span when administered after disease onset at 90 days of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12907804+12535368+10688913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Azzouz, M., Ralph, G. S., Storkebaum, E., Walmsley, L. E., Mitrophanous, K. A., Kingsman, S. M., Carmeliet, P., Mazarakis, N. D. &lt;strong&gt;VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model.&lt;/strong&gt; Nature 429: 413-417, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15164063/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15164063&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature02544&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15164063">Azzouz et al. (2004)</a> reported that a single injection of a vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>)-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene encoding the mutated G93A form of SOD1 (<a href="/entry/147450#0008">147450.0008</a>), even when treatment was initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30% without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field to that time. <a href="#114" class="mim-tip-reference" title="Storkebaum, E., Lambrechts, D., Dewerchin, M., Moreno-Murciano, M.-P., Appelmans, S., Oh, H., Van Damme, P., Rutten, B., Man, W., De Mol, M., Wyns, S., and 9 others. &lt;strong&gt;Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.&lt;/strong&gt; Nature Neurosci. 8: 85-92, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15568021/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15568021&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nn1360&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15568021">Storkebaum et al. (2005)</a> found that intracerebroventricular delivery of recombinant Vegf in a rat model of ALS with the G93A SOD1 mutation delayed onset of paralysis by 17 days, improved motor performance, and prolonged survival by 22 days. By protecting cervical motoneurons, intracerebroventricular delivery of Vegf was particularly effective in rats with the most severe form of disease ALS with forelimb onset, which may be analogous to patients with bulbar onset of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15164063+15568021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#122" class="mim-tip-reference" title="Urushitani, M., Ezzi, S. A., Julien, J.-P. &lt;strong&gt;Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 104: 2495-2500, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17277077/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17277077&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17277077[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0606201104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17277077">Urushitani et al. (2007)</a> reported that active vaccination with mutant SOD1 and passive immunization with anti-SOD1 antibody were effective in alleviating disease symptoms and delaying mortality of in ALS mice with a G37R SOD1 mutation and moderate expression of the mutant gene. Western blot analysis showed clearance of SOD1 species in the spinal cord of vaccinated mice. Vaccination was not effective in a different mouse strain with extreme overexpression of mutant SOD1. The results were consistent with the hypothesis that neurotoxicity of extracellular secreted SOD1 may also play a role in disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17277077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., Croft, G. F., Saphier, G., Leibel, R., Goland, R., Wichterle, H., Henderson, C. E., Eggan, K. &lt;strong&gt;Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons.&lt;/strong&gt; Science 321: 1218-1221, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18669821/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18669821&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1158799&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18669821">Dimos et al. (2008)</a> generated induced pluripotent stem (iPS) cells from skin fibroblasts collected from an 82-year-old woman diagnosed with a familial form of ALS caused by a mutation in the SOD1 gene (L144F; <a href="/entry/147450#0017">147450.0017</a>). These patient-specific iPS cells possessed properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18669821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#127" class="mim-tip-reference" title="Williams, A. H. Valdez, G., Moresi, V., Qi, X., McAnally, J., Elliott, J. L., Bassel-Duby, R., Sanes, J. R., Olson, E. N. &lt;strong&gt;MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.&lt;/strong&gt; Science 326: 1549-1554, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20007902/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20007902&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20007902[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1181046&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20007902">Williams et al. (2009)</a> showed that a key regulator of signaling between motor neurons and skeletal muscle fibers is miR206 (<a href="/entry/611599">611599</a>), a skeletal muscle-specific microRNA that is dramatically induced in the mouse model of ALS. Mice that are genetically deficient in miR206 form normal neuromuscular synapses during development, but deficiency of miR206 in the ALS mouse model accelerates disease progression. miR206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, which probably accounts for its salutary effects in ALS. miR206 mediates these effects at least in part through histone deacetylase 4 (<a href="/entry/605314">605314</a>) and fibroblast growth factor (see <a href="/entry/131220">131220</a>) signaling pathways. Thus, <a href="#127" class="mim-tip-reference" title="Williams, A. H. Valdez, G., Moresi, V., Qi, X., McAnally, J., Elliott, J. L., Bassel-Duby, R., Sanes, J. R., Olson, E. N. &lt;strong&gt;MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.&lt;/strong&gt; Science 326: 1549-1554, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20007902/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20007902&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20007902[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1181046&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20007902">Williams et al. (2009)</a> concluded that miR206 slows ALS progression by sensing motor neuron injury and promoting the compensatory regeneration of neuromuscular synapses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20007902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Based on their demonstration that the costimulatory pathway is activated in multiple tissues in the Sod1(G93A) preclinical model of ALS as well as in the blood of a subset of individuals with ALS, <a href="#68" class="mim-tip-reference" title="Lincecum, J. M., Vieira, F. G., Wang, M. Z., Thompson, K., De Zutter, G. S., Kidd, J., Moreno, A., Sanchez, R., Carrion, I. J., Levine, B. A., Al-Nakhala, B. M., Sullivan, S. M., Gill, A., Perrin, S. &lt;strong&gt;From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis.&lt;/strong&gt; Nature Genet. 42: 392-399, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20348957/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20348957&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.557&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20348957">Lincecum et al. (2010)</a> developed a therapy using a monoclonal antibody to CD40L (<a href="/entry/300386">300386</a>). Weight loss was slowed, paralysis delayed, and survival extended in an ALS mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20348957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Corti, S., Nizzardo, M., Nardini, M., Donadoni, C., Salani, S., Simone, C., Falcone, M., Riboldi, G., Govoni, A., Bresolin, N., Comi, G. P. &lt;strong&gt;Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis.&lt;/strong&gt; Hum. Molec. Genet. 19: 3782-3796, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20650960/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20650960&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq293&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20650960">Corti et al. (2010)</a> investigated a cell therapy using intravascular injection to transplant a specific population of c-kit+ (<a href="/entry/164920">164920</a>) stem/progenitor cells from bone marrow into the SOD1G93A mouse model of ALS. Transplanted cells engrafted within the host spinal cord. Cell transplantation significantly prolonged disease duration and lifespan in SOD1G93A mice, promoted the survival of motor neurons, and improved neuromuscular function. Neuroprotection was mediated by multiple effects, in particular by the expression of primary astrocyte glutamate transporter GLT1 (SLC1A2; <a href="/entry/600300">600300</a>) and by the nonmutant genome. The authors suggested that somatic cell transplantation may be an effective therapy for ALS and other neurodegenerative diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20650960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Gimenez-Roldan1977" class="mim-tip-reference" title="Gimenez-Roldan, S., Esteban, A. &lt;strong&gt;Prognosis in hereditary amyotrophic lateral sclerosis.&lt;/strong&gt; Arch. Neurol. 34: 706-708, 1977.">Gimenez-Roldan and Esteban (1977)</a>; <a href="#Haberlandt1961" class="mim-tip-reference" title="Haberlandt, W. F. &lt;strong&gt;Aspects genetiques de la sclerose laterale amyotrophique.&lt;/strong&gt; World Neurol. 2: 356-365, 1961.">Haberlandt (1961)</a>; <a href="#Phillips1978" class="mim-tip-reference" title="Phillips, J., Pyeritz, R., Brooks, B., Rosenthal, G., Weintraub, A., Weinblatt, J. &lt;strong&gt;Familial amyotrophic lateral sclerosis: an evaluation of genetic counseling. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 30: 63A, 1978.">Phillips et al.
(1978)</a>; <a href="#Swerts1976" class="mim-tip-reference" title="Swerts, L., Van den Bergh, R. &lt;strong&gt;Sclerose laterale amyotrophique familiale: etude d&#x27;une famille atteinte sur trois generations. [Familial amyotrophic lateral sclerosis: a study of a family suffering from this disease for three generations].&lt;/strong&gt; J. Genet. Hum. 24: 247-255, 1976.">Swerts and Van den Bergh (1976)</a>; <a href="#Takahashi1972" class="mim-tip-reference" title="Takahashi, K., Nakamura, H., Okada, E. &lt;strong&gt;Hereditary amyotrophic lateral sclerosis: histochemical and electron microscopic study of hyaline inclusions in motor neurons.&lt;/strong&gt; Arch. Neurol. 27: 292-299, 1972.">Takahashi et al. (1972)</a>
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<a id="references"class="mim-anchor"></a>
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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</h4>
<div>
<p />
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="Al-Chalabi1998" class="mim-anchor"></a>
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<p class="mim-text-font">
Al-Chalabi, A., Andersen, P. M., Chioza, B., Shaw, C., Sham, P. C., Robberecht, W., Matthijs, G., Camu, W., Marklund, S. L., Forsgren, L., Rouleau, G., Laing, N. G., Hurse, P. V., Siddique, T., Leigh, P. N., Powell, J. F.
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[<a href="https://doi.org/10.1093/hmg/7.13.2045" target="_blank">Full Text</a>]
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<a id="Alberca1981" class="mim-anchor"></a>
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Alberca, R., Castilla, J. M., Gil-Peralta, A.
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[<a href="https://doi.org/10.1016/0022-510x(81)90166-0" target="_blank">Full Text</a>]
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Albom, M.
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Alter, M., Schaumann, B.
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[<a href="https://doi.org/10.1159/000114747" target="_blank">Full Text</a>]
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Amick, L. D., Nelson, J. W., Zellweger, H.
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[<a href="https://doi.org/10.1111/j.1600-0404.1971.tb07488.x" target="_blank">Full Text</a>]
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Andersen, P. M., Nilsson, P., Ala-Hurula, V., Keranen, M.-L., Tarvainen, I., Haltia, T., Nilsson, L., Binzer, M., Forsgren, L., Marklund, S. L.
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[<a href="https://doi.org/10.1038/ng0595-61" target="_blank">Full Text</a>]
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Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D.
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[<a href="https://doi.org/10.1038/ng.2434" target="_blank">Full Text</a>]
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Askanas, V., Wojcik, S., Engel, W. K.
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[<a href="https://doi.org/10.1002/ana.21245" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0812297106" target="_blank">Full Text</a>]
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Azzouz, M., Ralph, G. S., Storkebaum, E., Walmsley, L. E., Mitrophanous, K. A., Kingsman, S. M., Carmeliet, P., Mazarakis, N. D.
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[<a href="https://doi.org/10.1038/nature02544" target="_blank">Full Text</a>]
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Blacher, E., Bashiardes, S., Shapiro, H., Rothschild, D., Mor, U., Dori-Bachash, M., Kleimeyer, C., Moresi, C., Harnik, Y., Zur, M., Zabari, M., Brik, R. B.-Z., and 21 others.
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[<a href="https://doi.org/10.1038/s41586-019-1443-5" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Blauw, H. M., Barnes, C. P., van Vught, P. W. J., van Rheenen, W., Verheul, M., Cuppen, E., Veldink, J. H., van den Berg, L. H.
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[<a href="https://doi.org/10.1212/WNL.0b013e318249f697" target="_blank">Full Text</a>]
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Boillee, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., Cleveland, D. W.
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[<a href="https://doi.org/10.1126/science.1123511" target="_blank">Full Text</a>]
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Bordet, T., Lesbordes, J.-C., Rouhani, S., Castelnau-Ptakhine, L., Schmalbruch, H., Haase, G., Kahn, A.
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[<a href="https://doi.org/10.1093/hmg/10.18.1925" target="_blank">Full Text</a>]
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Boulis, N. M., Willmarth, N. E., Song, D. K., Feldman, E. L., Imperiale, M. J.
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[<a href="https://doi.org/10.1227/01.neu.0000044459.24519.3e" target="_blank">Full Text</a>]
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<a id="Bradley2005" class="mim-anchor"></a>
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Bradley, M., Bradley, L., de Belleroche, J., Orrell, R. W.
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[<a href="https://doi.org/10.1212/01.WNL.0000160395.43761.AC" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Bradley, W. G., Krasin, F.
<strong>A new hypothesis of the etiology of amyotrophic lateral sclerosis: the DNA hypothesis.</strong>
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[<a href="https://doi.org/10.1001/archneur.1982.00510230003001" target="_blank">Full Text</a>]
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<a id="Broom2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Broom, W. J., Parton, M. J., Vance, C. A., Russ, C., Andersen, P. M., Hansen, V., Leigh, P. N., Powell, J. F., Al-Chalabi, A., Shaw, C. E.
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[<a href="https://doi.org/10.1212/01.wnl.0000147264.60349.eb" target="_blank">Full Text</a>]
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<a id="Brown1951" class="mim-anchor"></a>
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<p class="mim-text-font">
Brown, M. R.
<strong>'Wetherbee ail': the inheritance of progressive muscular atrophy as a dominant trait in two New England families.</strong>
New Eng. J. Med. 245: 645-647, 1951.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14875225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14875225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14875225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM195110252451704" target="_blank">Full Text</a>]
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<a id="Brown1960" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Brown, M. R.
<strong>The inheritance of progressive muscular atrophy as a dominant trait in two New England families.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13804989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13804989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13804989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM196006232622508" target="_blank">Full Text</a>]
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<a id="Chio2008" class="mim-anchor"></a>
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Chio, A., Traynor, B. J., Lombardo, F., Fimognari, M., Calvo, A., Ghiglione, P., Mutani, R., Restagno, G.
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[<a href="https://doi.org/10.1002/ana.21122" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp498" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s100480050031" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn375" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1972.00490160020003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn422" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh246" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(69)90044-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.93.7.3155" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0606201104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000174472.03292.dd" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0022-510x(90)90101-r" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1181046" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181a18674" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0896-6273(95)90259-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq106" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 03/16/2020<br>George E. Tiller - updated : 09/13/2017<br>George E. Tiller - updated : 06/22/2017<br>George E. Tiller - updated : 8/20/2013<br>Cassandra L. Kniffin - updated : 2/27/2013<br>Ada Hamosh - updated : 2/1/2013<br>Cassandra L. Kniffin - updated : 10/1/2012<br>Cassandra L. Kniffin - updated : 5/5/2011<br>Cassandra L. Kniffin - updated : 1/28/2011<br>George E. Tiller - updated : 12/29/2010<br>Ada Hamosh - updated : 10/19/2010<br>Cassandra L. Kniffin - updated : 9/27/2010<br>George E. Tiller - updated : 8/6/2010<br>Ada Hamosh - updated : 6/18/2010<br>Cassandra L. Kniffin - updated : 6/14/2010<br>Ada Hamosh - updated : 6/2/2010<br>Ada Hamosh - updated : 1/19/2010<br>Cassandra L. Kniffin - updated : 12/29/2009<br>Cassandra L. Kniffin - updated : 12/15/2009<br>George E. Tiller - updated : 8/14/2009<br>George E. Tiller - updated : 8/12/2009<br>Cassandra L. Kniffin - updated : 6/22/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Ada Hamosh - updated : 9/24/2008<br>Cassandra L. Kniffin - updated : 8/13/2008<br>Victor A. McKusick - updated : 5/28/2008<br>Ada Hamosh - updated : 5/8/2008<br>Cassandra L. Kniffin - updated : 3/14/2008<br>Patricia A. Hartz - updated : 3/3/2008<br>Cassandra L. Kniffin - updated : 1/7/2008<br>Cassandra L. Kniffin - updated : 9/17/2007<br>Cassandra L. Kniffin - updated : 8/28/2007<br>Cassandra L. Kniffin - updated : 4/12/2007<br>George E. Tiller - updated : 4/5/2007<br>Cassandra L. Kniffin - updated : 3/29/2007<br>Ada Hamosh - updated : 10/25/2006<br>Ada Hamosh - updated : 7/24/2006<br>Cassandra L. Kniffin - reorganized : 6/20/2006<br>Cassandra L. Kniffin - updated : 6/14/2006<br>Cassandra L. Kniffin - updated : 5/25/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 4/20/2006<br>Cassandra L. Kniffin - updated : 11/2/2005<br>Cassandra L. Kniffin - updated : 8/19/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Cassandra L. Kniffin - updated : 3/4/2005<br>Cassandra L. Kniffin - updated : 2/14/2005<br>Victor A. McKusick - updated : 12/14/2004<br>Cassandra L. Kniffin - updated : 12/14/2004<br>Ada Hamosh - updated : 6/11/2004<br>Victor A. McKusick - updated : 4/29/2004<br>Ada Hamosh - updated : 3/8/2004<br>Ada Hamosh - updated : 9/17/2003<br>Cassandra L. Kniffin - updated : 6/9/2003<br>Cassandra L. Kniffin - updated : 2/19/2003<br>Dawn Watkins-Chow - updated : 11/22/2002<br>Dawn Watkins-Chow - updated : 11/5/2002<br>Victor A. McKusick - updated : 10/1/2002<br>Cassandra L. Kniffin - updated : 7/23/2002<br>George E. Tiller - updated : 1/30/2002<br>Victor A. McKusick - updated : 6/25/2001<br>Ada Hamosh - updated : 4/13/2000<br>Victor A. McKusick - updated : 3/9/1999<br>Orest Hurko - updated : 1/21/1999<br>Victor A. McKusick - updated : 10/2/1998<br>Victor A. McKusick - updated : 5/6/1998<br>Orest Hurko - updated : 5/8/1996
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Creation Date:
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Victor A. McKusick : 6/16/1986
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 09/16/2024
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carol : 09/13/2024<br>alopez : 08/02/2023<br>ckniffin : 07/28/2023<br>alopez : 05/04/2022<br>carol : 11/08/2021<br>carol : 11/05/2021<br>carol : 01/07/2021<br>carol : 01/06/2021<br>ckniffin : 12/30/2020<br>alopez : 03/16/2020<br>carol : 04/02/2018<br>carol : 03/30/2018<br>alopez : 03/29/2018<br>ckniffin : 03/26/2018<br>alopez : 02/28/2018<br>carol : 01/29/2018<br>ckniffin : 01/23/2018<br>alopez : 09/13/2017<br>alopez : 06/22/2017<br>carol : 08/02/2016<br>carol : 07/18/2016<br>carol : 7/18/2016<br>carol : 7/15/2016<br>carol : 7/8/2016<br>alopez : 10/2/2015<br>ckniffin : 9/29/2015<br>alopez : 1/30/2015<br>carol : 8/20/2014<br>mcolton : 8/20/2014<br>ckniffin : 8/20/2014<br>ckniffin : 4/14/2014<br>carol : 11/6/2013<br>ckniffin : 11/6/2013<br>carol : 11/5/2013<br>carol : 10/1/2013<br>alopez : 9/24/2013<br>carol : 9/17/2013<br>tpirozzi : 9/10/2013<br>tpirozzi : 9/10/2013<br>tpirozzi : 8/28/2013<br>tpirozzi : 8/28/2013<br>tpirozzi : 8/27/2013<br>tpirozzi : 8/21/2013<br>tpirozzi : 8/21/2013<br>tpirozzi : 8/20/2013<br>terry : 4/4/2013<br>carol : 3/7/2013<br>ckniffin : 2/27/2013<br>alopez : 2/7/2013<br>terry : 2/1/2013<br>carol : 10/16/2012<br>carol : 10/8/2012<br>ckniffin : 10/1/2012<br>terry : 9/14/2012<br>carol : 9/6/2012<br>alopez : 9/6/2012<br>carol : 7/10/2012<br>ckniffin : 7/2/2012<br>terry : 6/6/2012<br>carol : 12/8/2011<br>ckniffin : 12/8/2011<br>carol : 10/4/2011<br>alopez : 9/23/2011<br>terry : 6/3/2011<br>wwang : 5/18/2011<br>ckniffin : 5/5/2011<br>wwang : 2/18/2011<br>ckniffin : 1/28/2011<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>alopez : 10/19/2010<br>wwang : 9/29/2010<br>ckniffin : 9/27/2010<br>alopez : 9/21/2010<br>terry : 9/14/2010<br>wwang : 8/12/2010<br>terry : 8/6/2010<br>alopez : 6/21/2010<br>terry : 6/18/2010<br>terry : 6/18/2010<br>wwang : 6/18/2010<br>ckniffin : 6/14/2010<br>alopez : 6/8/2010<br>terry : 6/2/2010<br>alopez : 1/19/2010<br>wwang : 1/13/2010<br>ckniffin : 12/29/2009<br>ckniffin : 12/29/2009<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 9/1/2009<br>ckniffin : 9/1/2009<br>wwang : 8/31/2009<br>wwang : 8/25/2009<br>terry : 8/12/2009<br>wwang : 7/21/2009<br>ckniffin : 6/22/2009<br>wwang : 3/3/2009<br>wwang : 1/16/2009<br>ckniffin : 1/14/2009<br>wwang : 10/6/2008<br>alopez : 9/24/2008<br>terry : 9/24/2008<br>wwang : 8/19/2008<br>ckniffin : 8/13/2008<br>alopez : 5/29/2008<br>terry : 5/28/2008<br>alopez : 5/21/2008<br>alopez : 5/21/2008<br>terry : 5/8/2008<br>wwang : 4/1/2008<br>ckniffin : 3/14/2008<br>mgross : 3/3/2008<br>wwang : 1/18/2008<br>ckniffin : 1/7/2008<br>alopez : 1/3/2008<br>ckniffin : 11/13/2007<br>wwang : 9/24/2007<br>ckniffin : 9/17/2007<br>wwang : 9/4/2007<br>ckniffin : 8/28/2007<br>wwang : 4/19/2007<br>ckniffin : 4/12/2007<br>alopez : 4/11/2007<br>terry : 4/5/2007<br>wwang : 3/30/2007<br>ckniffin : 3/29/2007<br>alopez : 11/2/2006<br>terry : 10/25/2006<br>alopez : 7/28/2006<br>terry : 7/24/2006<br>carol : 7/19/2006<br>ckniffin : 7/17/2006<br>ckniffin : 6/26/2006<br>terry : 6/21/2006<br>carol : 6/20/2006<br>ckniffin : 6/14/2006<br>wwang : 6/2/2006<br>ckniffin : 5/25/2006<br>joanna : 5/2/2006<br>alopez : 5/2/2006<br>terry : 4/27/2006<br>wwang : 4/25/2006<br>ckniffin : 4/20/2006<br>ckniffin : 3/13/2006<br>wwang : 11/11/2005<br>ckniffin : 11/2/2005<br>alopez : 10/20/2005<br>terry : 10/12/2005<br>terry : 9/12/2005<br>wwang : 8/26/2005<br>ckniffin : 8/19/2005<br>wwang : 6/15/2005<br>ckniffin : 6/9/2005<br>wwang : 3/16/2005<br>ckniffin : 3/4/2005<br>ckniffin : 3/4/2005<br>wwang : 2/23/2005<br>ckniffin : 2/14/2005<br>carol : 12/22/2004<br>ckniffin : 12/14/2004<br>ckniffin : 12/14/2004<br>ckniffin : 12/14/2004<br>alopez : 10/25/2004<br>alopez : 6/15/2004<br>terry : 6/11/2004<br>tkritzer : 4/30/2004<br>terry : 4/29/2004<br>tkritzer : 3/9/2004<br>terry : 3/8/2004<br>alopez : 9/17/2003<br>mgross : 8/12/2003<br>carol : 6/12/2003<br>ckniffin : 6/9/2003<br>carol : 2/24/2003<br>ckniffin : 2/19/2003<br>mgross : 11/22/2002<br>carol : 11/7/2002<br>tkritzer : 11/7/2002<br>carol : 11/7/2002<br>tkritzer : 11/5/2002<br>tkritzer : 11/5/2002<br>tkritzer : 10/2/2002<br>tkritzer : 10/1/2002<br>tkritzer : 10/1/2002<br>carol : 8/9/2002<br>tkritzer : 8/9/2002<br>ckniffin : 7/23/2002<br>cwells : 2/6/2002<br>cwells : 1/30/2002<br>terry : 6/25/2001<br>alopez : 4/13/2000<br>terry : 4/13/2000<br>terry : 4/30/1999<br>carol : 3/23/1999<br>terry : 3/9/1999<br>carol : 3/7/1999<br>carol : 1/21/1999<br>dkim : 11/6/1998<br>carol : 10/7/1998<br>terry : 10/2/1998<br>carol : 5/11/1998<br>terry : 5/6/1998<br>alopez : 5/5/1998<br>joanna : 12/15/1997<br>jenny : 11/5/1997<br>mark : 5/14/1997<br>mark : 3/12/1997<br>mark : 1/29/1997<br>jenny : 12/23/1996<br>terry : 12/18/1996<br>terry : 12/18/1996<br>terry : 5/10/1996<br>mark : 5/8/1996<br>terry : 5/3/1996<br>mark : 2/22/1996<br>mark : 1/31/1996<br>terry : 1/26/1996<br>mark : 3/29/1995<br>davew : 8/16/1994<br>carol : 6/8/1994<br>warfield : 4/21/1994<br>mimadm : 4/14/1994<br>pfoster : 3/25/1994
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<strong>#</strong> 105400
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AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
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<em>Alternative titles; symbols</em>
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AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL; FALS<br />
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL DOMINANT
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<span class="mim-font">
Other entities represented in this entry:
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<span class="h3 mim-font">
AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL RECESSIVE, INCLUDED
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<span class="h4 mim-font">
AMYOTROPHIC LATERAL SCLEROSIS, SPORADIC, INCLUDED
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<strong>SNOMEDCT:</strong> 1201863001; &nbsp;
<strong>ORPHA:</strong> 803; &nbsp;
<strong>DO:</strong> 0060193; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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<th>
Location
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Phenotype
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<th>
Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
2p13.1
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{Amyotrophic lateral sclerosis, susceptibility to}
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105400
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Autosomal dominant; Autosomal recessive
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3
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DCTN1
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601143
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12q13.12
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<span class="mim-font">
{Amyotrophic lateral sclerosis, susceptibility to}
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<span class="mim-font">
105400
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<span class="mim-font">
Autosomal dominant; Autosomal recessive
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3
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PRPH
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170710
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21q22.11
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<span class="mim-font">
Amyotrophic lateral sclerosis 1
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<span class="mim-font">
105400
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Autosomal dominant; Autosomal recessive
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3
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SOD1
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147450
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22q12.2
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<td>
<span class="mim-font">
{?Amyotrophic lateral sclerosis, susceptibility to}
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<span class="mim-font">
105400
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<span class="mim-font">
Autosomal dominant; Autosomal recessive
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3
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NEFH
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<span class="mim-font">
162230
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because 15 to 20% of cases of familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1, are associated with mutations in the superoxide dismutase-1 gene (SOD1; 147450) on chromosome 21q22. Although most cases of SOD1-related familial ALS follow autosomal dominant inheritance, rare cases of autosomal recessive inheritance have been reported.</p>
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<strong>Description</strong>
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<p>Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. </p><p>Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. </p><p>Some forms of ALS occur with frontotemporal dementia (FTD); see 105500. Ranganathan et al. (2020) provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration. </p><p>Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture. </p><p><strong><em>Genetic Heterogeneity of Amyotrophic Lateral Sclerosis</em></strong></p><p>
ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci.</p><p>ALS6 (608030) is caused by mutation in the FUS gene (137070) on chromosome 16p11; ALS8 (608627) is caused by mutation in the VAPB gene (605704) on chromosome 13; ALS9 (611895) is caused by mutation in the ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by mutation in the TARDBP gene (605078) on 1p36; ALS11 (612577) is caused by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435) is caused by mutation in the OPTN gene (602432) on chromosome 10p13; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11; ALS18 (614808) is caused by mutation in the PFN1 gene (176610) on chromosome 17p13; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13; ALS21 (606070) is caused by mutation in the MATR3 gene (164015) on chromosome 5q31; ALS22 (616208) is caused by mutation in the TUBA4A gene (191110) on chromosome 2q35; ALS23 (617839) is caused by mutation in the ANXA11 gene (602572) on chromosome 10q23; ALS26 (619133) is caused by mutation in the TIA1 gene (603518) on chromosome 2p13; ALS27 (620285) is caused by mutation in the SPTLC1 gene (605712) on chromosome 9q22; and ALS28 (620452) is caused by mutation in the LRP12 gene (618299) on chromosome 8q22.</p><p>Loci associated with ALS have been found on chromosomes 18q21 (ALS3; 606640) and 20p13 (ALS7; 608031).</p><p>Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (601517) contribute to susceptibility to ALS (ALS13; 183090). Susceptibility to ALS24 (617892) is conferred by mutation in the NEK1 gene (604588) on chromosome 4q33, and susceptibility to ALS25 (617921) is conferred by mutation in the KIF5A gene (602821) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; 162230); deletions in the gene encoding peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1; 601143).</p><p>Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100), caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433), caused by mutation in the senataxin gene (SETX; 608465) on 9q34; ALS5 (602099), caused by mutation in the SPG11 gene (610844) on 15q21; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13.</p>
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<strong>Clinical Features</strong>
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</h4>
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<span class="mim-text-font">
<p>Horton et al. (1976) suggested that there are 3 phenotypic forms of familial ALS, each inherited as an autosomal dominant disorder. The first form they delineated is characterized by rapidly progressive loss of motor function with predominantly lower motor neuron manifestations and a course of less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second form is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke column, and spinocerebellar tracts. The third form is similar to the second except for a much longer survival, usually beyond 10 and often 20 years. Examples of type 1 include the families of Green (1960), Poser et al. (1965) and Thomson and Alvarez (1969). Examples of type 2 include the families of Kurland and Mulder (1955) and Engel et al. (1959). Engel et al. (1959) described 2 American families, 1 of which was of Pennsylvania Dutch stock with at least 11 members of 4 generations affected with what was locally and popularly termed 'Pecks disease.' Examples of type 3 include the families of Amick et al. (1971) and Alberca et al. (1981). In the Spanish kindred reported by Alberca et al. (1981), early onset and persistence of muscle cramps, unilateral proximal segmental myoclonus, and early abolition of ankle jerks were conspicuous clinical features. </p><p>Brown (1951, 1960) described 2 New England families, Wetherbee and Farr by name, with autosomal dominant inheritance of a rapidly progressive neurodegenerative disorder with loss of anterior horn cells of the spinal cord and bulbar palsy. (See also Hammond, 1888 and Myrianthopoulos and Brown, 1954). Neuropathology showed a classic 'middle-root zone' pattern of posterior column demyelination in addition to involvement of the anteriolateral columns and ventral horn cells. Although the disorder was clinically indistinguishable from ALS, the pattern of posterior column demyelinations was unexpected. Osler (1880) had described the Farr family earlier (McKusick, 1976). Variability in disease severity in the Farr family was indicated by the case of a 78-year-old woman with relatively minor findings who had buried a son and whose mother had been affected (Siddique, 1993). </p><p>Powers et al. (1974) reported the first autopsy in a member of the Wetherbee family from Vermont. The patient was a 35-year-old woman who began to experience weakness in the left leg 1 year before her terminal admission. She then gradually developed weakness and atrophy of the left hand, right lower limb, and right hand. One month before admission she developed dyspnea which steadily worsened, and she was admitted to hospital because of severe ventilatory insufficiency secondary to muscle weakness. She showed atrophy of all extremities, areflexia, and, except for slight movement of the left shoulder and right foot, quadriplegia. The patient died on the second hospital day. Autopsy showed severe demyelination type of atrophy of all muscles. Gray atrophy of the lumbar and cervical anterior roots was evident grossly. Microscopic neuronal changes included a moderate loss of neurons from the hypoglossal nuclei and dorsal motor vagal nuclei, severe neuronal loss from the anterior horns of the cervical and lumbar cord with reactive gliosis, eosinophilic intracytoplasmic inclusions in many of the remaining lumbar anterior horn cells, and a moderately symmetric loss of neurons from the Clarke column. A severe asymmetric loss of axons and myelin was demonstrated throughout the cervical dorsal spinocerebellar tracts and lumbar posterior columns, with moderate loss in the lumbar lateral corticospinal tracts. Powers et al. (1974) concluded that the disorder corresponded exactly to a subgroup of familial ALS described by Hirano et al. (1967). Engel (1976) concluded that the 'Wetherbee ail' and the Farr family disease were consistent with ALS (Engel et al., 1959). </p><p>Alter and Schaumann (1976) reported 14 cases in 2 families and attempted a refinement of the classification of hereditary ALS. Hudson (1981) stated that posterior column disease is found in association with ALS in 80% of familial cases. </p><p>In a kindred with an apparently 'new' microcephaly-cataract syndrome (212540), reported by Scott-Emuakpor et al. (1977), 10 persons had died of a seemingly unrelated genetic defect--amyotrophic lateral sclerosis. </p><p>Veltema et al. (1990) described adult ALS in 18 individuals from 6 generations of a Dutch family. Onset occurred between ages 19 and 46; duration of disease averaged 1.7 years. The clinical symptoms were predominantly those of initial shoulder girdle and ultimate partial bulbar muscle involvement. </p><p>Iwasaki et al. (1991) reported a Japanese family in which members in at least 3 generations had ALS. At least 2 individuals in the family also had Ribbing disease (601477), a skeletal dysplasia that was presumably unrelated to the ALS. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Familial ALS caused by mutations in the SOD1 gene usually causes autosomal dominant disease, but can also cause autosomal recessive ALS.</p><p>In Germany, Haberlandt (1963) concluded that ALS is an 'irregular' autosomal dominant disorder in many instances. Gardner and Feldmahn (1966) described adult-onset ALS in a family in which 15 members spanning 7 generations were affected.</p><p>Husquinet and Franck (1980) reported a family with ALS suggesting autosomal dominant inheritance with incomplete penetrance. Twelve men and 6 women were affected; 4 unaffected members of the family transmitted the disease. The first signs of the disease, which ran its course in 5 to 6 years, were in either the arms or the legs. As in most cases of ALS, death was caused by bulbar paralysis. Mean age at death was about 57 years. </p><p>In a review of a familial ALS, de Belleroche et al. (1995) found autosomal dominant inheritance with incomplete penetrance; by age 85 years, about 80% of carriers had manifested the disorder, and it was not uncommon to see obligate carriers in a family who died without manifesting the disease. Phenotypic heterogeneity was also common within families: for example, age of onset varying over 30 years within a family and duration of illness varying from 6 months to 5 years. Signs at onset were variable, but the disease usually began with focal and asymmetric wasting of hand muscles. Lower motor neuron involvement was usually conspicuous, whereas involvement of upper motor neurons was less marked. </p><p>Bradley et al. (2005) found no evidence for preferential maternal or paternal transmission among 185 families in which at least 2 individuals were diagnosed with ALS. Initial evidence suggesting anticipation was rejected following further analysis. </p><p>By analysis of a Swedish multigeneration registry spanning from 1961 to 2005, Fang et al. (2009) identified 6,671 probands with ALS. There was a 17-fold increased risk for development of ALS among sibs, and a 9-fold increased risk among children of probands. Sibs and children had a greater risk if the proband was diagnosed at a younger age, and the risk decreased with increasing age at diagnosis of the proband. Two cases were identified among the cotwins of ALS probands, yielding a relative risk of 32 for monozygotic twins. Spouses of probands had no significantly increased risk compared to controls. The findings indicated that there is a major genetic role in the development of ALS. </p><p><strong><em>Possible X-linked Inheritance</em></strong></p><p>
In a family with ALS reported by Wilkins et al. (1977), X-linked dominant inheritance was suggested by the late onset in females and the lack of male-to-male transmission.</p><p>Siddique et al. (1987) did linkage studies in a family with 13 affected persons in 4 generations. There was no instance of male-to-male transmission. Kunst (2004) referenced an X-linked dominant, late-onset form linked to Xp11-q12 but reported only in abstract (Siddique et al., 1998). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Siddique et al. (1989) presented preliminary data from genetic linkage analysis in 150 families with familial ALS. Two regions of possible linkage were identified on chromosomes 11 and 21. The highest lod score observed was 1.46, obtained with D21S13 at theta = 0.20. The next highest lod score was observed with marker D11S21 (lod score = 1.05 at maximum theta of 0.001).</p><p>Siddique et al. (1991) presented evidence for linkage of familial ALS, termed ALS1, to markers on chromosome 21q22.1-q22.2 (maximum lod score of 5.03 10 cM telomeric to marker D21S58). Tests for heterogeneity in these families yielded a probability of less than 0.0001 that of genetic-locus heterogeneity, i.e., a low probability of homogeneity. </p><p><strong><em>Genetic Heterogeneity</em></strong></p><p>
King et al. (1993) failed to find linkage to loci on chromosome 21 in 8 U.K. families with ALS, indicating genetic heterogeneity. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
In a genomewide association study (GWAS) of 1,014 deceased patients with sporadic ALS and 2,258 controls from the U.S. and Europe, Landers et al. (2009) found a significant association between rs1541160 in intron 8 of the KIFAP3 gene (601836) on chromosome 1q24 and survival (p = 1.84 x 10(-8), p = 0.021 after Bonferroni correction). Homozygosity for the favorable allele, CC, conferred a 14-month survival advantage compared to TT. There was linkage disequilibrium between rs1541160 and rs522444 within the KIFAP3 promoter, and the favorable alleles of both SNPs correlated with decreased KIFAP3 expression in brain. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. The findings suggested that genetic factors may modify phenotypes in ALS. </p><p>Van Es et al. (2009) conducted a genomewide association study among 2,323 individuals with sporadic ALS and 9,013 control subjects and evaluated all SNPs with P less than 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genomewide data revealed genomewide significance for 1 SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort, and a combined analysis over the 2 stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A (609894), which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
Wills et al. (2009) conducted a metaanalysis of 10 published studies, including 4 GWAS, and 1 unpublished study that had reported findings on association of sporadic ALS and paraoxonase (see PON1; 168820) SNPs on chromosome 7q21.3. The metaanalysis found no association between sporadic ALS and the PON locus and encompassed 4,037 ALS patients and 4,609 controls, including GWAS data from 2,018 ALS cases and 2,425 controls. The authors stated that this was the largest metaanalysis of a candidate gene in ALS to date and the first ALS metaanalysis to include data from GWAS. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bradley and Krasin (1982) suggested that a defect in DNA repair may underlie ALS. </p><p>Rothstein et al. (1992) found in in vitro studies that synaptosomes in neural tissue obtained from 13 ALS patients showed a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in spinal cord, motor cortex, and somatosensory cortex compared to controls. The decrease in glutamate uptake was not observed in tissue from visual cortex, striatum, or hippocampus. Neural tissue from patients with other neurodegenerative disorders did not show this defect. In ALS tissue, there was no defect in affinity of the transporter for glutamate and no decrease in the transport of other molecules (gamma-aminobutyric acid and phenylalanine). Rothstein et al. (1992) suggested that defects in a high-affinity glutamate transporter (see, e.g., SLC1A1, 133550) could lead to neurotoxic levels of extracellular glutamate, contributing to neurodegeneration in ALS. </p><p>Liu et al. (1998) demonstrated increased free radical production in the spinal cord but not the brain of transgenic mice expressing mutant human SOD1 (G93A; 147450.0008), which preceded the degeneration of motor neurons. They hypothesized that in situ production of free radicals initiates oxidative injury and that antioxidants that penetrate into the central nervous system may be of therapeutic benefit. </p><p>Li et al. (2000) demonstrated an 81.5% elevation of caspase-1 (CASP1; 147678) activity in the spinal cord of humans with ALS when compared with normal controls, and, using an animal model, suggested that caspases play an instrumental role in the neurodegenerative processing of ALS. Caspase inhibition using zVAD-fmk delayed disease onset and mortality in the mouse model of ALS. Moreover, zVAD-fmk was found to inhibit caspase-1 activity as well as caspase-1 and caspase-3 (600636) mRNA upregulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. The findings also showed that zVAD-fmk decreased IL1-beta (147720), an indication that caspase-1 activity was inhibited. </p><p>Okado-Matsumoto and Fridovich (2002) proposed a mechanism by which missense mutations in SOD1 lead to ALS. They suggested that the binding of mutant SOD1 to heat-shock proteins leads to formation of sedimentable aggregates, making the heat shock proteins unavailable for their antiapoptotic functions and leading ultimately to motor neuron death. </p><p>Kawahara et al. (2004) extracted RNA from single motor neurons isolated with a laser microdissector from 5 individuals with sporadic ALS and 5 normal control subjects. GluR2 (GRIA2; 138247) RNA editing was 100% efficient in the control samples, but the editing efficiency varied between 0 and 100% in the motor neurons from each individual with ALS and was incomplete in 44 (56%) of them. Mice transgenic for GluR2 made artificially permeable to calcium ions developed motor neuron disease late in life (Feldmeyer et al., 1999), indicating that motor neurons may be specifically vulnerable to defective RNA editing. Kawahara et al. (2004) suggested that defective GluR2 RNA editing at the Q/R site may be relevant to ALS etiology. </p><p>Shibata et al. (1994) found SOD1-like immunoreactivity within Lewy body-like inclusions in the spinal cords of 10 of 20 patients with sporadic ALS. Skein-like inclusions and Bunina bodies, which were found in all 20 ALS cases, showed no SOD1-like immunoreactivity. </p><p>He and Hays (2004) identified Lewy body-like ubiquitinated (see UBB; 191339) inclusions in motor neurons from 9 of 40 ALS patients; all of the inclusions expressed peripherin. Similar inclusions were not identified in 39 controls. </p><p>Neumann et al. (2006) identified TDP43 (605078) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration (see 607485) and ALS. Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected CNS regions, including hippocampus, neocortex, and spinal cord. Neumann et al. (2006) concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders. </p><p>In mice, Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage within muscles was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression. </p><p>Pradat et al. (2007) found muscle NOGOA (604475) expression in 17 of 33 patients with spinal lower motor neuron syndrome observed for 12 months. NOGOA expression correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was detected as early as 3 months after symptom onset in patients who later developed typical ALS. Pradat et al. (2007) suggested that muscle NOGOA may be a prognostic marker for ALS in lower motor neuron syndromes. Tagerud et al. (2007) and Askanas et al. (2007) both commented that studies have demonstrated that NOGOA expression is increased in denervated muscles in mouse models and in other human neuropathies and myopathies. Both groups suggested that it may be premature to consider NOGOA muscle expression as a specific biomarker for ALS, as suggested by Pradat et al. (2007). </p><p>Using a specific antibody to monomer or misfolded forms of SOD1 (Rakhit et al., 2007), Liu et al. (2009) detected monomer/misfolded SOD1 in spinal cord sections of all 5 patients with familial ALS due to mutations in the SOD1 gene. The antibody localized primarily to hyaline conglomerate inclusions in motor neuron perikarya and occasionally to neuritic processes. In contrast, no immunostaining was observed in spinal cord tissue from ALS patients without SOD1 mutations, including 13 with sporadic disease and 1 with non-SOD1 familial ALS. The findings indicated a distinct difference between familial ALS1 and sporadic ALS, and supported the idea that monomer or misfolded SOD1 is not a common disease mechanism. </p><p>Rabin et al. (2010) studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. Whole-genome exon splicing was profiled from RNA pools collected from motor neurons and from the surrounding anterior horns. In the motor neuron-enriched mRNA pool, there were 2 distinct cohorts of mRNA signals, most of which were upregulated: 148 differentially expressed genes and 411 aberrantly spliced genes. The aberrantly spliced genes were highly enriched in cell adhesion, especially cell-matrix as opposed to cell-cell adhesion. Most of the enriching genes encoded transmembrane or secreted as opposed to nuclear or cytoplasmic proteins. The differentially expressed genes were not biologically enriched. In the anterior horn enriched mRNA pool, there were no clearly identified mRNA signals or biologic enrichment. Rabin et al. (2010) suggested possible mechanisms in cell adhesion for the contiguously progressive nature of motor neuron degeneration. </p><p>Using unbiased transcript profiling in the SOD1G93A mouse model of ALS, Lincecum et al. (2010) identified a role for the costimulatory pathway, a key regulator of immune responses. Furthermore, Lincecum et al. (2010) observed that this pathway is upregulated in the blood of 56% of human patients with ALS. </p><p>Kudo et al. (2010) used laser capture microdissection coupled with microarrays to identify early transcriptome changes occurring in spinal cord motor neurons or surrounding glial cells in models of ALS. Two transgenic mouse models of familial motor neuron disease, Sod1G93A and TAUP301L (157140.0001), were used at the presymptomatic stage. Identified gene expression changes were predominantly model-specific. However, several genes were regulated in both models. The relevance of identified genes as clinical biomarkers was tested in the peripheral blood transcriptome of presymptomatic Sod1G93A animals using custom-designed ALS microarray. To confirm the relevance of identified genes in human sporadic ALS (SALS), selected corresponding protein products were examined by high-throughput immunoassays using tissue microarrays constructed from human postmortem spinal cord tissues. Genes that were identified by these experiments and were located within a linkage region associated with familial ALS/frontotemporal dementia were sequenced in several families. This large-scale gene and protein expression study pointing to distinct molecular mechanisms of TAU- and SOD1-induced motor neuron degeneration identified several novel SALS-relevant proteins, including CNGA3 (600053), CRB1 (604210), OTUB2 (608338), MMP14 (600754), SLK (FYN; 137025), DDX58 (609631), RSPO2 (610575) and the putative blood biomarker Mgll (609699). </p><p>Pedrini et al. (2010) showed that the toxicity of mutant SOD1 (147450) relies on its spinal cord mitochondria-specific interaction with BCL2 (151430). Mutant SOD1 induced morphologic changes and compromised mitochondrial membrane integrity leading to the release of cytochrome c only in the presence of BCL2. In cells and in mouse and human spinal cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a conformational change in BCL2 that resulted in the exposure of its BH3 domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain failed to support mutant SOD1-mediated mitochondrial toxicity. </p><p>Ferri et al. (2010) exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and IMS, where Grx1 (GLRX; 600443) is localized, or in the mitochondrial matrix, where Grx2 (GLRX2; 606820) is localized, as a tool for restoring a correct redox environment and preventing aggregation of mutant SOD1 (G93A; 147450.0008). Overexpression of Grx1 increased the solubility of mutant SOD1 in the cytosol but did not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells or in immortalized motoneurons. Conversely, the overexpression of Grx2 increased the solubility of mutant SOD1 in mitochondria, interfered with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserved mitochondrial function and strongly protected neuronal cells from apoptosis. The authors concluded that the toxicity of mutant SOD1 primarily arises from mitochondrial dysfunction, and that rescue of mitochondrial damage may represent a therapeutic strategy. </p><p>Meissner et al. (2010) found that G93A mutant SOD1 activated caspase-1 (CASP1; 147678) and CASP1-mediated secretion of mature IL1-beta (147720) in a dose-dependent manner in microglia and macrophages. In cells in which CASP1 was activated, there was rapid endocytosis of mutant SOD1 into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm dampened the proinflammatory response. Mutant SOD1 induced caspase activation through a gain of amyloid conformation, not through its enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the life span of mutant Sod1 mice and was associated with decreased microgliosis and astrogliosis; however, age at disease onset was not affected. Treatment of mutant mice with an IL1 receptor inhibitor also extended survival and improved motor performance. The findings suggested that IL1-beta contributes to neuroinflammation and disease progression in ALS. </p><p>To determine whether increased SOD1 protects the heart from ischemia Armakola et al. (2012) reported results from 2 genomewide loss-of-function TDP43 (605078) toxicity suppressor screens in yeast. The strongest suppressor of TDP43 toxicity was deletion of DBR1 (607024), which encodes an RNA lariat debranching enzyme. Armakola et al. (2012) showed that, in the absence of DBR1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal cell line or in primary rat neurons was also sufficient to rescue TDP43 toxicity. Armakola et al. (2012) concluded that their findings provided insight into TDP43-mediated cytotoxicity and suggested that decreasing DBR1 activity could be a potential therapeutic approach for ALS. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Autosomal Dominant Mutations</em></strong></p><p>
In affected members of 13 unrelated families with ALS, Rosen et al. (1993) identified 11 different heterozygous mutations in exons 2 and 4 of the SOD1 gene (147450.0001-147450.0011). Deng et al. (1993) identified 3 mutations in exons 1 and 5 of the SOD1 gene in affected members of ALS families. Eight families had the same mutation (A4V; 147450.0012). One of the families with the A4V mutation was the Farr family reported by Brown (1951, 1960). </p><p>Pramatarova et al. (1995) estimated that approximately 10% of ALS cases are inherited as an autosomal dominant and that SOD1 mutations are responsible for at least 13% of familial ALS cases. </p><p>Jones et al. (1993) demonstrated that mutation in the SOD1 gene can also be responsible for sporadic cases of ALS. They found the same mutation (I113T; 147450.0011) in 3 of 56 sporadic cases of ALS drawn from a population-based study in Scotland. </p><p>Among 233 sporadic ALS patients, Broom et al. (2004) found no association between disease susceptibility or phenotype and a deletion and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing against a major role for wildtype SOD1 in sporadic ALS. </p><p>In a review of familial ALS, de Belleroche et al. (1995) listed 30 missense mutations and a 2-bp deletion in the SOD1 gene. Siddique and Deng (1996) reviewed the genetics of ALS, including a tabulation of SOD1 mutations in familial ALS. </p><p>Millecamps et al. (2010) identified 18 different SOD1 missense mutations in 20 (12.3%) of 162 French probands with familial ALS. Compared to those with ALS caused by mutations in other genes, those with SOD1 tended to have disease onset predominantly in the lower limbs. One-third of SOD1 patients survived for more than 7 years: these patients had an earlier disease onset compared to those presenting with a more rapid course. No patients with SOD1 mutations developed cognitive impairment. </p><p><strong><em>Autosomal Recessive Mutations</em></strong></p><p>
Andersen et al. (1995) found homozygosity for a mutation in the SOD1 gene (D90A; 147450.0015) in 14 ALS patients from 4 unrelated families and 4 apparently sporadic ALS patients from Sweden and Finland. Consanguinity was present in several of the families, consistent with autosomal recessive inheritance. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Age at onset ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1 to 4 years' disease duration in all patients, and none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype like that in the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Thus, familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms. Al-Chalabi et al. (1998) concluded that a 'tightly linked protective factor' in some families modifies the toxic effect of the mutant SOD1, resulting in recessive inheritance. </p><p><strong><em>Susceptibility Genes and Association Studies</em></strong></p><p>
Siddique et al. (1998) could demonstrate no relationship between APOE genotype (107741) and sporadic ALS. Previous studies had resulted in contradictory results. Siddique et al. (1998) found no significant difference in age at onset between patients with 1, 2, or no APOE*4 alleles. </p><p>In 1 of 189 ALS patients, Gros-Louis et al. (2004) identified a 1-bp deletion in the peripherin gene (170710.0001), suggesting that the mutation conferred an increased susceptibility to development of the disease. </p><p>Among 250 patients with a putative diagnosis of ALS, Munch et al. (2004) identified 3 mutations in the DCTN1 gene (601143.0002-601143.0004) in 3 families. One of the mutations showed incomplete penetrance. The authors suggested that mutations in the DCTN1 gene may be a susceptibility risk factor for ALS. </p><p>Veldink et al. (2005) presented evidence suggesting that SMN genotypes producing less SMN protein increased susceptibility to and severity of ALS. Among 242 ALS patients, the presence of 1 SMN1 (600354) copy, which represents spinal muscular atrophy (SMA; 253300) carrier status, was significantly increased in patients (6.6%) compared to controls (1.7%). The presence of 1 copy of SMN2 (601627) was significantly increased in patients (58.7%) compared to controls (29.7%), whereas 2, 3, or 4 SMN2 copies were significantly decreased in patients compared to controls. </p><p>In 167 ALS patients and 167 matched controls, Corcia et al. (2002) found that 14% of ALS patients had an abnormal copy number of the SMN1 gene, either 1 or 3 copies, compared to 4% of controls. Among 600 patients with sporadic ALS, Corcia et al. (2006) found an association between disease and 1 or 3 copies of the SMN1 gene (p less than 0.0001; odds ratio of 2.8). There was no disease association with SMN2 copy number. </p><p>Dunckley et al. (2007) provided evidence suggestive of an association between the FLJ10986 gene (611370) on chromosome 1 and sporadic amyotrophic lateral sclerosis in 3 independent patient populations. The susceptibility allele of rs6690993 conferred an odds ratio of 1.35 (p = 3.0 x 10(-4)). </p><p>Simpson et al. (2009) performed a multistage association study using 1,884 microsatellite markers in 3 populations totaling 781 ALS patients and 702 control individuals. They identified a significant association (p = 1.96 x 10(-9)) with the 15-allele marker D8S1820 in intron 10 of the ELP3 gene (612722). Fine mapping with SNPs in and around the ELP3 gene identified a haplotype consisting of allele 6 of D8S1820 and rs12682496 strongly associated with ALS (p = 1.05 x 10(-6)). </p><p>Lambrechts et al. (2009) performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene (192240) and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype (rs699947; 192240.0002), which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing. </p><p>Sabatelli et al. (2009) identified nonsynonymous variants in the CHRNA3 (118503) and CHRNB4 (118509) genes on chromosome 15q25.1 and the CHRNA4 gene (118504) on chromosome 20q13.2-q13.3, encoding neuronal nicotinic acetylcholine receptor (nAChR) subunits, in 19 sporadic ALS patients and in 14 controls. NAChRs formed by mutant alpha-3 and alpha-4 and wildtype beta-4 subunits exhibited altered affinity for nicotine (Nic), reduced use-dependent rundown of Nic-activated currents, and reduced desensitization leading to sustained intracellular calcium concentration, in comparison with wildtype nAChR. Sabatelli et al. (2009) suggested that gain-of-function nAChR variants may contribute to disease susceptibility in a subset of ALS patients because calcium signals mediate the neuromodulatory effects of nAChRs, including regulation of glutamate release and control of cell survival. </p><p>In a 3-generation kindred with familial ALS, Mitchell et al. (2010) found linkage to markers D12S1646 and D12S354 on chromosome 12q24 (2-point lod score of 2.7). Screening of candidate genes identified a heterozygous arg199-to-trp (R199W) mutation in exon 7 of the DAO gene (124050) in 3 affected members and in 1 obligate carrier, who died at age 73 years of cardiac failure and reportedly had right-sided weakness and dysarthria. The proband had onset at age 40, and the mean age at death in 7 cases was 44 years (range, 42 to 55 years). The mutation was also present in 3 at-risk individuals of 33, 44, and 48 years of age, respectively. The R199W mutation was not found in 780 Caucasian controls. Postmortem examination of the obligate carrier showed some loss of motor neurons in the spinal cord and degeneration of 1 of the lateral corticospinal tracts. There was markedly decreased DAO enzyme activity in the spinal cord compared to controls. Coexpression of mutant protein with wildtype protein in COS-7 cells indicated a dominant-negative effect for the mutant protein. Rat neuronal cell lines expressing the R199W-mutant protein showed decreased viability and increased ubiquitinated aggregates compared to wildtype. Mitchell et al. (2010) suggested a role for the DAO gene in ALS, but noted that a causal role for the R199W-mutant protein remained to be unequivocally established. </p><p>In a study of 847 patients with ALS and 984 controls, Blauw et al. (2012) found that SMN1 duplications were associated with increased susceptibility to ALS (odds ratio (OR) of 2.07; p = 0.001). A metaanalysis with previous data including 3,469 individuals showed a similar effect, with an OR of 1.85 (p = 0.008). SMN1 deletions or point mutations and SMN2 copy number status were not associated with ALS, and SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. </p><p>For discussion of a possible association between variation in the SS18L1 gene and ALS, see 606472.0001-606472.0003.</p><p>Among 376 individuals with sporadic ALS, Course et al. (2020) identified a 69-bp variable number tandem repeat (VNTR) in the last intron of the WDR7 gene (613473.0001) that was associated with the disease. For a more detailed discussion of the association and potential pathogenic mechanisms, see 613473.0001. </p><p><strong><em>Modifier Genes</em></strong></p><p>
Giess et al. (2002) reported a 25-year-old man with ALS who died after a rapid disease course of only 11 months. Genetic analysis identified a heterozygous mutation in the SOD1 gene and a homozygous mutation in the ciliary neurotrophic factor gene (CNTF; 118945.0001). The patient's mother, who developed ALS at age 54, had the SOD1 mutation and was heterozygous for the CNTF mutation. His healthy 35-year-old sister had the SOD1 mutation, but did not have the CNTF mutation. Two maternal aunts had died from ALS at 56 and 43 years of age, and a maternal grandmother and a great-grandmother had died from progressive muscle weakness and atrophy at ages 62 and less than 50 years, respectively. Giess et al. (2002) found that transgenic SOD1 mutant mice who were Cntf-deficient had a significantly earlier age at disease onset compared to in transgenic mice that were wildtype for CNTF. Although linkage analysis in mice revealed that the SOD1 gene was solely responsible for the disease, disease onset as a quantitative trait was regulated by the CNTF locus. In addition, patients with sporadic ALS who had a homozygous CNTF gene defect showed significantly earlier disease onset, but did not show a significant difference in disease duration. Giess et al. (2002) concluded that CNTF acts as a modifier gene that leads to early onset of disease in patients with SOD1 mutations. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between ALS and mutation in the PDIA3 gene, see 602046.</p>
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<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
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<p>De Belleroche et al. (1995) noted that the SOD1 H46R mutation (147450.0013) was associated with a more benign form of ALS with average duration of 17 years and only slightly reduced levels of SOD1 enzyme activity. The authors referred to a family with an I113T mutation (147450.0011) in which 1 affected member of the family died after a short progression and another member survived more than 20 years. </p><p>Cudkowicz et al. (1997) registered 366 families in a study of dominantly inherited ALS. They screened 290 families for mutations in the SOD1 gene and detected mutations in 68 families; the most common SOD1 mutation, A4V (147450.0012), was present in 50% of the families. The presence of either of 2 SOD1 mutations, G37R (147450.0001) or L38V (147450.0002), predicted an earlier age at onset. Additionally, the presence of the A4V mutation correlated with shorter survival, whereas G37R, G41D (147450.0004), and G93C (147450.0007) mutations predicted longer survival. The clinical characteristics of patients with familial ALS arising from SOD1 mutations were similar to those without SOD1 defects. However, Cudkowicz et al. (1997) reported that mean age at onset was earlier in the SOD1 group than in the non-SOD1 group, and Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times. </p><p>Sato et al. (2005) measured the ratio of mutant-to-normal SOD1 protein in 29 ALS patients with mutations in the SOD1 gene. Although there was no relation to age at onset, turnover of mutant SOD1 was correlated with a shorter disease survival time. </p><p>Regal et al. (2006) reported the clinical features of 20 ALS patients from 4 families with the SOD1 G93C mutation (147450.0007). Mean age at onset was 45.9 years, and all patients had slowly progressive weakness and atrophy starting in the distal lower limbs. Although symptoms gradually spread proximally and to the upper extremities, bulbar function was preserved. None of the patients developed upper motor neuron signs. Postmortem findings of 1 patient showed severe loss of anterior horn cells and loss of myelinated fibers in the posterior column and spinocerebellar tracts, but only mild changes in the lateral corticospinal tracts. Lipofuscin and hyaline inclusions were observed in many neurons. Patients with the G93C mutation had significantly longer survival compared to patients with other SOD1 mutations. </p>
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<strong>Clinical Management</strong>
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<p>Amyotrophic lateral sclerosis is a disorder that has prominently been mentioned as justification for assisted suicide. Ganzini et al. (1998) found that in the states of Oregon and Washington most patients with ALS whom they surveyed would consider assisted suicide. Many would request a prescription for a lethal dose of medication well before they intended to use it. Rowland (1998) reviewed the question of what it is about ALS that raised the question of suicide. The progressive paralysis leads to increase of loss of function, culminating in complete dependence on the help of others for all activities of daily living and, if life is sustained by assisted ventilation, loss of the ability to communicate or swallow. Ten percent of patients are under the age of 40 years. Some patients, wanting to live as long as possible, opted for tracheostomy and assisted ventilation at home. In a study of 92 patients receiving long-term assisted ventilation with tracheostomy, 20 lived for 8 to 17 years with the tracheostomy, and 9 became 'locked in' (they were conscious but severely paralyzed and unable to communicate except by eye movements). In the Oregon series, however, only 2 patients opted for tracheostomy with long-term mechanical ventilation, and among patients at the ALS Center at Columbia Presbyterian Medical Center, only 2.9% chose it (Rowland, 1998). The last year in the life of an ALS victim, Professor Morris Schwartz, was chronicled in a bestselling book written by Albom (1997). </p><p>In a prospective randomized control trial of 44 ALS patients, Fornai et al. (2008) reported that treatment of 16 patients with lithium plus riluzole resulted in slower disease progression compared to 28 patients treated with riluzole alone. All 16 patients treated with lithium survived for 15 months; 29% of the patients receiving riluzole alone did not survive by this endpoint. Studies in transgenic ALS mice showed a similar delay in disease progression and longer survival. Mice treated with lithium showed delayed cell death in spinal cord motor neurons, increased numbers of normal mitochondria in motor neurons, decreased SOD1 aggregation, and decreased reactive astrogliosis. Studies of cultured mutant murine motor neurons suggested that lithium treatment increased endosomal autophagy of aggregated proteins or abnormal mitochondria, which may have contributed to the observed neuroprotective effects. </p>
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<strong>Population Genetics</strong>
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<p>In 2 regions of northwestern Italy with a total population of approximately 4.5 million, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (2001) determined a mean annual incidence rate of 2.5 per 100,000 from 1995 to 1996. The data were comparable to similar studies in other Western countries, suggesting diffuse genetic or environmental factors in the pathogenesis of ALS. </p><p>Chio et al. (2008) found that 5 of 325 patients with ALS in Turin province of the Piemonte region of Italy had mutations in the SOD1 gene. Mutations were identified in 3 (13.6%) of 22 patients with a family history of ALS, and 2 (0.7%) of 303 sporadic cases. Chio et al. (2008) noted that the frequency of FALS (5.7%) was lower in this population-based series compared to series reported from ALS referral centers. </p>
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<strong>Animal Model</strong>
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<p>See also ANIMAL MODEL in 147450.</p><p>The murine Mnd (motor neuron degeneration) mutation causes a late-onset, progressive degeneration of upper and lower motor neurons. Using endogenous retroviruses as markers, Messer et al. (1992) mapped the Mnd gene in the mouse to proximal chromosome 8. Messer et al. (1992) suggested that examination of human chromosome 8, which shows homology of synteny, in human kindreds with ALS as well as related hereditary neurologic diseases might be fruitful. They presented evidence suggesting that a combination of genetic and environmental modifiers can alter the time course of the phenotypic expression in the mouse model. </p><p>Gurney et al. (1994) found that expression of high levels of human SOD containing the gly93-to-ala mutation (G93A; 147450.0008), a change that had little effect on enzyme activity, resulted in motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. Ongoing reinnervation and remodeling of muscle innervation suggested that 'sprouting' probably compensates for the loss of motor neurons until late in the course of the disease. Gurney et al. (1994) suggested that the toxicity of SOD1 from motor neurons could involve the formation of the strong oxidant peroxynitrite from oxygen and nitric oxide free radicals, representing a dominant, gain-of-function role for SOD1 mutations in the pathogenesis of familial ALS. The fact that mice with the abnormal human SOD became paralyzed even though copies of the animals' own normal Sod gene remained intact supported the gain-of-function role. Gurney et al. (1994) and other groups studying transgenic mice found that animals making the highest amounts of mutant Sod proteins were the ones that become paralyzed, a finding that runs counter to the idea that decreased SOD activity is at fault in ALS. </p><p>Wong et al. (1995) generated transgenic mice carrying a gly37-to-arg (G37R; 147450.0001) mutation in the SOD1 gene associated with a subset of familial ALS cases. The mice developed severe, progressive motor neuron disease and provided an animal model for ALS. Wong et al. (1995) observed that at lower levels of mutant accumulation, pathology was restricted to lower motor neurons, whereas higher levels caused more severe abnormalities and affected a variety of other neuronal populations. The authors noted that the most obvious cellular abnormality in the mutant mice was the presence in axons and dendrites of membrane-bound vacuoles, which they hypothesized were derived from degenerating mitochondria. Wong et al. (1995) concluded that the disease in mice expressing G37R arises from the acquisition of an adverse property by the mutant enzyme rather than elevation or loss of SOD1 activity. </p><p>Ripps et al. (1995) produced a transgenic mouse model of familial ALS by introducing an SOD1 mutation (gly86-to-arg). In 2 lines of mice that produced high levels of transgene mRNA in the CNS, motor paralysis developed and was associated with degenerative changes of motor neurons within the spinal cord, brainstem, and neocortex. Biochemical measurements in these animals revealed no diminution of Sod activity, indicating a dominant gain-of-function mutation. Tu et al. (1996) reported that transgenic mice expressing a human SOD1 gene containing the G92A mutation developed a motor neuron disease similar to familial ALS, but transgenic mice expressing a wildtype human SOD1 transgene did not. Neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of ALS. Tu et al. (1996) found that such inclusions were detectable in spinal cord motor neurons of the mutant carrying transgenic mice at 82 days of age and about the time that the mice first showed clinical evidence of the disease. In contrast, NF inclusions were not seen in the mice with the wildtype transgene until they were 132 days old, and ubiquitin immunoreactivity, which likewise started at about 82 days in mutant-bearing mice, was not increased in wildtype mice even at 199 days of age. A striking similarity between the cytoskeletal pathology of the mutant transgenic mice and the patients with ALS was demonstrated. </p><p>Using immunohistochemistry and immunoblot experiments, Nguyen et al. (2001) found that the p25/p35 (see 603460) ratio and Cdk5 (123831) activity were abnormally elevated in the spinal cord of transgenic mice with the G37R mutation in SOD1 (Wong et al., 1995). This elevation was associated with the hyperphosphorylation of neurofilament and tau (157140) proteins. By analyzing transgenic mouse lines with differing G37R transgene expression levels, Nguyen et al. (2001) observed a correlation between Cdk5 activity and the longevity of the mutant mice. Nguyen et al. (2001) bred the G37R transgene onto neurofilament mutant backgrounds and observed that the absence of neurofilament light subunit (NEFL; 162280) provoked an accumulation of unassembled neurofilament subunits in the perikaryon of motor neurons and extended the average life span of the mutant mice. Using double immunofluorescence microscopy, Nguyen et al. (2001) confirmed that Cdk5 and p25 colocalized with perikaryal neurofilament accumulations in G37R mice on the neurofilament mutant background. Using immunoblotting, Nguyen et al. (2001) observed that the occurrence of perikaryal neurofilament accumulations in the mutant mice was associated with a reduction in the elevated phosphorylation of tau, another p25/cdk5 substrate. Nguyen et al. (2001) hypothesized that perikaryal accumulations of neurofilament proteins in motor neurons may alleviate ALS pathogenesis in SOD1(G37R) mice by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates. </p><p>LaMonte et al. (2002) generated a mouse model of ALS by overexpressing dynamitin (DCTN2; 607376) in postnatal motor neurons of transgenic mice. They found that dynamitin overexpression disrupted the dynein-dynactin complex, resulting in an inhibition of retrograde axonal transport. The authors observed a late-onset, slowly progressive motor neuron degenerative disease characterized by muscle weakness, spontaneous trembling, abnormal posture and gaits, and deficits in strength and endurance. LaMonte et al. (2002) detected histologic changes in spinal cord motor neurons and skeletal muscle indicative of degeneration of motor neurons and denervation atrophy of muscle. The transgenic mice also displayed neurofilament accumulations. LaMonte et al. (2002) concluded that their mouse model confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease. </p><p>Raoul et al. (2002) showed that Fas (134637), a member of the death receptor family, triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase (600289). ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (602457)/caspase-8 (601763) cell death pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing ALS-linked SOD1 mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell death pathways may contribute to motor neuron loss in ALS. Raoul et al. (2006) reported that exogenous NO triggered expression of Fas ligand (FASL; 134638) in cultured motoneurons. In motoneurons from ALS model mice with mutations in the SOD1 gene, this upregulation resulted in activation of Fas, leading through Daxx and p38 to further NO synthesis. The authors suggested that chronic low activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS. </p><p>To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2 subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (see GLUR2, 138247) to SOD1-related motoneuronal death, Tateno et al. (2004) generated choline acetyltransferase (ChAT; 118490)-GluR2 transgenic mice with significantly reduced Ca(2)+ permeability of these receptors in spinal motoneurons. Crossbreeding of the SOD1(G93A) transgenic mouse model of ALS with ChAT-GluR2 mice led to marked delay of disease onset, mortality, and the pathologic hallmarks such as release of cytochrome c from mitochondria, induction of cox2 (600262), and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species accumulated in 2 fractions (P1, composed of nuclei and certain kinds of cytoskeletons such as neurofilaments and glial fibrillary acidic protein (GFAP; 137780), and P2, composed of mitochondria) long before disease onset and then extensively accumulated in the P1 fractions by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca(2+) influx through atypical motoneuronal AMPA receptors thus promoted a misfolding of mutant SOD1 protein and eventual death of these neurons. </p><p>Using mice carrying a deletable mutant Sod1 gene, Boillee et al. (2006) demonstrated that expression within motor neurons is a primary determinant of ALS disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early phase but sharply slowed later disease progression. Boillee et al. (2006) concluded that onset and progression thus represent distinct ALS disease phases defined by mutant action within different cell types to generate non-cell autonomous killing of motor neurons; their findings validate therapies, including cell replacement, targeted to the nonneuronal cells. </p><p>Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage within muscles of mice was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression. </p><p>Marden et al. (2007) evaluated the effects of NADPH oxidase-1 (NOX1; 300225) or Nox2 (CYBB; 300481) deletion on transgenic mice overexpressing human SOD1 with the G93A mutation by monitoring the onset and progression of disease using various indices. Disruption of either Nox1 or Nox2 significantly delayed progression of motor neuron disease in these mice. However, 50% survival rates were enhanced significantly more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased survival rates, suggesting that in the setting of random X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a substantial therapeutic benefit in ALS mice. Marden et al. (2007) concluded that NOX1 and NOX2 contribute to the progression of ALS. </p><p>Kieran et al. (2007) detected a significant upregulation of Puma (BBC3; 605854), a proapoptotic protein, in motoneurons of G93A-mutant mice before symptom onset. Deletion of Puma in these mice improved motoneuron survival and delayed disease onset and motor dysfunction, but did not extend life span. The findings suggested that Puma may play a role in the early stages of neurodegeneration in ALS by increasing ER stress-mediated apoptosis. </p><p>Awano et al. (2009) found that canine degenerative myelopathy, a spontaneously occurring adult-onset neurodegenerative disease, was highly associated with a homozygous glu40-to-lys (E40K) mutation in the canine Sod1 gene. The mutation was found in affected breeds including Pembroke Welsh corgi, boxer, Rhodesian ridgeback, Chesapeake Bay retriever, and German shepherd. The disorder was characterized clinically by adult onset of spasticity and proprioceptive ataxia, followed by weakness, paraplegia, and hyporeflexia. Histopathologic examination of the spinal cord of 46 affected dogs showed white matter degeneration with axonal and myelin loss and cytoplasmic Sod1-positive inclusions in surviving neurons. The disorder closely resembled human ALS. </p><p>Tateno et al. (2009) demonstrated that, starting from the pre-onset stage of ALS, misfolded SOD1 species associated specifically with Kap3 (KIFAP3; 601836) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargoes including ChAT. Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. Using a purified hybrid mouse neuroblastoma/rat glioma cell line NG108-15 transfected with SOD1 mutations, the authors showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species and that impairment was normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in spinal motor neurons from human ALS patients as well. Tateno et al. (2009) suggested that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the pathophysiology of ALS. </p><p>Wong and Martin (2010) created transgenic mice expressing wildtype, G37R (147450.0001), and G93A (147450.0008) human SOD1 in only skeletal muscle. These mice developed age-related neurologic and pathologic phenotypes consistent with ALS. Affected mice showed limb weakness and paresis with motor deficits. Skeletal muscles developed severe pathology involving oxidative damage, protein nitration, myofiber cell death, and marked neuromuscular junction abnormalities. Spinal motor neurons developed distal axonopathy, formed ubiquitinated inclusions, and degenerated through an apoptotic-like pathway involving caspase-3 (600636). Mice expressing wildtype and mutant forms of SOD1 developed motor neuron pathology. The authors concluded that SOD1 in skeletal muscle has a causal role in ALS, and they proposed a nonautonomous mechanism to explain the degeneration and selective vulnerability of these motor neurons. </p><p>Blacher et al. (2019) showed that ALS-prone Sod1 transgenic mice have a presymptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. Blacher et al. (2019) correlated 11 distinct commensal bacteria with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1 transgenic mice they demonstrated that Akkermansia muciniphila (AM) ameliorates, whereas Ruminococcus torques and Parabacteroides distasonis exacerbate, the symptoms of ALS. Furthermore, Sod1 transgenic mice that are administered AM accumulated AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improved motor symptoms and gene expression patterns in the spinal cord of Sod1 transgenic mice. In humans, Blacher et al. (2019) identified distinct microbiome and metabolite configurations, including reduced levels of nicotinamide systemically and in the CSF, in a small preliminary study that compared patients with ALS with household controls. Blacher et al. (2019) suggested that environmentally driven microbiome-brain interactions may modulate ALS in mice, and called for similar investigations in the human form of the disease. </p><p><strong><em>Therapeutic Strategies</em></strong></p><p>
Transgenic mice overexpressing a mutated form of human SOD1 with a gly93-to-ala substitution (G93A; 147450.0008) develop progressive muscle wasting and paralysis as a result of spinal motor neuron loss and die at 5 to 6 months. Bordet et al. (2001) found that intramuscular injection of an adenoviral vector encoding CTF1 (600435) in SOD1(G93A) newborn mice delayed the onset of motor impairment as assessed in the rotarod test. By CTF1 treatment, axonal degeneration was slowed, skeletal muscle atrophy was largely reduced, and the time-course of motor impairment was significantly decreased. </p><p>In a transgenic mouse model of ALS with the human G93A SOD1 mutation, Drachman et al. (2002) demonstrated that treatment with the cyclooxygenase-2 (COX2; 600262) inhibitor celecoxib resulted in significant delay of onset of weakness and weight loss, prolonged survival, preservation of ventral gray neurons in the spinal cord, and reduced spinal cord astroglial and microglial proliferation. The authors suggested that COX2 inhibition prevents prostaglandin-mediated release of glutamate from astrocytes and interrupts the inflammatory processes that result in the production of toxic reactive oxygen species. </p><p>Adeno-associated virus (AAV) can be retrogradely transported efficiently from muscle to motor neurons of the spinal cord (Davidson et al., 2000; Boulis et al., 2003). In the Sod1-overexpressing model of ALS in the mouse, Kaspar et al. (2003) found that IGF1 (147440) administered through an AAV vector by intramuscular injection into hindlimb quadriceps and intercostal muscles at 60 days of age, approximately 30 days prior to disease onset, delayed onset by 31 days, twice as long as that seen in mice given GDNF (600837) through an AAV vector. GDNF-treated animals showed a smaller, 11-day increase in median survival compared to GFP-treated controls. IGF1-treated animals showed a larger, significant improvement in life span, with a 37-day increase in median survival compared to controls. The maximal life span of IGF1-treated animals was 265 days, compared to 140 days in the control group. Kaspar et al. (2003) concluded that injection of IGF1 not only delayed the onset of disease but also slowed the rate of disease progression. In contrast, GDNF appeared only to have delayed the onset of symptoms. IGF1 treatment was even able to expand life span when administered after disease onset at 90 days of age. </p><p>Azzouz et al. (2004) reported that a single injection of a vascular endothelial growth factor (VEGF; 192240)-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene encoding the mutated G93A form of SOD1 (147450.0008), even when treatment was initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30% without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field to that time. Storkebaum et al. (2005) found that intracerebroventricular delivery of recombinant Vegf in a rat model of ALS with the G93A SOD1 mutation delayed onset of paralysis by 17 days, improved motor performance, and prolonged survival by 22 days. By protecting cervical motoneurons, intracerebroventricular delivery of Vegf was particularly effective in rats with the most severe form of disease ALS with forelimb onset, which may be analogous to patients with bulbar onset of ALS. </p><p>Urushitani et al. (2007) reported that active vaccination with mutant SOD1 and passive immunization with anti-SOD1 antibody were effective in alleviating disease symptoms and delaying mortality of in ALS mice with a G37R SOD1 mutation and moderate expression of the mutant gene. Western blot analysis showed clearance of SOD1 species in the spinal cord of vaccinated mice. Vaccination was not effective in a different mouse strain with extreme overexpression of mutant SOD1. The results were consistent with the hypothesis that neurotoxicity of extracellular secreted SOD1 may also play a role in disease pathogenesis. </p><p>Dimos et al. (2008) generated induced pluripotent stem (iPS) cells from skin fibroblasts collected from an 82-year-old woman diagnosed with a familial form of ALS caused by a mutation in the SOD1 gene (L144F; 147450.0017). These patient-specific iPS cells possessed properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS. </p><p>Williams et al. (2009) showed that a key regulator of signaling between motor neurons and skeletal muscle fibers is miR206 (611599), a skeletal muscle-specific microRNA that is dramatically induced in the mouse model of ALS. Mice that are genetically deficient in miR206 form normal neuromuscular synapses during development, but deficiency of miR206 in the ALS mouse model accelerates disease progression. miR206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, which probably accounts for its salutary effects in ALS. miR206 mediates these effects at least in part through histone deacetylase 4 (605314) and fibroblast growth factor (see 131220) signaling pathways. Thus, Williams et al. (2009) concluded that miR206 slows ALS progression by sensing motor neuron injury and promoting the compensatory regeneration of neuromuscular synapses. </p><p>Based on their demonstration that the costimulatory pathway is activated in multiple tissues in the Sod1(G93A) preclinical model of ALS as well as in the blood of a subset of individuals with ALS, Lincecum et al. (2010) developed a therapy using a monoclonal antibody to CD40L (300386). Weight loss was slowed, paralysis delayed, and survival extended in an ALS mouse model. </p><p>Corti et al. (2010) investigated a cell therapy using intravascular injection to transplant a specific population of c-kit+ (164920) stem/progenitor cells from bone marrow into the SOD1G93A mouse model of ALS. Transplanted cells engrafted within the host spinal cord. Cell transplantation significantly prolonged disease duration and lifespan in SOD1G93A mice, promoted the survival of motor neurons, and improved neuromuscular function. Neuroprotection was mediated by multiple effects, in particular by the expression of primary astrocyte glutamate transporter GLT1 (SLC1A2; 600300) and by the nonmutant genome. The authors suggested that somatic cell transplantation may be an effective therapy for ALS and other neurodegenerative diseases. </p>
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<span class="mim-font">
<strong>See Also:</strong>
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</h4>
<span class="mim-text-font">
Gimenez-Roldan and Esteban (1977); Haberlandt (1961); Phillips et al.
(1978); Swerts and Van den Bergh (1976); Takahashi et al. (1972)
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</h4>
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<ol>
<li>
<p class="mim-text-font">
Al-Chalabi, A., Andersen, P. M., Chioza, B., Shaw, C., Sham, P. C., Robberecht, W., Matthijs, G., Camu, W., Marklund, S. L., Forsgren, L., Rouleau, G., Laing, N. G., Hurse, P. V., Siddique, T., Leigh, P. N., Powell, J. F.
<strong>Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.</strong>
Hum. Molec. Genet. 7: 2045-2050, 1998.
[PubMed: 9817920]
[Full Text: https://doi.org/10.1093/hmg/7.13.2045]
</p>
</li>
<li>
<p class="mim-text-font">
Alberca, R., Castilla, J. M., Gil-Peralta, A.
<strong>Hereditary amyotrophic lateral sclerosis.</strong>
J. Neurol. Sci. 50: 201-206, 1981.
[PubMed: 7229665]
[Full Text: https://doi.org/10.1016/0022-510x(81)90166-0]
</p>
</li>
<li>
<p class="mim-text-font">
Albom, M.
<strong>Tuesdays with Morrie: an old man, a young man, and the last great lesson.</strong>
New York: Doubleday (pub) 1997. P. 162.
</p>
</li>
<li>
<p class="mim-text-font">
Alter, M., Schaumann, B.
<strong>Hereditary amyotrophic lateral sclerosis: a report of two families.</strong>
Europ. Neurol. 14: 250-265, 1976.
[PubMed: 954772]
[Full Text: https://doi.org/10.1159/000114747]
</p>
</li>
<li>
<p class="mim-text-font">
Amick, L. D., Nelson, J. W., Zellweger, H.
<strong>Familial motor neuron disease, non-Chamorro type: report of kinship.</strong>
Acta Neurol. Scand. 47: 341-349, 1971.
[PubMed: 5096760]
[Full Text: https://doi.org/10.1111/j.1600-0404.1971.tb07488.x]
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</li>
<li>
<p class="mim-text-font">
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Storkebaum, E., Lambrechts, D., Dewerchin, M., Moreno-Murciano, M.-P., Appelmans, S., Oh, H., Van Damme, P., Rutten, B., Man, W., De Mol, M., Wyns, S., and 9 others.
<strong>Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.</strong>
Nature Neurosci. 8: 85-92, 2005.
[PubMed: 15568021]
[Full Text: https://doi.org/10.1038/nn1360]
</p>
</li>
<li>
<p class="mim-text-font">
Swerts, L., Van den Bergh, R.
<strong>Sclerose laterale amyotrophique familiale: etude d&#x27;une famille atteinte sur trois generations. [Familial amyotrophic lateral sclerosis: a study of a family suffering from this disease for three generations].</strong>
J. Genet. Hum. 24: 247-255, 1976.
[PubMed: 1003176]
</p>
</li>
<li>
<p class="mim-text-font">
Tagerud, S., Libelius, R., Magnusson, C.
<strong>Muscle Nogo-A: a marker for amyotrophic lateral sclerosis or for denervation? (Letter)</strong>
Ann. Neurol. 62: 676 only, 2007.
[PubMed: 17702029]
[Full Text: https://doi.org/10.1002/ana.21187]
</p>
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<li>
<p class="mim-text-font">
Takahashi, K., Nakamura, H., Okada, E.
<strong>Hereditary amyotrophic lateral sclerosis: histochemical and electron microscopic study of hyaline inclusions in motor neurons.</strong>
Arch. Neurol. 27: 292-299, 1972.
[PubMed: 4115557]
[Full Text: https://doi.org/10.1001/archneur.1972.00490160020003]
</p>
</li>
<li>
<p class="mim-text-font">
Tateno, M., Kato, S., Sakurai, T., Nukina, N., Takahashi, R., Araki, T.
<strong>Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.</strong>
Hum. Molec. Genet. 18: 942-955, 2009.
[PubMed: 19088126]
[Full Text: https://doi.org/10.1093/hmg/ddn422]
</p>
</li>
<li>
<p class="mim-text-font">
Tateno, M., Sadakata, H., Tanaka, M., Itohara, S., Shin, R.-M., Miura, M., Masuda, M., Aosaki, T., Urushitani, M., Misawa, H., Takahashi, R.
<strong>Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model.</strong>
Hum. Molec. Genet. 13: 2183-2196, 2004.
[PubMed: 15294873]
[Full Text: https://doi.org/10.1093/hmg/ddh246]
</p>
</li>
<li>
<p class="mim-text-font">
Thomson, A. F., Alvarez, F. A.
<strong>Hereditary amyotrophic lateral sclerosis.</strong>
J. Neurol. Sci. 8: 101-110, 1969.
[PubMed: 5790363]
[Full Text: https://doi.org/10.1016/0022-510x(69)90044-6]
</p>
</li>
<li>
<p class="mim-text-font">
Tu, P.-H., Raju, P., Robinson, K. A., Gurney, M. E., Trojanowski, J. Q., Lee, V. M.-Y.
<strong>Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.</strong>
Proc. Nat. Acad. Sci. 93: 3155-3160, 1996.
[PubMed: 8610185]
[Full Text: https://doi.org/10.1073/pnas.93.7.3155]
</p>
</li>
<li>
<p class="mim-text-font">
Urushitani, M., Ezzi, S. A., Julien, J.-P.
<strong>Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis.</strong>
Proc. Nat. Acad. Sci. 104: 2495-2500, 2007.
[PubMed: 17277077]
[Full Text: https://doi.org/10.1073/pnas.0606201104]
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van Es, M. A., Veldink, J. H., Saris, C. G. J., Blauw, H. M., van Vught, P. W. J., Birve, A., Lemmens, R., Schelhaas, H. J., Groen, E. J. N., Huisman, M. H. B., van der Kooi, A. J., de Visser, M.
<strong>{and 42 others}: Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.</strong>
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<p class="mim-text-font">
Veldink, J. H., Kalmijn, S., Van der Hout, A. H., Lemmink, H. H., Groeneveld, G. J., Lummen, C., Scheffer, H., Wokke, J. H. J., Van den Berg, L. H.
<strong>SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.</strong>
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[PubMed: 16093455]
[Full Text: https://doi.org/10.1212/01.wnl.0000174472.03292.dd]
</p>
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<li>
<p class="mim-text-font">
Veltema, A. N., Roos, R. A. C., Bruyn, G. W.
<strong>Autosomal dominant adult amyotrophic lateral sclerosis: a six generation Dutch family.</strong>
J. Neurol. Sci. 97: 93-115, 1990.
[PubMed: 2370562]
[Full Text: https://doi.org/10.1016/0022-510x(90)90101-r]
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Wilkins, L. E., Winter, R. M., Myer, E. C., Nance, W. E.
<strong>Dominantly inherited amyotrophic lateral sclerosis (motor neuron disease).</strong>
Med. Coll. Va. Quart. 13(4): 182-186, 1977.
</p>
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<p class="mim-text-font">
Williams, A. H. Valdez, G., Moresi, V., Qi, X., McAnally, J., Elliott, J. L., Bassel-Duby, R., Sanes, J. R., Olson, E. N.
<strong>MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.</strong>
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[PubMed: 20007902]
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</p>
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<li>
<p class="mim-text-font">
Wills, A.-M., Cronin, S., Slowik, A., Kasperaviciute, D., Van Es, M. A., Morahan, J. M., Valdmanis, P. N., Meininger, V., Melki, J., Shaw, C. E., Rouleau, G. A., Fisher, E. M. C., and 11 others.
<strong>A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.</strong>
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</p>
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<li>
<p class="mim-text-font">
Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., Sisodia, S. S., Cleveland, D. W., Price, D. L.
<strong>An adverse property of familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.</strong>
Neuron 14: 1105-1116, 1995.
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</p>
</li>
<li>
<p class="mim-text-font">
Wong, W., Martin, L. J.
<strong>Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice.</strong>
Hum. Molec. Genet. 19: 2284-2302, 2010.
[PubMed: 20223753]
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</p>
</li>
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Contributors:
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Cassandra L. Kniffin - updated : 12/30/2020<br>Ada Hamosh - updated : 03/16/2020<br>George E. Tiller - updated : 09/13/2017<br>George E. Tiller - updated : 06/22/2017<br>George E. Tiller - updated : 8/20/2013<br>Cassandra L. Kniffin - updated : 2/27/2013<br>Ada Hamosh - updated : 2/1/2013<br>Cassandra L. Kniffin - updated : 10/1/2012<br>Cassandra L. Kniffin - updated : 5/5/2011<br>Cassandra L. Kniffin - updated : 1/28/2011<br>George E. Tiller - updated : 12/29/2010<br>Ada Hamosh - updated : 10/19/2010<br>Cassandra L. Kniffin - updated : 9/27/2010<br>George E. Tiller - updated : 8/6/2010<br>Ada Hamosh - updated : 6/18/2010<br>Cassandra L. Kniffin - updated : 6/14/2010<br>Ada Hamosh - updated : 6/2/2010<br>Ada Hamosh - updated : 1/19/2010<br>Cassandra L. Kniffin - updated : 12/29/2009<br>Cassandra L. Kniffin - updated : 12/15/2009<br>George E. Tiller - updated : 8/14/2009<br>George E. Tiller - updated : 8/12/2009<br>Cassandra L. Kniffin - updated : 6/22/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Ada Hamosh - updated : 9/24/2008<br>Cassandra L. Kniffin - updated : 8/13/2008<br>Victor A. McKusick - updated : 5/28/2008<br>Ada Hamosh - updated : 5/8/2008<br>Cassandra L. Kniffin - updated : 3/14/2008<br>Patricia A. Hartz - updated : 3/3/2008<br>Cassandra L. Kniffin - updated : 1/7/2008<br>Cassandra L. Kniffin - updated : 9/17/2007<br>Cassandra L. Kniffin - updated : 8/28/2007<br>Cassandra L. Kniffin - updated : 4/12/2007<br>George E. Tiller - updated : 4/5/2007<br>Cassandra L. Kniffin - updated : 3/29/2007<br>Ada Hamosh - updated : 10/25/2006<br>Ada Hamosh - updated : 7/24/2006<br>Cassandra L. Kniffin - reorganized : 6/20/2006<br>Cassandra L. Kniffin - updated : 6/14/2006<br>Cassandra L. Kniffin - updated : 5/25/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 4/20/2006<br>Cassandra L. Kniffin - updated : 11/2/2005<br>Cassandra L. Kniffin - updated : 8/19/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Cassandra L. Kniffin - updated : 3/4/2005<br>Cassandra L. Kniffin - updated : 2/14/2005<br>Victor A. McKusick - updated : 12/14/2004<br>Cassandra L. Kniffin - updated : 12/14/2004<br>Ada Hamosh - updated : 6/11/2004<br>Victor A. McKusick - updated : 4/29/2004<br>Ada Hamosh - updated : 3/8/2004<br>Ada Hamosh - updated : 9/17/2003<br>Cassandra L. Kniffin - updated : 6/9/2003<br>Cassandra L. Kniffin - updated : 2/19/2003<br>Dawn Watkins-Chow - updated : 11/22/2002<br>Dawn Watkins-Chow - updated : 11/5/2002<br>Victor A. McKusick - updated : 10/1/2002<br>Cassandra L. Kniffin - updated : 7/23/2002<br>George E. Tiller - updated : 1/30/2002<br>Victor A. McKusick - updated : 6/25/2001<br>Ada Hamosh - updated : 4/13/2000<br>Victor A. McKusick - updated : 3/9/1999<br>Orest Hurko - updated : 1/21/1999<br>Victor A. McKusick - updated : 10/2/1998<br>Victor A. McKusick - updated : 5/6/1998<br>Orest Hurko - updated : 5/8/1996
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Creation Date:
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Victor A. McKusick : 6/16/1986
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