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Entry
- #169500 - LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, TYPICAL; ADLDTY
- OMIM
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<span class="h4">#169500</span>
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<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/169500"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS169500"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<a href="#mapping">Mapping</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, TYPICAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0060785" 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/169500" 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://wormbase.org/resources/disease/DOID:0060785" 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>
</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>ORPHA:</strong> 99027<br />
<strong>DO:</strong> 0060785<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>
169500
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
<div class="mim-changed mim-change">LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, TYPICAL; ADLDTY</div>
</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">
PELIZAEUS-MERZBACHER DISEASE, AUTOSOMAL DOMINANT OR LATE-ONSET TYPE, FORMERLY
</span>
</h4>
</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/5/408?start=-3&limit=10&highlight=408">
5q23.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Leukodystrophy, demyelinating, adult-onset, autosomal dominant, typical
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/169500"> 169500 </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">
LMNB1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/150340"> 150340 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group mim-changed mim-change">
<a href="/clinicalSynopsis/169500" 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>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS169500" 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')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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</div>
&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/169500" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/169500" 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 />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br />
<div class="mim-changed mim-change"> - Disrupted saccadic pursuit<br /></div>
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Orthostatic hypotension due to autonomic dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868528&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868528</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004926" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004926</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004926" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004926</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28651003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28651003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I95.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I95.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/458.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">458.0</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
<div class="mim-changed mim-change"> - Dysphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br /></div>
<div class="mim-changed mim-change"> - Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br /></div>
- Abnormal bowel regulation due to autonomic dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868526&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868526</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Impotence due to autonomic dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868524&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868524</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008652" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008652</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008652" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008652</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/860914002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">860914002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N52.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N52.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N52</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F52.21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F52.21</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Bladder </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Abnormal bladder regulation due to autonomic dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868525&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868525</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Decreased sweating due to autonomic dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868527&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868527</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007480" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007480</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007480" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007480</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111980002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111980002</a>]</span><br />
</span>
</div>
</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">
- Cerebellar signs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0742038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0742038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001317</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001317</a>]</span><br />
- Cerebellar ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br />
- Loss of fine motor skills <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868513&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868513</a>]</span><br />
<div class="mim-changed mim-change"> - Tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26079004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26079004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span><br /></div>
<div class="mim-changed mim-change"> - Dysmetria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32566006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32566006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234162&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234162</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001310" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001310</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001310" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001310</a>]</span><br /></div>
- Pyramidal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14648003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14648003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234132&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234132</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span><br />
<div class="mim-changed mim-change"> - Impaired gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /></div>
- 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 />
<div class="mim-changed mim-change"> - Spastic tetraparesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298282001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298282001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575059&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575059</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001285" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001285</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001285" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001285</a>]</span><br /></div>
- 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 />
- Extensor plantar responses <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246586009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246586009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366575004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366575004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034935&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034935</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</a>]</span><br />
<div class="mim-changed mim-change"> - Lower limb weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836296&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836296</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007340" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007340</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007340" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007340</a>]</span><br /></div>
- Pseudobulbar syndrome <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">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0033790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033790</a> 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> <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 />
- Autonomic dysfunction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15241006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15241006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G90.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">337</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/337.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">337.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1145628&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1145628</a>, <a href="https://bioportal.bioontology.org/search?q=C0013363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013363</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012332</a>]</span><br />
- Cognitive impairment (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338656</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span><br />
- Leukodystrophy, demyelinating <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674659&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674659</a>]</span><br />
- Leukoencephalopathy, diffuse <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006994" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006994</a>]</span><br />
- Demyelination, symmetric <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868515&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868515</a>]</span><br />
- Decreased white matter density <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231398&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231398</a>]</span><br />
- Cavitating white matter degeneration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868517&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868517</a>]</span><br />
- Atrophy of the corpus callosum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253142006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253142006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0431370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431370</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007371</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007371</a>]</span><br />
- Hypotrophic brainstem <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805840&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805840</a>]</span><br />
- White matter lesions in the brainstem may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805841&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805841</a>]</span><br />
- Neuropathologic findings include leukoencephalopathy, predominantly in the upper corticospinal tract and cerebellar peduncles (initially) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550012</a>]</span><br />
- Leukoencephalopathy in the frontal and parietal lobes (later) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550013&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550013</a>]</span><br />
- Atrophic spinal cord <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1389102&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1389102</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006827" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006827</a>]</span><br />
- Oligodendrocytes with foamy cytoplasm <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868519&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868519</a>]</span><br />
- Decreased numbers of astrocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868520&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868520</a>]</span><br />
- Astrocytes show reactive changes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868521&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868521</a>]</span><br />
- Lack of inflammatory infiltrate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868523&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868523</a>]</span><br />
- Preservation of U fibers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838583</a>]</span><br />
- Sparing of optic tracts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3810482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3810482</a>]</span><br />
</span>
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<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
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<div style="margin-left: 2em;">
<span class="mim-font">
<div class="mim-changed mim-change"> - Sensory impairment (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398026008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398026008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5551413&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5551413</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003474" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003474</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003474" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003474</a>]</span><br /> -
Hyporeflexia later in disease course<br /></div>
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<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
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<div style="margin-left: 2em;">
<span class="mim-font">
<div class="mim-changed mim-change"> - Executive dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748208</a>]</span><br /></div>
- Personality changes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/192073007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">192073007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/102943000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">102943000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000751</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000751</a>]</span><br />
- Depression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78667006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78667006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35489007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35489007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366979004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366979004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255339005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255339005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F34.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F34.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F32.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F32.A</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F33.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F33.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0812393&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0812393</a>, <a href="https://bioportal.bioontology.org/search?q=C0011581&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011581</a>, <a href="https://bioportal.bioontology.org/search?q=C0460137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0460137</a>, <a href="https://bioportal.bioontology.org/search?q=C1579931&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1579931</a>, <a href="https://bioportal.bioontology.org/search?q=C0344315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344315</a>, <a href="https://bioportal.bioontology.org/search?q=C4085311&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4085311</a>, <a href="https://bioportal.bioontology.org/search?q=C0011570&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011570</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span><br />
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<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Patient cells have increased levels of LMNB1 mRNA and protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805842&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805842</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset in the fourth to sixth decades (mean 40 years)<br />
- Autonomic dysfunction usually precedes obvious neurologic deterioration<br />
<div class="mim-changed mim-change"> - Slowly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854494</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span><br /></div>
<div class="mim-changed mim-change"> - Acute neurologic deterioration with fever, heat, stress<br /></div>
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<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
<div class="mim-changed mim-change"> - Caused by a heterozygous tandem genomic duplication on chromosome 5q23<br /></div>
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<h5>
Leukodystrophy, demyelinating, adult-onset
- <a href="/phenotypicSeries/PS169500">PS169500</a>
- 2 Entries
</h5>
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<strong>Location</strong>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
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<strong>Inheritance</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
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<strong>Gene/Locus</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<td>
<span class="mim-font">
<a href="/geneMap/5/408?start=-3&limit=10&highlight=408"> 5q23.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/621061"> Leukodystrophy, demyelinating, adult-onset, autosomal dominant, atypical </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/621061"> 621061 </a>
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<span class="mim-font">
<a href="/entry/150340"> LMNB1 </a>
</span>
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<span class="mim-font">
<a href="/entry/150340"> 150340 </a>
</span>
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<span class="mim-font">
<a href="/geneMap/5/408?start=-3&limit=10&highlight=408"> 5q23.2 </a>
</span>
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<td>
<span class="mim-font">
<a href="/entry/169500"> Leukodystrophy, demyelinating, adult-onset, autosomal dominant, typical </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>
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<span class="mim-font">
<a href="/entry/169500"> 169500 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/150340"> LMNB1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/150340"> 150340 </a>
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<div class="mim-changed mim-change"><p>A number sign (#) is used with this entry because typical autosomal dominant adult-onset demyelinating leukodystrophy (ADLDTY) is caused by a heterozygous tandem genomic duplication on chromosome 5q23 that results in an extra copy of the lamin B1 gene (LMNB1; <a href="/entry/150340">150340</a>), but also alters regulatory sequences that affect expression of other genes.</p></div>
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<strong>Description</strong>
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<div class="mim-changed mim-change"><p>Typical autosomal dominant adult-onset demyelinating leukodystrophy (ADLDTY) is an autosomal dominant slowly progressive neurologic disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by <a href="#16" class="mim-tip-reference" title="Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A., Hogan, K., Ptacek, L. J., Fu, Y.-H. &lt;strong&gt;Lamin B1 duplications cause autosomal dominant leukodystrophy.&lt;/strong&gt; Nature Genet. 38: 1114-1123, 2006. Note: Erratum: Nature Genet. 39: 276 only, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16951681/&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;16951681&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1872&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="16951681">Padiath et al., 2006</a>). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by <a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21225301+16951681" 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></div>
<div class="mim-changed mim-change"><p>Atypical ADLD (ADLDAT; <a href="/entry/621061">621061</a>) is caused by heterozygous deletion on chromosome 5q23 involving regulatory regions upstream of the LMNB1 gene. Atypical ADLD is distinguished from typical ADLD by onset of pyramidal symptoms before autonomic symptoms and by lack of clinical and radiologic cerebellar involvement (<a href="#7" class="mim-tip-reference" title="Dimartino, P., Zadorozhna, M., Yumiceba, V., Basile, A., Cani, I., Melo, U. S., Henck, J., Breur, M., Tonon, C., Lodi, R., Brusco, A., Pippucci, T., and 12 others. &lt;strong&gt;Structural variants at the LMNB1 locus: deciphering pathomechanisms in autosomal dominant adult-onset demyelinating leukodystrophy.&lt;/strong&gt; Ann. Neurol. 96: 855-870, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39078102/&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;39078102&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.27038&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="39078102">Dimartino et al., 2024</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39078102" 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></div>
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<strong>Clinical Features</strong>
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<div class="mim-changed mim-change"><p><a href="#9" class="mim-tip-reference" title="Eldridge, R., Anayiotos, C. P., Schlesinger, S., Cowen, D., Bever, C., Patronas, N., McFarland, H. &lt;strong&gt;Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.&lt;/strong&gt; New Eng. J. Med. 311: 948-953, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6472420/&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;6472420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198410113111504&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="6472420">Eldridge et al. (1984)</a> described a large American-Irish kindred with a chronic progressive neurologic disorder affecting at least 10 men and 11 women in 4 generations in an autosomal dominant pattern. Multiple sclerosis was diagnosed in 20 of the patients evaluated before the availability of CT imaging and without regard to the family history. Neurologic symptoms began in the 4th and 5th decades and included cerebellar, pyramidal, and autonomic abnormalities. The autonomic dysfunction involved bowel and bladder regulation and orthostatic hypotension; these were often the earliest changes but were frequently disregarded. Survival for 20 years after onset was common. CT imaging showed symmetrical decreases in white-matter density, beginning in the frontal lobes and extending to all of the centrum ovale and cerebellar white matter. In patients from this family, <a href="#1" class="mim-tip-reference" title="Brown, R. T., Polinsky, R. J., Schwankhaus, J., Eldridge, R., McFarland, H., Schlesinger, S., Dailey, W. A. &lt;strong&gt;Adrenergic dysfunction in hereditary adult-onset leukodystrophy.&lt;/strong&gt; Neurology 37: 1421-1424, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3302762/&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;3302762&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.37.8.1421&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="3302762">Brown et al. (1987)</a> demonstrated findings consistent with denervation supersensitivity, suggesting a distal lesion of sympathetic noradrenergic neurons. Absence of the epinephrine response to insulin-induced hypoglycemia indicated that autonomic neuropathy was attended by severe adrenal medullary dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6472420+3302762" 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></div>
<div class="mim-changed mim-change"><p><a href="#15" class="mim-tip-reference" title="Laxova, A., Hogan, K., Haun, J. &lt;strong&gt;A new autosomal dominant adult onset progressive leukodystrophy. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 37: A65 only, 1985."None>Laxova et al. (1985)</a> described a Scottish-Irish family with a similar, possibly identical disorder. Onset in the late 30s was marked by autonomic symptoms, including postural hypotension, neurogenic bladder, and rectal incontinence. Progressive spasticity followed, with death in 10 to 15 years. Orientation and affect remained intact. CT scans and magnetic resonance imaging showed symmetric atrophy of white matter. Some clinically unaffected offspring showed the same change. The condition was often misdiagnosed as multiple sclerosis.</p></div>
<div class="mim-changed mim-change"><p><a href="#21" class="mim-tip-reference" title="Schwankhaus, J. D., Katz, D. A., Eldridge, R., Schlesinger, S., McFarland, H. &lt;strong&gt;Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.&lt;/strong&gt; Arch. Neurol. 51: 757-766, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8042923/&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;8042923&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1994.00540200033013&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="8042923">Schwankhaus et al. (1994)</a> reported autopsy findings from a 64-year-old affected woman of the kindred reported by <a href="#9" class="mim-tip-reference" title="Eldridge, R., Anayiotos, C. P., Schlesinger, S., Cowen, D., Bever, C., Patronas, N., McFarland, H. &lt;strong&gt;Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.&lt;/strong&gt; New Eng. J. Med. 311: 948-953, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6472420/&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;6472420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198410113111504&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="6472420">Eldridge et al. (1984)</a>. Her symptoms began at age 44 years. The most striking finding was leukoencephalopathy preferentially affecting the frontal and parietal lobes, including the lateral margins of the corpus callosum, and diminishing in severity toward the occipital lobes. Subcortical U fibers were spared. There was no inflammation or metachromasia. No lipid accumulation was seen by oil red O or with Sudan black. No histologic abnormality was seen in the peripheral nervous system or in the adrenal glands, despite clinical evidence of autonomic dysfunction which is typically a presenting feature of adult-onset leukodystrophy. Although there were vacuolar changes in the white matter reminiscent of a classic spongiform encephalopathy, <a href="#21" class="mim-tip-reference" title="Schwankhaus, J. D., Katz, D. A., Eldridge, R., Schlesinger, S., McFarland, H. &lt;strong&gt;Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.&lt;/strong&gt; Arch. Neurol. 51: 757-766, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8042923/&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;8042923&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1994.00540200033013&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="8042923">Schwankhaus et al. (1994)</a> thought that the large size of the vacuoles, the absence of any changes in the gray matter, and the clinical course argued against this. No prion studies were done. The authors suggested that the early autonomic insufficiency seen in their patient was a feature that distinguished autosomal dominant, adult-onset leukodystrophy from adult-onset Pelizaeus-Merzbacher disease, which they referred to as Lowenberg-Hill disease (<a href="#19" class="mim-tip-reference" title="Rodriguez, M., Powell, H. C., Lampert, P. W. &lt;strong&gt;Demyelination and leukodystrophy. In: Rosenberg, R. N.: The Clinical Neurosciences: Neuropathology.&lt;/strong&gt; New York: Churchill Livingstone (pub.) 1983. Pp. 419-445."None>Rodriguez et al., 1983</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6472420+8042923" 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></div>
<div class="mim-changed mim-change"><p><a href="#13" class="mim-tip-reference" title="Labauge, P., Fogli, A., Castelnovo, G., Le Bayon, A., Horzinski, L., Nicoli, F., Cozzone, P., Pages, M., Briere, C., Marty-Double, C., Delhaume, O., Gelot, A., Boespflug-Tanguy, O., Rodriguez, D. &lt;strong&gt;Dominant form of vanishing white matter-like leukoencephalopathy.&lt;/strong&gt; Ann. Neurol. 58: 634-639, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16047349/&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;16047349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20573&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="16047349">Labauge et al. (2005)</a> reported a mother and son with an adult-onset disorder similar to vanishing white matter disease (see VWM1; <a href="/entry/603896">603896</a>) except for apparent autosomal dominant inheritance. At age 35, the son had an acute episode of brain dysfunction after a viral illness. Features included excessive somnolence and mental confusion, apathy, vomiting, and left-sided hemiparesis requiring mechanical ventilation. Brain CT scan showed extensive hypodensity of the cerebral white matter. Similar episodes occurred following viral infections at ages 36, 39, and 40 years. After the fourth episode, progressive neurologic deterioration was observed, including cerebellar ataxia, spastic quadriparesis, and pseudobulbar syndrome. MRI showed progressive cortical and subcortical diffuse white matter abnormalities suggesting cavitating white matter degeneration. The patient's mother developed progressive ataxia at age 38, suffered a fall with head trauma, and subsequently died. Neuropathologic examination showed grayish, gelatinous, and precavitary changes in the white matter; U fibers and part of the optic radiations were unaffected. Myelin stains showed a severe depletion of myelin sheaths with spongiform changes and precavitary appearance in the most affected areas. There was a preservation of oligodendrocytes with abundant foamy cytoplasm and decreased numbers of astrocytes, although those that remained showed highly reactive features. Although <a href="#13" class="mim-tip-reference" title="Labauge, P., Fogli, A., Castelnovo, G., Le Bayon, A., Horzinski, L., Nicoli, F., Cozzone, P., Pages, M., Briere, C., Marty-Double, C., Delhaume, O., Gelot, A., Boespflug-Tanguy, O., Rodriguez, D. &lt;strong&gt;Dominant form of vanishing white matter-like leukoencephalopathy.&lt;/strong&gt; Ann. Neurol. 58: 634-639, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16047349/&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;16047349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20573&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="16047349">Labauge et al. (2005)</a> concluded that the phenotype was consistent with VWM disease, genetic analysis of the proband excluded mutations in the EIF2B genes (see, e.g., EIF2B1; <a href="/entry/606686">606686</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16047349" 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></div>
<div class="mim-changed mim-change"><p><a href="#18" class="mim-tip-reference" title="Ptacek, L. J., Fu, Y.-H., Koeppen, A. &lt;strong&gt;The dominant form of vanishing white matter-like leukoencephalopathy represents autosomal dominant leukodystrophy. (Letter)&lt;/strong&gt; Ann. Neurol. 59: 434 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16437562/&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;16437562&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20773&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="16437562">Ptacek et al. (2006)</a> suggested that the mother and son reported by <a href="#13" class="mim-tip-reference" title="Labauge, P., Fogli, A., Castelnovo, G., Le Bayon, A., Horzinski, L., Nicoli, F., Cozzone, P., Pages, M., Briere, C., Marty-Double, C., Delhaume, O., Gelot, A., Boespflug-Tanguy, O., Rodriguez, D. &lt;strong&gt;Dominant form of vanishing white matter-like leukoencephalopathy.&lt;/strong&gt; Ann. Neurol. 58: 634-639, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16047349/&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;16047349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20573&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="16047349">Labauge et al. (2005)</a> had ADLD. They suggested that the acute episodes of brain dysfunction after mild insults may represent uncovering of compromised nervous system function. In a response to <a href="#18" class="mim-tip-reference" title="Ptacek, L. J., Fu, Y.-H., Koeppen, A. &lt;strong&gt;The dominant form of vanishing white matter-like leukoencephalopathy represents autosomal dominant leukodystrophy. (Letter)&lt;/strong&gt; Ann. Neurol. 59: 434 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16437562/&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;16437562&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20773&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="16437562">Ptacek et al. (2006)</a>, <a href="#14" class="mim-tip-reference" title="Labauge, P., Gelot, A., Fogli, A., Boespflug-Tanguy, O., Rodiguez, D. &lt;strong&gt;Autosomal dominant leukodystrophy and childhood ataxia with central nervous system hypomyelination syndrome. (Letter)&lt;/strong&gt; Ann. Neurol. 60: 485 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16847948/&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;16847948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20930&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="16847948">Labauge et al. (2006)</a> stated that their patients lacked early autonomic features characteristic of ADLD and that acute neurologic deterioration observed in their patients had not been described in ADLD, but noted that overlap exists among various leukodystrophies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16847948+16437562+16047349" 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></div>
<p><a href="#3" class="mim-tip-reference" title="Brussino, A., Vaula, G., Cagnoli, C., Mauro, A., Pradotto, L., Daniele, D., Di Gregorio, E., Barberis, M., Arduino, C., Squadrone, S., Abete, M. C., Migone, N., Calabrese, O., Brusco, A. &lt;strong&gt;A novel family with Lamin B1 duplication associated with adult-onset leucoencephalopathy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 80: 237-240, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19151023/&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;19151023&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.2008.147330&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="19151023">Brussino et al. (2009)</a> reported a 3-generation Italian family with ADLD that was confirmed genetically in 2 affected individuals. These 2 patients presented as adults with autonomic dysfunction, including micturition defects and impotence. The disorder progressed to involve walking difficulties; 1 patient became wheelchair-bound. Brain MRI of both patients showed diffuse subcortical infra- and supratentorial white matter abnormalities with sparing of the U-fibers and optic radiations. Genetic analysis identified a heterozygous 140- to 190-kb duplication of a region including the LMNB1 gene as well as neighboring sequences. There was a positive family history of a similar neurodegenerative disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19151023" 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="#22" class="mim-tip-reference" title="Sundblom, J., Melberg, A., Kalimo, H., Smits, A., Raininko, R. &lt;strong&gt;MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.&lt;/strong&gt; Am. J. Neuroradiol. 30: 328-335, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18945794/&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;18945794&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18945794[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/10.3174/ajnr.A1354&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="18945794">Sundblom et al. (2009)</a> reported 2 unrelated Swedish families with ADLD. Twelve individuals examined, including 11 patients and 1 asymptomatic individual, were found to have a thin spinal cord on MRI. There was also a slight general white matter signal intensity increase in the whole spinal cord, mainly visible in T2-weighted transverse images. Postmortem examination of 1 patient showed discrete demyelination in the spinal cord. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18945794" 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="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al. (2011)</a> reported 4 unrelated families with ADLD. Two families were of Swedish origin and had previously been reported (<a href="#22" class="mim-tip-reference" title="Sundblom, J., Melberg, A., Kalimo, H., Smits, A., Raininko, R. &lt;strong&gt;MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.&lt;/strong&gt; Am. J. Neuroradiol. 30: 328-335, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18945794/&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;18945794&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18945794[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/10.3174/ajnr.A1354&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="18945794">Sundblom et al., 2009</a>). The other 2 families were of German and Israeli-Arab descent, respectively. One of the Swedish families had 31 affected individuals spanning at least 4 generations. Disease onset occurred in the fifth or sixth decade. Autonomic symptoms included urinary bladder symptoms, constipation, postural hypotension, erectile dysfunction, and heat intolerance. Affected individuals later developed ataxia and pyramidal signs. Some patients showed cognitive decline. Brain MRI showed signs characteristic of this type of leukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18945794+21225301" 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>
<div class="mim-changed mim-change"><p><a href="#10" class="mim-tip-reference" title="Finnsson, J., Sundblom, J., Dahl, N., Melberg, A., Raininko, R. &lt;strong&gt;LMNB1-related autosomal-dominant leukodystrophy: clinical and radiological course.&lt;/strong&gt; Ann. Neurol. 78: 412-425, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26053668/&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;26053668&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26053668[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/10.1002/ana.24452&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="26053668">Finnsson et al. (2015)</a> reported follow-up of 22 individuals from the 2 Swedish families reported by <a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al. (2011)</a>. Onset of autonomic symptoms, usually urinary dysfunction, occurred in 14 patients between 40 and 58 years of age. Six patients presented with autonomic and gait problems, whereas only 2 presented with gait problems. Additional autonomic features included orthostatic hypotension, erectile dysfunction, and constipation. Six patients had dry skin. Most (91%) had slowly progressive pyramidal signs with spastic paraplegia, weakness, brisk reflexes, and extensor plantar responses. This progressed to tetraparesis with absent reflexes, involvement of the upper limbs, and pseudobulbar palsy with swallowing difficulties. Four patients eventually required gastrostomy. Walking difficulties were progressive, and many were later wheelchair-bound. About half of the patients had tremor, both intention and postural, and some later had dysmetria and dysdiadochokinesis. Two had nystagmus and a few had saccadic smooth pursuit. Seven (32%) had sensory deficits affecting the lower limbs. Many patients reported worsening of neurologic symptoms during stress, infection, or heat exposure. Cognition was normal early in the disease course, but patients at the advanced stage often had pseudobulbar palsy with speech difficulties and apraxia; 2 had frank dementia. CT findings, performed in 5 individuals, showed hypodensities in the cerebral white matter and middle cerebellar peduncles with progressive loss of white matter. Brain MRI, performed in most, showed progressive T2-weighted hyperintensities in the motor cortex, cerebral white matter, pyramidal tracts, and cerebellar peduncles. Abnormal brain imaging preceded symptom onset in several patients. Median survival time after symptom onset was 18 years. The authors concluded that the features of the disorder are consistent with a myelopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26053668+21225301" 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></div>
<div class="mim-changed mim-change"><p><a href="#8" class="mim-tip-reference" title="Dos Santos, M. M., Grond-Ginsbach, C., Aksay, S. S., Chen, B., Tchatchou, S., Wolf, N. I., van der Knaap, M. S., Grau, A. J. &lt;strong&gt;Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication. (Letter)&lt;/strong&gt; J. Neurol. 259: 579-581, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21909802/&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;21909802&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00415-011-6225-4&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="21909802">Dos Santos et al. (2012)</a> reported a 3-generation family in Germany with ADLD. The proband presented at age 47 with a 2-year history of urinary difficulties, personality changes, and depression. He was found to have gait and limb ataxia, spastic paraparesis, hyperreflexia, and extensor plantar responses. Brain MRI showed extensive T2-weighted hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of the periventricular rim and corpus callosum. Other affected brain regions included the middle cerebellar peduncles, the pyramidal tracts, medial lemniscus in the midbrain, pons, medulla, and the decussation of the superior cerebellar peduncles. Family history revealed numerous affected members in an autosomal dominant pattern. The patient's 44-year-old sister was clinically asymptomatic, but her cerebral MRI showed extensive bilateral signal hyperintensities in the subcortical and deep cerebral white matter and in the middle cerebellar peduncles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21909802" 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></div>
<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Flanagan, E. P., Gavrilova, R. H., Boeve, B. F., Kumar, N., Jelsing, E. J., Silber, M. H. &lt;strong&gt;Adult-onset autosomal dominant leukodystrophy presenting with REM sleep behavior disorder.&lt;/strong&gt; Neurology 80: 118-120, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23243074/&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;23243074&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31827b1b2a&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="23243074">Flanagan et al. (2013)</a> reported a 63-year-old man with genetically confirmed ADLD who presented with REM sleep behavior disorder (RBD) characterized by dream enactment behavior up to 3 times per week for the previous 4 years. During the episodes, he would scream, shout, flail his arms, and kick his legs. Polysomnography showed markedly increased muscle tone during REM sleep. Additional neurologic features included left-sided spasticity and cerebellar signs, hyperreflexia, and rare bowel incontinence. Brain MRI showed cervical spinal cord atrophy and T2-weighted hyperintense lesions in the brainstem, cerebellar peduncles, and subcortical white matter. <a href="#11" class="mim-tip-reference" title="Flanagan, E. P., Gavrilova, R. H., Boeve, B. F., Kumar, N., Jelsing, E. J., Silber, M. H. &lt;strong&gt;Adult-onset autosomal dominant leukodystrophy presenting with REM sleep behavior disorder.&lt;/strong&gt; Neurology 80: 118-120, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23243074/&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;23243074&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31827b1b2a&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="23243074">Flanagan et al. (2013)</a> postulated that damage to the myelinated axons from the subceruleus nucleus and adjacent areas to alpha-motor neurons may have impaired normal motor inhibition during REM sleep. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243074" 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></div>
<div class="mim-changed mim-change"><p><a href="#23" class="mim-tip-reference" title="Terlizzi, R., Calandra-Buonaura, G., Zanigni, S., Barletta, G., Capellari, S., Guaraldi, P., Donadio, V., Cason, E., Contin, M., Poda, R., Tonon, C., Sambati, L., Gallassi, R., Liguori, R., Lodi, R., Cortelli, P. &lt;strong&gt;A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: clinical, autonomic and neuropsychological findings.&lt;/strong&gt; Auton. Neurosci 195: 20-26, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26896090/&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;26896090&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.autneu.2016.02.005&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="26896090">Terlizzi et al. (2016)</a> reported 3 affected sibs (mean age of 54 years) with genetically confirmed ADLD and an asymptomatic carrier family member (23 years) from a southern Italian family with a history of the disease. The 3 affected sibs presented with autonomic dysfunction and later developed cerebellar signs (ataxia, nystagmus, dysmetria, tremor) and pyramidal signs (spasticity with brisk tendon reflexes), resulting in progressive gait impairment. Neuropsychologic testing showed progressive impairment of executive function, including attention, abstract thinking, and semantic fluency. Additional testing indicated post-ganglionic sympathetic noradrenergic failure. The authors postulated astrocyte dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26896090" 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></div>
<div class="mim-changed mim-change"><p>In a postmortem histopathologic study of a patient with typical ADLD, <a href="#7" class="mim-tip-reference" title="Dimartino, P., Zadorozhna, M., Yumiceba, V., Basile, A., Cani, I., Melo, U. S., Henck, J., Breur, M., Tonon, C., Lodi, R., Brusco, A., Pippucci, T., and 12 others. &lt;strong&gt;Structural variants at the LMNB1 locus: deciphering pathomechanisms in autosomal dominant adult-onset demyelinating leukodystrophy.&lt;/strong&gt; Ann. Neurol. 96: 855-870, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39078102/&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;39078102&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.27038&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="39078102">Dimartino et al. (2024)</a> found patchy myelin in the cerebral white matter, and lack of myelin with tissue rarefaction and dysmorphic astrocytes in the cerebellar white matter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39078102" 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></div>
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<div class="mim-changed mim-change"><p>The transmission pattern of typical ADLD in the 4 unrelated families reported by <a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al. (2011)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21225301" 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></div>
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<p><a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al. (2011)</a> found about a 2-fold increased level of LMNB1 protein in white blood cells from 5 patients with genetically confirmed ADLD. LMNB1 mRNA was also increased compared to controls. <a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al. (2011)</a> concluded that an accurate molecular diagnosis of the disorder could be made by direct analysis of LMNB1 in peripheral leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21225301" 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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<strong>Mapping</strong>
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<p><a href="#5" class="mim-tip-reference" title="Coffeen, C. M., McKenna, C. E., Koeppen, A. H., Plaster, N. M., Maragakis, N., Mihalopoulos, J., Schwankhaus, J. D., Flanigan, K. M., Gregg, R. G., Ptacek, L. J., Fu, Y.-H. &lt;strong&gt;Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.&lt;/strong&gt; Hum. Molec. Genet. 9: 787-793, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10749986/&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;10749986&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.5.787&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="10749986">Coffeen et al. (2000)</a> reported additional clinical, neuroradiologic, and neuropathologic data from the family with autosomal dominant leukodystrophy originally reported by <a href="#9" class="mim-tip-reference" title="Eldridge, R., Anayiotos, C. P., Schlesinger, S., Cowen, D., Bever, C., Patronas, N., McFarland, H. &lt;strong&gt;Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.&lt;/strong&gt; New Eng. J. Med. 311: 948-953, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6472420/&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;6472420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198410113111504&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="6472420">Eldridge et al. (1984)</a>. Furthermore, they localized the ADLD gene to a 4-cM region on chromosome 5q31. Linkage analysis of this family yielded a lod score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6472420+10749986" 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="cytogenetics" class="mim-anchor"></a>
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<strong>Cytogenetics</strong>
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<div class="mim-changed mim-change"><p><a href="#16" class="mim-tip-reference" title="Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A., Hogan, K., Ptacek, L. J., Fu, Y.-H. &lt;strong&gt;Lamin B1 duplications cause autosomal dominant leukodystrophy.&lt;/strong&gt; Nature Genet. 38: 1114-1123, 2006. Note: Erratum: Nature Genet. 39: 276 only, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16951681/&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;16951681&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1872&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="16951681">Padiath et al. (2006)</a> found heterozygous duplication of 5q23, including the LMNB1 gene, as the cause of typical ADLD in affected members of 4 families. One of these was the family described by <a href="#9" class="mim-tip-reference" title="Eldridge, R., Anayiotos, C. P., Schlesinger, S., Cowen, D., Bever, C., Patronas, N., McFarland, H. &lt;strong&gt;Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.&lt;/strong&gt; New Eng. J. Med. 311: 948-953, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6472420/&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;6472420&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198410113111504&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="6472420">Eldridge et al. (1984)</a>; haplotype analysis suggested that this family and a second Irish-American family shared a common founder. Lamin B1 was found to be overexpressed in brain tissue from affected individuals. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. The clinical similarity of ADLD to multiple sclerosis and the identification of autoantibodies to lamin B suggested to <a href="#16" class="mim-tip-reference" title="Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A., Hogan, K., Ptacek, L. J., Fu, Y.-H. &lt;strong&gt;Lamin B1 duplications cause autosomal dominant leukodystrophy.&lt;/strong&gt; Nature Genet. 38: 1114-1123, 2006. Note: Erratum: Nature Genet. 39: 276 only, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16951681/&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;16951681&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1872&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="16951681">Padiath et al. (2006)</a> that a closer examination of the involvement of lamin B in multiple sclerosis is warranted. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6472420+16951681" 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></div>
<div class="mim-changed mim-change"><p><a href="#3" class="mim-tip-reference" title="Brussino, A., Vaula, G., Cagnoli, C., Mauro, A., Pradotto, L., Daniele, D., Di Gregorio, E., Barberis, M., Arduino, C., Squadrone, S., Abete, M. C., Migone, N., Calabrese, O., Brusco, A. &lt;strong&gt;A novel family with Lamin B1 duplication associated with adult-onset leucoencephalopathy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 80: 237-240, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19151023/&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;19151023&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.2008.147330&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="19151023">Brussino et al. (2009)</a> found a 140- to 190-kb duplication of 5q including the entire LMNB1 gene, the AX748201 transcript, and the 3-prime end of the MARCH3 gene (<a href="/entry/613333">613333</a>) in 1 of 8 Italian probands with adult-onset leukoencephalopathy. The patient's affected cousin also carried the duplication, and there was a family history of a similar disorder. Lamin B1 expression was increased in lymphoblasts from one of the patients with the duplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19151023" 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></div>
<div class="mim-changed mim-change"><p>In affected members of 4 unrelated families with ADLD, <a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al. (2011)</a> found duplication of 5q23 including the LMNB1 gene. All 4 duplications were of different sizes, ranging from 107 to 218 kb, supporting independent events. Each duplication extended over part of the MARCH3 gene, but MARCH3 mRNA was not increased in patient leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21225301" 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></div>
<div class="mim-changed mim-change"><p>In a symptomatic man with ADLD and his asymptomatic sister who had leukodystrophy on brain imaging, <a href="#8" class="mim-tip-reference" title="Dos Santos, M. M., Grond-Ginsbach, C., Aksay, S. S., Chen, B., Tchatchou, S., Wolf, N. I., van der Knaap, M. S., Grau, A. J. &lt;strong&gt;Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication. (Letter)&lt;/strong&gt; J. Neurol. 259: 579-581, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21909802/&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;21909802&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00415-011-6225-4&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="21909802">Dos Santos et al. (2012)</a> identified a 148-kb duplication on chromosome 5q23.2 including the LMNB1 gene, but not the MARCH3 gene. The findings confirmed the central role of the LMNB1 gene in ADLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21909802" 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></div>
<div class="mim-changed mim-change"><p>Using a custom array, <a href="#12" class="mim-tip-reference" title="Giorgio, E., Rolyan, H., Kropp, L., Chakka, A. B., Yatsenko, S., Di Gregorio, E., Lacerenza, D., Vaula, G., Talarico, F., Mandich, P., Toro, C., Pierre, E. E., and 26 others. &lt;strong&gt;Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.&lt;/strong&gt; Hum. Mutat. 34: 1160-1171, 2013. Note: Erratum: Hum. Mutat. 35: 149 only, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23649844/&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;23649844&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23649844[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/10.1002/humu.22348&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="23649844">Giorgio et al. (2013)</a> performed detailed breakpoint junction sequence analysis of the duplicated 5q23 region containing the LMNB1 gene in 20 independent families with ADLD in whom genomic LMNB1 duplication was initially identified by aCGH, QT-PCR, or MLPA. Seven families had previously been reported (<a href="#3" class="mim-tip-reference" title="Brussino, A., Vaula, G., Cagnoli, C., Mauro, A., Pradotto, L., Daniele, D., Di Gregorio, E., Barberis, M., Arduino, C., Squadrone, S., Abete, M. C., Migone, N., Calabrese, O., Brusco, A. &lt;strong&gt;A novel family with Lamin B1 duplication associated with adult-onset leucoencephalopathy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 80: 237-240, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19151023/&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;19151023&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.2008.147330&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="19151023">Brussino et al., 2009</a>; <a href="#20" class="mim-tip-reference" title="Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N. &lt;strong&gt;Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.&lt;/strong&gt; Neurogenetics 12: 65-72, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21225301/&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;21225301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-010-0269-y&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="21225301">Schuster et al., 2011</a>; <a href="#8" class="mim-tip-reference" title="Dos Santos, M. M., Grond-Ginsbach, C., Aksay, S. S., Chen, B., Tchatchou, S., Wolf, N. I., van der Knaap, M. S., Grau, A. J. &lt;strong&gt;Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication. (Letter)&lt;/strong&gt; J. Neurol. 259: 579-581, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21909802/&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;21909802&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00415-011-6225-4&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="21909802">Dos Santos et al., 2012</a>). There were a total of 16 unique rearrangements. Three of the duplications were shared by more than 1 family: 1 was found in 3 families and the other 2 duplications were found in 2 families each. Individuals with identical junctions shared the same haplotype, consistent with a founder effect. Duplication sizes ranged from about 128 kb to 475 kb. The largest duplication also included the PHAX (<a href="/entry/604924">604924</a>), ALDH7A1 (<a href="/entry/107323">107323</a>), and GRAMD3 (GRAMD2B; <a href="/entry/620182">620182</a>) genes. Comparison of all the samples identified a 72-kb minimal critical duplicated region required for ADLD that contained only the LMNB1 gene. Characterization of the junction sequences showed that most (11 of 15) showed short stretches of microhomology overlap ranging from 1 to 6 nucleotides, whereas the others showed small insertions at the breakpoints. All duplications resulted from intrachromosomal rearrangements. Analysis of the genomic architecture suggested several potential mechanisms for the duplications, including nonhomologous end joining (NHEJ) or fork stalling and template switching/microhomology-mediated break-induced repair (FoSTeS/MMBIR). The enrichment of Alu repetitive elements at the centromeric breakpoints (found in 4 cases), higher GC content, and high frequency of repetitive sequences at breakpoints likely also played a role in mediating ADLD duplications. RT-PCR of patients fibroblasts or blood showed increased LMNB1 expression (2.1- to 4.8-fold compared to controls), as well as increased protein levels (1.6- to 3.2-fold compared to controls). There was no apparent difference in phenotype according to duplication size. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21225301+21909802+19151023+23649844" 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></div>
<div class="mim-changed mim-change"><p>In a 42-year-old woman of Italian ancestry, who was born in Brazil, with clinical features of ADLD, <a href="#17" class="mim-tip-reference" title="Pedroso, J. L., Munford, V., Bastos, A. U., Castro, L. P., Marussi, V. H. R., Silva, G. S., Arita, J. H., Menck, C. F. M., Barsottini, O. G. &lt;strong&gt;LMNB1 mutation causes cerebellar involvement and a genome instability defect.&lt;/strong&gt; J. Neurol. Sci. 379: 249-252, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28716252/&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;28716252&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jns.2017.06.027&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="28716252">Pedroso et al. (2017)</a> identified a heterozygous missense variant in the LMNB1 gene (R29W). The variant, which was found by whole-exome sequencing, was not present in several public databases, including the Exome Sequencing Project and ExAC. Patient-derived cells showed increased expression of variant LMNB1 mRNA and nuclear structural abnormalities. Functional studies indicated an impaired response to DNA damage, suggesting genomic instability. The patient presented at 23 years of age with progressive cerebellar atrophy and cognitive impairment. Brain imaging showed white matter abnormalities in the cerebellum, as well as atrophy of the corpus callosum, brainstem, and spinal cord. In in vitro studies, <a href="#6" class="mim-tip-reference" title="Cristofoli, F., Moss, T., Moore, H. W., Devriendt, K., Flanagan-Steet, H., May, M., Jones, J., Roelens, F., Fons, C., Fernandez, A., Martorell, L., Selicorni, A., Maitz, S., Vitiello, G., Van der Hoeven, G., Skinner, S. A., Bollen, M., Vermeesch, J. R., Steet, R., Van Esch, H. &lt;strong&gt;De novo variants in LMNB1 cause pronounced syndromic microcephaly and disruption of nuclear envelope integrity.&lt;/strong&gt; Am. J. Hum. Genet. 107: 753-762, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32910914/&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;32910914&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=32910914[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.2020.08.015&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="32910914">Cristofoli et al. (2020)</a> demonstrated that the R29W mutant protein was present in the nuclear extract, suggesting that it did not disrupt nuclear lamina localization of LMNB1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28716252+32910914" 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></div>
<div class="mim-changed mim-change"><p>Using high-throughput chromosome conformation capture (Hi-C) techniques to analyze topologically associating domains (TADs), <a href="#7" class="mim-tip-reference" title="Dimartino, P., Zadorozhna, M., Yumiceba, V., Basile, A., Cani, I., Melo, U. S., Henck, J., Breur, M., Tonon, C., Lodi, R., Brusco, A., Pippucci, T., and 12 others. &lt;strong&gt;Structural variants at the LMNB1 locus: deciphering pathomechanisms in autosomal dominant adult-onset demyelinating leukodystrophy.&lt;/strong&gt; Ann. Neurol. 96: 855-870, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39078102/&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;39078102&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.27038&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="39078102">Dimartino et al. (2024)</a> found that patients with typical ADLD (<a href="#12" class="mim-tip-reference" title="Giorgio, E., Rolyan, H., Kropp, L., Chakka, A. B., Yatsenko, S., Di Gregorio, E., Lacerenza, D., Vaula, G., Talarico, F., Mandich, P., Toro, C., Pierre, E. E., and 26 others. &lt;strong&gt;Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.&lt;/strong&gt; Hum. Mutat. 34: 1160-1171, 2013. Note: Erratum: Hum. Mutat. 35: 149 only, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23649844/&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;23649844&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23649844[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/10.1002/humu.22348&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="23649844">Giorgio et al., 2013</a>; <a href="#2" class="mim-tip-reference" title="Brunetti, V., Ferilli, M. A., Nociti, V., Silvestri, G. &lt;strong&gt;Teaching NeuroImages: Autosomal dominant leukodystrophy in a sporadic case.&lt;/strong&gt; Neurology 83: e121, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25224534/&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;25224534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0000000000000803&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="25224534">Brunetti et al., 2014</a>) carried intra-TAD duplications on 5q23 within the LMNB1 TAD that did not extend beyond TAD boundaries and maintained the physiologic regulatory context of LMNB1. This resulted in overexpression of the LMNB1 gene. The authors concluded that duplication of the LMNB1 gene per se is not causative of typical ADLD, which will affect ADLD diagnosis and genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=39078102+25224534+23649844" 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></div>
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<strong>History</strong>
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<div class="mim-changed mim-change"><p><a href="#24" class="mim-tip-reference" title="Zerbin-Rudin, E., Peiffer, J. &lt;strong&gt;Ein genetischer Beitrag zur Frage der Spaetform der Pelizaeus-Merzbacherschen Krankheit.&lt;/strong&gt; Humangenetik 1: 107-122, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5869474/&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;5869474&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00389627&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="5869474">Zerbin-Rudin and Peiffer (1964)</a> described a familial disorder similar to Pelizaeus-Merzbacher disease (PMD; <a href="/entry/312080">312080</a>) except that it showed later onset and autosomal dominant inheritance rather than X-linked inheritance typical of PMD. The disease was noted to be similar to multiple sclerosis (MS; <a href="/entry/126200">126200</a>) in some respects. It may be the same disorder as that reported by <a href="#4" class="mim-tip-reference" title="Camp, C. D., Lowenberg, K. &lt;strong&gt;An American family with Pelizaeus-Merzbacher disease.&lt;/strong&gt; Arch. Neurol. Psychiat. 45: 261-264, 1941."None>Camp and Lowenberg (1941)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5869474" 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></div>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Brown1987" class="mim-anchor"></a>
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Brown, R. T., Polinsky, R. J., Schwankhaus, J., Eldridge, R., McFarland, H., Schlesinger, S., Dailey, W. A.
<strong>Adrenergic dysfunction in hereditary adult-onset leukodystrophy.</strong>
Neurology 37: 1421-1424, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3302762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3302762</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3302762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.37.8.1421" target="_blank">Full Text</a>]
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<a id="Brunetti2014" class="mim-anchor"></a>
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Brunetti, V., Ferilli, M. A., Nociti, V., Silvestri, G.
<strong>Teaching NeuroImages: Autosomal dominant leukodystrophy in a sporadic case.</strong>
Neurology 83: e121, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25224534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25224534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25224534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/WNL.0000000000000803" target="_blank">Full Text</a>]
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<a id="Brussino2009" class="mim-anchor"></a>
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Brussino, A., Vaula, G., Cagnoli, C., Mauro, A., Pradotto, L., Daniele, D., Di Gregorio, E., Barberis, M., Arduino, C., Squadrone, S., Abete, M. C., Migone, N., Calabrese, O., Brusco, A.
<strong>A novel family with Lamin B1 duplication associated with adult-onset leucoencephalopathy.</strong>
J. Neurol. Neurosurg. Psychiat. 80: 237-240, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19151023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19151023</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19151023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jnnp.2008.147330" target="_blank">Full Text</a>]
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<a id="Camp1941" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Camp, C. D., Lowenberg, K.
<strong>An American family with Pelizaeus-Merzbacher disease.</strong>
Arch. Neurol. Psychiat. 45: 261-264, 1941.
</p>
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<a id="Coffeen2000" class="mim-anchor"></a>
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Coffeen, C. M., McKenna, C. E., Koeppen, A. H., Plaster, N. M., Maragakis, N., Mihalopoulos, J., Schwankhaus, J. D., Flanigan, K. M., Gregg, R. G., Ptacek, L. J., Fu, Y.-H.
<strong>Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.</strong>
Hum. Molec. Genet. 9: 787-793, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/9.5.787" target="_blank">Full Text</a>]
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<a id="Cristofoli2020" class="mim-anchor"></a>
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Cristofoli, F., Moss, T., Moore, H. W., Devriendt, K., Flanagan-Steet, H., May, M., Jones, J., Roelens, F., Fons, C., Fernandez, A., Martorell, L., Selicorni, A., Maitz, S., Vitiello, G., Van der Hoeven, G., Skinner, S. A., Bollen, M., Vermeesch, J. R., Steet, R., Van Esch, H.
<strong>De novo variants in LMNB1 cause pronounced syndromic microcephaly and disruption of nuclear envelope integrity.</strong>
Am. J. Hum. Genet. 107: 753-762, 2020.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32910914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32910914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32910914[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32910914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2020.08.015" target="_blank">Full Text</a>]
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<a id="Dimartino2024" class="mim-anchor"></a>
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Dimartino, P., Zadorozhna, M., Yumiceba, V., Basile, A., Cani, I., Melo, U. S., Henck, J., Breur, M., Tonon, C., Lodi, R., Brusco, A., Pippucci, T., and 12 others.
<strong>Structural variants at the LMNB1 locus: deciphering pathomechanisms in autosomal dominant adult-onset demyelinating leukodystrophy.</strong>
Ann. Neurol. 96: 855-870, 2024.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39078102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39078102</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39078102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.27038" target="_blank">Full Text</a>]
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<a id="Dos Santos2012" class="mim-anchor"></a>
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Dos Santos, M. M., Grond-Ginsbach, C., Aksay, S. S., Chen, B., Tchatchou, S., Wolf, N. I., van der Knaap, M. S., Grau, A. J.
<strong>Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication. (Letter)</strong>
J. Neurol. 259: 579-581, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21909802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21909802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21909802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s00415-011-6225-4" target="_blank">Full Text</a>]
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<a id="Eldridge1984" class="mim-anchor"></a>
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Eldridge, R., Anayiotos, C. P., Schlesinger, S., Cowen, D., Bever, C., Patronas, N., McFarland, H.
<strong>Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.</strong>
New Eng. J. Med. 311: 948-953, 1984.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6472420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6472420</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6472420" 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/NEJM198410113111504" target="_blank">Full Text</a>]
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<a id="Finnsson2015" class="mim-anchor"></a>
<div class="mim-changed mim-change">
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Finnsson, J., Sundblom, J., Dahl, N., Melberg, A., Raininko, R.
<strong>LMNB1-related autosomal-dominant leukodystrophy: clinical and radiological course.</strong>
Ann. Neurol. 78: 412-425, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26053668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26053668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26053668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26053668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.24452" target="_blank">Full Text</a>]
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<a id="Flanagan2013" class="mim-anchor"></a>
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Flanagan, E. P., Gavrilova, R. H., Boeve, B. F., Kumar, N., Jelsing, E. J., Silber, M. H.
<strong>Adult-onset autosomal dominant leukodystrophy presenting with REM sleep behavior disorder.</strong>
Neurology 80: 118-120, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/WNL.0b013e31827b1b2a" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="12" class="mim-anchor"></a>
<a id="Giorgio2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Giorgio, E., Rolyan, H., Kropp, L., Chakka, A. B., Yatsenko, S., Di Gregorio, E., Lacerenza, D., Vaula, G., Talarico, F., Mandich, P., Toro, C., Pierre, E. E., and 26 others.
<strong>Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.</strong>
Hum. Mutat. 34: 1160-1171, 2013. Note: Erratum: Hum. Mutat. 35: 149 only, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23649844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23649844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23649844[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23649844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.22348" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="13" class="mim-anchor"></a>
<a id="Labauge2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Labauge, P., Fogli, A., Castelnovo, G., Le Bayon, A., Horzinski, L., Nicoli, F., Cozzone, P., Pages, M., Briere, C., Marty-Double, C., Delhaume, O., Gelot, A., Boespflug-Tanguy, O., Rodriguez, D.
<strong>Dominant form of vanishing white matter-like leukoencephalopathy.</strong>
Ann. Neurol. 58: 634-639, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16047349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16047349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16047349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.20573" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="14" class="mim-anchor"></a>
<a id="Labauge2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Labauge, P., Gelot, A., Fogli, A., Boespflug-Tanguy, O., Rodiguez, D.
<strong>Autosomal dominant leukodystrophy and childhood ataxia with central nervous system hypomyelination syndrome. (Letter)</strong>
Ann. Neurol. 60: 485 only, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16847948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16847948</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16847948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.20930" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="15" class="mim-anchor"></a>
<a id="Laxova1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Laxova, A., Hogan, K., Haun, J.
<strong>A new autosomal dominant adult onset progressive leukodystrophy. (Abstract)</strong>
Am. J. Hum. Genet. 37: A65 only, 1985.
</p>
</div>
</li>
<li>
<a id="16" class="mim-anchor"></a>
<a id="Padiath2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A., Hogan, K., Ptacek, L. J., Fu, Y.-H.
<strong>Lamin B1 duplications cause autosomal dominant leukodystrophy.</strong>
Nature Genet. 38: 1114-1123, 2006. Note: Erratum: Nature Genet. 39: 276 only, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951681</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1872" target="_blank">Full Text</a>]
</p>
</div>
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<a id="17" class="mim-anchor"></a>
<a id="Pedroso2017" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pedroso, J. L., Munford, V., Bastos, A. U., Castro, L. P., Marussi, V. H. R., Silva, G. S., Arita, J. H., Menck, C. F. M., Barsottini, O. G.
<strong>LMNB1 mutation causes cerebellar involvement and a genome instability defect.</strong>
J. Neurol. Sci. 379: 249-252, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28716252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28716252</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28716252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.jns.2017.06.027" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="18" class="mim-anchor"></a>
<a id="Ptacek2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ptacek, L. J., Fu, Y.-H., Koeppen, A.
<strong>The dominant form of vanishing white matter-like leukoencephalopathy represents autosomal dominant leukodystrophy. (Letter)</strong>
Ann. Neurol. 59: 434 only, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437562</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.20773" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="19" class="mim-anchor"></a>
<a id="Rodriguez1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rodriguez, M., Powell, H. C., Lampert, P. W.
<strong>Demyelination and leukodystrophy. In: Rosenberg, R. N.: The Clinical Neurosciences: Neuropathology.</strong>
New York: Churchill Livingstone (pub.) 1983. Pp. 419-445.
</p>
</div>
</li>
<li>
<a id="20" class="mim-anchor"></a>
<a id="Schuster2011" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N.
<strong>Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms.</strong>
Neurogenetics 12: 65-72, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21225301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21225301</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21225301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10048-010-0269-y" target="_blank">Full Text</a>]
</p>
</div>
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<a id="21" class="mim-anchor"></a>
<a id="Schwankhaus1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Schwankhaus, J. D., Katz, D. A., Eldridge, R., Schlesinger, S., McFarland, H.
<strong>Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.</strong>
Arch. Neurol. 51: 757-766, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8042923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8042923</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8042923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.1994.00540200033013" target="_blank">Full Text</a>]
</p>
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<a id="22" class="mim-anchor"></a>
<a id="Sundblom2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sundblom, J., Melberg, A., Kalimo, H., Smits, A., Raininko, R.
<strong>MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.</strong>
Am. J. Neuroradiol. 30: 328-335, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18945794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18945794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18945794[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18945794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.3174/ajnr.A1354" target="_blank">Full Text</a>]
</p>
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<li>
<a id="23" class="mim-anchor"></a>
<a id="Terlizzi2016" class="mim-anchor"></a>
<div class="mim-changed mim-change">
<p class="mim-text-font">
Terlizzi, R., Calandra-Buonaura, G., Zanigni, S., Barletta, G., Capellari, S., Guaraldi, P., Donadio, V., Cason, E., Contin, M., Poda, R., Tonon, C., Sambati, L., Gallassi, R., Liguori, R., Lodi, R., Cortelli, P.
<strong>A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: clinical, autonomic and neuropsychological findings.</strong>
Auton. Neurosci 195: 20-26, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26896090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26896090</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26896090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.autneu.2016.02.005" target="_blank">Full Text</a>]
</p>
</div>
</li>
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<a id="24" class="mim-anchor"></a>
<a id="Zerbin-Rudin1964" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zerbin-Rudin, E., Peiffer, J.
<strong>Ein genetischer Beitrag zur Frage der Spaetform der Pelizaeus-Merzbacherschen Krankheit.</strong>
Humangenetik 1: 107-122, 1964.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5869474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5869474</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5869474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00389627" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="mim-text-font">
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 01/16/2025
</span>
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 02/12/2021<br>Cassandra L. Kniffin - updated : 7/8/2015<br>Cassandra L. Kniffin - updated : 12/29/2014<br>Cassandra L. Kniffin - updated : 10/24/2013<br>Cassandra L. Kniffin - updated : 6/5/2012<br>Cassandra L. Kniffin - updated : 12/2/2008<br>Victor A. McKusick - updated : 10/27/2006<br>Cassandra L. Kniffin - updated : 5/3/2006<br>George E. Tiller - updated : 4/26/2000
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<div>
<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Victor A. McKusick : 6/2/1986
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 01/17/2025
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alopez : 01/17/2025<br>ckniffin : 01/16/2025<br>carol : 08/06/2024<br>carol : 04/18/2023<br>alopez : 02/19/2021<br>ckniffin : 02/12/2021<br>carol : 08/23/2016<br>carol : 07/13/2015<br>mcolton : 7/9/2015<br>ckniffin : 7/8/2015<br>carol : 1/6/2015<br>mcolton : 1/2/2015<br>ckniffin : 12/29/2014<br>carol : 2/21/2014<br>carol : 10/25/2013<br>ckniffin : 10/24/2013<br>alopez : 6/18/2012<br>ckniffin : 6/5/2012<br>carol : 12/8/2011<br>carol : 12/8/2011<br>wwang : 12/5/2008<br>ckniffin : 12/2/2008<br>ckniffin : 11/25/2008<br>joanna : 11/25/2008<br>alopez : 3/3/2008<br>alopez : 2/19/2007<br>alopez : 10/27/2006<br>wwang : 5/4/2006<br>ckniffin : 5/3/2006<br>alopez : 3/17/2004<br>alopez : 4/26/2000<br>alopez : 4/26/2000<br>carol : 6/26/1998<br>mimadm : 1/14/1995<br>carol : 10/7/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988
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<h3>
<span class="mim-font">
<strong>#</strong> 169500
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</h3>
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<h3>
<span class="mim-font">
LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT, TYPICAL; ADLDTY
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<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
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<h4>
<span class="mim-font">
PELIZAEUS-MERZBACHER DISEASE, AUTOSOMAL DOMINANT OR LATE-ONSET TYPE, FORMERLY
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<p>
<span class="mim-text-font">
<strong>ORPHA:</strong> 99027; &nbsp;
<strong>DO:</strong> 0060785; &nbsp;
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
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<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
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<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
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Gene/Locus
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Gene/Locus <br /> MIM number
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<td>
<span class="mim-font">
5q23.2
</span>
</td>
<td>
<span class="mim-font">
Leukodystrophy, demyelinating, adult-onset, autosomal dominant, typical
</span>
</td>
<td>
<span class="mim-font">
169500
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
LMNB1
</span>
</td>
<td>
<span class="mim-font">
150340
</span>
</td>
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</tbody>
</table>
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<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because typical autosomal dominant adult-onset demyelinating leukodystrophy (ADLDTY) is caused by a heterozygous tandem genomic duplication on chromosome 5q23 that results in an extra copy of the lamin B1 gene (LMNB1; 150340), but also alters regulatory sequences that affect expression of other genes.</p>
</span>
<div>
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<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
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<span class="mim-text-font">
<p>Typical autosomal dominant adult-onset demyelinating leukodystrophy (ADLDTY) is an autosomal dominant slowly progressive neurologic disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by Padiath et al., 2006). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by Schuster et al., 2011). </p><p>Atypical ADLD (ADLDAT; 621061) is caused by heterozygous deletion on chromosome 5q23 involving regulatory regions upstream of the LMNB1 gene. Atypical ADLD is distinguished from typical ADLD by onset of pyramidal symptoms before autonomic symptoms and by lack of clinical and radiologic cerebellar involvement (Dimartino et al., 2024). </p>
</span>
<div>
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<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Eldridge et al. (1984) described a large American-Irish kindred with a chronic progressive neurologic disorder affecting at least 10 men and 11 women in 4 generations in an autosomal dominant pattern. Multiple sclerosis was diagnosed in 20 of the patients evaluated before the availability of CT imaging and without regard to the family history. Neurologic symptoms began in the 4th and 5th decades and included cerebellar, pyramidal, and autonomic abnormalities. The autonomic dysfunction involved bowel and bladder regulation and orthostatic hypotension; these were often the earliest changes but were frequently disregarded. Survival for 20 years after onset was common. CT imaging showed symmetrical decreases in white-matter density, beginning in the frontal lobes and extending to all of the centrum ovale and cerebellar white matter. In patients from this family, Brown et al. (1987) demonstrated findings consistent with denervation supersensitivity, suggesting a distal lesion of sympathetic noradrenergic neurons. Absence of the epinephrine response to insulin-induced hypoglycemia indicated that autonomic neuropathy was attended by severe adrenal medullary dysfunction. </p><p>Laxova et al. (1985) described a Scottish-Irish family with a similar, possibly identical disorder. Onset in the late 30s was marked by autonomic symptoms, including postural hypotension, neurogenic bladder, and rectal incontinence. Progressive spasticity followed, with death in 10 to 15 years. Orientation and affect remained intact. CT scans and magnetic resonance imaging showed symmetric atrophy of white matter. Some clinically unaffected offspring showed the same change. The condition was often misdiagnosed as multiple sclerosis.</p><p>Schwankhaus et al. (1994) reported autopsy findings from a 64-year-old affected woman of the kindred reported by Eldridge et al. (1984). Her symptoms began at age 44 years. The most striking finding was leukoencephalopathy preferentially affecting the frontal and parietal lobes, including the lateral margins of the corpus callosum, and diminishing in severity toward the occipital lobes. Subcortical U fibers were spared. There was no inflammation or metachromasia. No lipid accumulation was seen by oil red O or with Sudan black. No histologic abnormality was seen in the peripheral nervous system or in the adrenal glands, despite clinical evidence of autonomic dysfunction which is typically a presenting feature of adult-onset leukodystrophy. Although there were vacuolar changes in the white matter reminiscent of a classic spongiform encephalopathy, Schwankhaus et al. (1994) thought that the large size of the vacuoles, the absence of any changes in the gray matter, and the clinical course argued against this. No prion studies were done. The authors suggested that the early autonomic insufficiency seen in their patient was a feature that distinguished autosomal dominant, adult-onset leukodystrophy from adult-onset Pelizaeus-Merzbacher disease, which they referred to as Lowenberg-Hill disease (Rodriguez et al., 1983). </p><p>Labauge et al. (2005) reported a mother and son with an adult-onset disorder similar to vanishing white matter disease (see VWM1; 603896) except for apparent autosomal dominant inheritance. At age 35, the son had an acute episode of brain dysfunction after a viral illness. Features included excessive somnolence and mental confusion, apathy, vomiting, and left-sided hemiparesis requiring mechanical ventilation. Brain CT scan showed extensive hypodensity of the cerebral white matter. Similar episodes occurred following viral infections at ages 36, 39, and 40 years. After the fourth episode, progressive neurologic deterioration was observed, including cerebellar ataxia, spastic quadriparesis, and pseudobulbar syndrome. MRI showed progressive cortical and subcortical diffuse white matter abnormalities suggesting cavitating white matter degeneration. The patient's mother developed progressive ataxia at age 38, suffered a fall with head trauma, and subsequently died. Neuropathologic examination showed grayish, gelatinous, and precavitary changes in the white matter; U fibers and part of the optic radiations were unaffected. Myelin stains showed a severe depletion of myelin sheaths with spongiform changes and precavitary appearance in the most affected areas. There was a preservation of oligodendrocytes with abundant foamy cytoplasm and decreased numbers of astrocytes, although those that remained showed highly reactive features. Although Labauge et al. (2005) concluded that the phenotype was consistent with VWM disease, genetic analysis of the proband excluded mutations in the EIF2B genes (see, e.g., EIF2B1; 606686). </p><p>Ptacek et al. (2006) suggested that the mother and son reported by Labauge et al. (2005) had ADLD. They suggested that the acute episodes of brain dysfunction after mild insults may represent uncovering of compromised nervous system function. In a response to Ptacek et al. (2006), Labauge et al. (2006) stated that their patients lacked early autonomic features characteristic of ADLD and that acute neurologic deterioration observed in their patients had not been described in ADLD, but noted that overlap exists among various leukodystrophies. </p><p>Brussino et al. (2009) reported a 3-generation Italian family with ADLD that was confirmed genetically in 2 affected individuals. These 2 patients presented as adults with autonomic dysfunction, including micturition defects and impotence. The disorder progressed to involve walking difficulties; 1 patient became wheelchair-bound. Brain MRI of both patients showed diffuse subcortical infra- and supratentorial white matter abnormalities with sparing of the U-fibers and optic radiations. Genetic analysis identified a heterozygous 140- to 190-kb duplication of a region including the LMNB1 gene as well as neighboring sequences. There was a positive family history of a similar neurodegenerative disorder. </p><p>Sundblom et al. (2009) reported 2 unrelated Swedish families with ADLD. Twelve individuals examined, including 11 patients and 1 asymptomatic individual, were found to have a thin spinal cord on MRI. There was also a slight general white matter signal intensity increase in the whole spinal cord, mainly visible in T2-weighted transverse images. Postmortem examination of 1 patient showed discrete demyelination in the spinal cord. </p><p>Schuster et al. (2011) reported 4 unrelated families with ADLD. Two families were of Swedish origin and had previously been reported (Sundblom et al., 2009). The other 2 families were of German and Israeli-Arab descent, respectively. One of the Swedish families had 31 affected individuals spanning at least 4 generations. Disease onset occurred in the fifth or sixth decade. Autonomic symptoms included urinary bladder symptoms, constipation, postural hypotension, erectile dysfunction, and heat intolerance. Affected individuals later developed ataxia and pyramidal signs. Some patients showed cognitive decline. Brain MRI showed signs characteristic of this type of leukodystrophy. </p><p>Finnsson et al. (2015) reported follow-up of 22 individuals from the 2 Swedish families reported by Schuster et al. (2011). Onset of autonomic symptoms, usually urinary dysfunction, occurred in 14 patients between 40 and 58 years of age. Six patients presented with autonomic and gait problems, whereas only 2 presented with gait problems. Additional autonomic features included orthostatic hypotension, erectile dysfunction, and constipation. Six patients had dry skin. Most (91%) had slowly progressive pyramidal signs with spastic paraplegia, weakness, brisk reflexes, and extensor plantar responses. This progressed to tetraparesis with absent reflexes, involvement of the upper limbs, and pseudobulbar palsy with swallowing difficulties. Four patients eventually required gastrostomy. Walking difficulties were progressive, and many were later wheelchair-bound. About half of the patients had tremor, both intention and postural, and some later had dysmetria and dysdiadochokinesis. Two had nystagmus and a few had saccadic smooth pursuit. Seven (32%) had sensory deficits affecting the lower limbs. Many patients reported worsening of neurologic symptoms during stress, infection, or heat exposure. Cognition was normal early in the disease course, but patients at the advanced stage often had pseudobulbar palsy with speech difficulties and apraxia; 2 had frank dementia. CT findings, performed in 5 individuals, showed hypodensities in the cerebral white matter and middle cerebellar peduncles with progressive loss of white matter. Brain MRI, performed in most, showed progressive T2-weighted hyperintensities in the motor cortex, cerebral white matter, pyramidal tracts, and cerebellar peduncles. Abnormal brain imaging preceded symptom onset in several patients. Median survival time after symptom onset was 18 years. The authors concluded that the features of the disorder are consistent with a myelopathy. </p><p>Dos Santos et al. (2012) reported a 3-generation family in Germany with ADLD. The proband presented at age 47 with a 2-year history of urinary difficulties, personality changes, and depression. He was found to have gait and limb ataxia, spastic paraparesis, hyperreflexia, and extensor plantar responses. Brain MRI showed extensive T2-weighted hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of the periventricular rim and corpus callosum. Other affected brain regions included the middle cerebellar peduncles, the pyramidal tracts, medial lemniscus in the midbrain, pons, medulla, and the decussation of the superior cerebellar peduncles. Family history revealed numerous affected members in an autosomal dominant pattern. The patient's 44-year-old sister was clinically asymptomatic, but her cerebral MRI showed extensive bilateral signal hyperintensities in the subcortical and deep cerebral white matter and in the middle cerebellar peduncles. </p><p>Flanagan et al. (2013) reported a 63-year-old man with genetically confirmed ADLD who presented with REM sleep behavior disorder (RBD) characterized by dream enactment behavior up to 3 times per week for the previous 4 years. During the episodes, he would scream, shout, flail his arms, and kick his legs. Polysomnography showed markedly increased muscle tone during REM sleep. Additional neurologic features included left-sided spasticity and cerebellar signs, hyperreflexia, and rare bowel incontinence. Brain MRI showed cervical spinal cord atrophy and T2-weighted hyperintense lesions in the brainstem, cerebellar peduncles, and subcortical white matter. Flanagan et al. (2013) postulated that damage to the myelinated axons from the subceruleus nucleus and adjacent areas to alpha-motor neurons may have impaired normal motor inhibition during REM sleep. </p><p>Terlizzi et al. (2016) reported 3 affected sibs (mean age of 54 years) with genetically confirmed ADLD and an asymptomatic carrier family member (23 years) from a southern Italian family with a history of the disease. The 3 affected sibs presented with autonomic dysfunction and later developed cerebellar signs (ataxia, nystagmus, dysmetria, tremor) and pyramidal signs (spasticity with brisk tendon reflexes), resulting in progressive gait impairment. Neuropsychologic testing showed progressive impairment of executive function, including attention, abstract thinking, and semantic fluency. Additional testing indicated post-ganglionic sympathetic noradrenergic failure. The authors postulated astrocyte dysfunction. </p><p>In a postmortem histopathologic study of a patient with typical ADLD, Dimartino et al. (2024) found patchy myelin in the cerebral white matter, and lack of myelin with tissue rarefaction and dysmorphic astrocytes in the cerebellar white matter. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The transmission pattern of typical ADLD in the 4 unrelated families reported by Schuster et al. (2011) was consistent with autosomal dominant inheritance. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Schuster et al. (2011) found about a 2-fold increased level of LMNB1 protein in white blood cells from 5 patients with genetically confirmed ADLD. LMNB1 mRNA was also increased compared to controls. Schuster et al. (2011) concluded that an accurate molecular diagnosis of the disorder could be made by direct analysis of LMNB1 in peripheral leukocytes. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Coffeen et al. (2000) reported additional clinical, neuroradiologic, and neuropathologic data from the family with autosomal dominant leukodystrophy originally reported by Eldridge et al. (1984). Furthermore, they localized the ADLD gene to a 4-cM region on chromosome 5q31. Linkage analysis of this family yielded a lod score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Cytogenetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Padiath et al. (2006) found heterozygous duplication of 5q23, including the LMNB1 gene, as the cause of typical ADLD in affected members of 4 families. One of these was the family described by Eldridge et al. (1984); haplotype analysis suggested that this family and a second Irish-American family shared a common founder. Lamin B1 was found to be overexpressed in brain tissue from affected individuals. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. The clinical similarity of ADLD to multiple sclerosis and the identification of autoantibodies to lamin B suggested to Padiath et al. (2006) that a closer examination of the involvement of lamin B in multiple sclerosis is warranted. </p><p>Brussino et al. (2009) found a 140- to 190-kb duplication of 5q including the entire LMNB1 gene, the AX748201 transcript, and the 3-prime end of the MARCH3 gene (613333) in 1 of 8 Italian probands with adult-onset leukoencephalopathy. The patient's affected cousin also carried the duplication, and there was a family history of a similar disorder. Lamin B1 expression was increased in lymphoblasts from one of the patients with the duplication. </p><p>In affected members of 4 unrelated families with ADLD, Schuster et al. (2011) found duplication of 5q23 including the LMNB1 gene. All 4 duplications were of different sizes, ranging from 107 to 218 kb, supporting independent events. Each duplication extended over part of the MARCH3 gene, but MARCH3 mRNA was not increased in patient leukocytes. </p><p>In a symptomatic man with ADLD and his asymptomatic sister who had leukodystrophy on brain imaging, Dos Santos et al. (2012) identified a 148-kb duplication on chromosome 5q23.2 including the LMNB1 gene, but not the MARCH3 gene. The findings confirmed the central role of the LMNB1 gene in ADLD. </p><p>Using a custom array, Giorgio et al. (2013) performed detailed breakpoint junction sequence analysis of the duplicated 5q23 region containing the LMNB1 gene in 20 independent families with ADLD in whom genomic LMNB1 duplication was initially identified by aCGH, QT-PCR, or MLPA. Seven families had previously been reported (Brussino et al., 2009; Schuster et al., 2011; Dos Santos et al., 2012). There were a total of 16 unique rearrangements. Three of the duplications were shared by more than 1 family: 1 was found in 3 families and the other 2 duplications were found in 2 families each. Individuals with identical junctions shared the same haplotype, consistent with a founder effect. Duplication sizes ranged from about 128 kb to 475 kb. The largest duplication also included the PHAX (604924), ALDH7A1 (107323), and GRAMD3 (GRAMD2B; 620182) genes. Comparison of all the samples identified a 72-kb minimal critical duplicated region required for ADLD that contained only the LMNB1 gene. Characterization of the junction sequences showed that most (11 of 15) showed short stretches of microhomology overlap ranging from 1 to 6 nucleotides, whereas the others showed small insertions at the breakpoints. All duplications resulted from intrachromosomal rearrangements. Analysis of the genomic architecture suggested several potential mechanisms for the duplications, including nonhomologous end joining (NHEJ) or fork stalling and template switching/microhomology-mediated break-induced repair (FoSTeS/MMBIR). The enrichment of Alu repetitive elements at the centromeric breakpoints (found in 4 cases), higher GC content, and high frequency of repetitive sequences at breakpoints likely also played a role in mediating ADLD duplications. RT-PCR of patients fibroblasts or blood showed increased LMNB1 expression (2.1- to 4.8-fold compared to controls), as well as increased protein levels (1.6- to 3.2-fold compared to controls). There was no apparent difference in phenotype according to duplication size. </p><p>In a 42-year-old woman of Italian ancestry, who was born in Brazil, with clinical features of ADLD, Pedroso et al. (2017) identified a heterozygous missense variant in the LMNB1 gene (R29W). The variant, which was found by whole-exome sequencing, was not present in several public databases, including the Exome Sequencing Project and ExAC. Patient-derived cells showed increased expression of variant LMNB1 mRNA and nuclear structural abnormalities. Functional studies indicated an impaired response to DNA damage, suggesting genomic instability. The patient presented at 23 years of age with progressive cerebellar atrophy and cognitive impairment. Brain imaging showed white matter abnormalities in the cerebellum, as well as atrophy of the corpus callosum, brainstem, and spinal cord. In in vitro studies, Cristofoli et al. (2020) demonstrated that the R29W mutant protein was present in the nuclear extract, suggesting that it did not disrupt nuclear lamina localization of LMNB1. </p><p>Using high-throughput chromosome conformation capture (Hi-C) techniques to analyze topologically associating domains (TADs), Dimartino et al. (2024) found that patients with typical ADLD (Giorgio et al., 2013; Brunetti et al., 2014) carried intra-TAD duplications on 5q23 within the LMNB1 TAD that did not extend beyond TAD boundaries and maintained the physiologic regulatory context of LMNB1. This resulted in overexpression of the LMNB1 gene. The authors concluded that duplication of the LMNB1 gene per se is not causative of typical ADLD, which will affect ADLD diagnosis and genetic counseling. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Zerbin-Rudin and Peiffer (1964) described a familial disorder similar to Pelizaeus-Merzbacher disease (PMD; 312080) except that it showed later onset and autosomal dominant inheritance rather than X-linked inheritance typical of PMD. The disease was noted to be similar to multiple sclerosis (MS; 126200) in some respects. It may be the same disorder as that reported by Camp and Lowenberg (1941). </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
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Brown, R. T., Polinsky, R. J., Schwankhaus, J., Eldridge, R., McFarland, H., Schlesinger, S., Dailey, W. A.
<strong>Adrenergic dysfunction in hereditary adult-onset leukodystrophy.</strong>
Neurology 37: 1421-1424, 1987.
[PubMed: 3302762]
[Full Text: https://doi.org/10.1212/wnl.37.8.1421]
</p>
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Brunetti, V., Ferilli, M. A., Nociti, V., Silvestri, G.
<strong>Teaching NeuroImages: Autosomal dominant leukodystrophy in a sporadic case.</strong>
Neurology 83: e121, 2014.
[PubMed: 25224534]
[Full Text: https://doi.org/10.1212/WNL.0000000000000803]
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Brussino, A., Vaula, G., Cagnoli, C., Mauro, A., Pradotto, L., Daniele, D., Di Gregorio, E., Barberis, M., Arduino, C., Squadrone, S., Abete, M. C., Migone, N., Calabrese, O., Brusco, A.
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Camp, C. D., Lowenberg, K.
<strong>An American family with Pelizaeus-Merzbacher disease.</strong>
Arch. Neurol. Psychiat. 45: 261-264, 1941.
</p>
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Coffeen, C. M., McKenna, C. E., Koeppen, A. H., Plaster, N. M., Maragakis, N., Mihalopoulos, J., Schwankhaus, J. D., Flanigan, K. M., Gregg, R. G., Ptacek, L. J., Fu, Y.-H.
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Cristofoli, F., Moss, T., Moore, H. W., Devriendt, K., Flanagan-Steet, H., May, M., Jones, J., Roelens, F., Fons, C., Fernandez, A., Martorell, L., Selicorni, A., Maitz, S., Vitiello, G., Van der Hoeven, G., Skinner, S. A., Bollen, M., Vermeesch, J. R., Steet, R., Van Esch, H.
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Am. J. Hum. Genet. 107: 753-762, 2020.
[PubMed: 32910914]
[Full Text: https://doi.org/10.1016/j.ajhg.2020.08.015]
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Dimartino, P., Zadorozhna, M., Yumiceba, V., Basile, A., Cani, I., Melo, U. S., Henck, J., Breur, M., Tonon, C., Lodi, R., Brusco, A., Pippucci, T., and 12 others.
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Ann. Neurol. 96: 855-870, 2024.
[PubMed: 39078102]
[Full Text: https://doi.org/10.1002/ana.27038]
</p>
</li>
<li>
<p class="mim-text-font">
Dos Santos, M. M., Grond-Ginsbach, C., Aksay, S. S., Chen, B., Tchatchou, S., Wolf, N. I., van der Knaap, M. S., Grau, A. J.
<strong>Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication. (Letter)</strong>
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[PubMed: 21909802]
[Full Text: https://doi.org/10.1007/s00415-011-6225-4]
</p>
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Eldridge, R., Anayiotos, C. P., Schlesinger, S., Cowen, D., Bever, C., Patronas, N., McFarland, H.
<strong>Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.</strong>
New Eng. J. Med. 311: 948-953, 1984.
[PubMed: 6472420]
[Full Text: https://doi.org/10.1056/NEJM198410113111504]
</p>
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Finnsson, J., Sundblom, J., Dahl, N., Melberg, A., Raininko, R.
<strong>LMNB1-related autosomal-dominant leukodystrophy: clinical and radiological course.</strong>
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[PubMed: 26053668]
[Full Text: https://doi.org/10.1002/ana.24452]
</p>
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Flanagan, E. P., Gavrilova, R. H., Boeve, B. F., Kumar, N., Jelsing, E. J., Silber, M. H.
<strong>Adult-onset autosomal dominant leukodystrophy presenting with REM sleep behavior disorder.</strong>
Neurology 80: 118-120, 2013.
[PubMed: 23243074]
[Full Text: https://doi.org/10.1212/WNL.0b013e31827b1b2a]
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<p class="mim-text-font">
Giorgio, E., Rolyan, H., Kropp, L., Chakka, A. B., Yatsenko, S., Di Gregorio, E., Lacerenza, D., Vaula, G., Talarico, F., Mandich, P., Toro, C., Pierre, E. E., and 26 others.
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[PubMed: 23649844]
[Full Text: https://doi.org/10.1002/humu.22348]
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Labauge, P., Fogli, A., Castelnovo, G., Le Bayon, A., Horzinski, L., Nicoli, F., Cozzone, P., Pages, M., Briere, C., Marty-Double, C., Delhaume, O., Gelot, A., Boespflug-Tanguy, O., Rodriguez, D.
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[PubMed: 16047349]
[Full Text: https://doi.org/10.1002/ana.20573]
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Labauge, P., Gelot, A., Fogli, A., Boespflug-Tanguy, O., Rodiguez, D.
<strong>Autosomal dominant leukodystrophy and childhood ataxia with central nervous system hypomyelination syndrome. (Letter)</strong>
Ann. Neurol. 60: 485 only, 2006.
[PubMed: 16847948]
[Full Text: https://doi.org/10.1002/ana.20930]
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Laxova, A., Hogan, K., Haun, J.
<strong>A new autosomal dominant adult onset progressive leukodystrophy. (Abstract)</strong>
Am. J. Hum. Genet. 37: A65 only, 1985.
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Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A., Hogan, K., Ptacek, L. J., Fu, Y.-H.
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Pedroso, J. L., Munford, V., Bastos, A. U., Castro, L. P., Marussi, V. H. R., Silva, G. S., Arita, J. H., Menck, C. F. M., Barsottini, O. G.
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Ptacek, L. J., Fu, Y.-H., Koeppen, A.
<strong>The dominant form of vanishing white matter-like leukoencephalopathy represents autosomal dominant leukodystrophy. (Letter)</strong>
Ann. Neurol. 59: 434 only, 2006.
[PubMed: 16437562]
[Full Text: https://doi.org/10.1002/ana.20773]
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Rodriguez, M., Powell, H. C., Lampert, P. W.
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Schuster, J., Sundblom, J., Thuresson, A.-C., Hassin-Baer, S., Klopstock, T., Dichgans, M., Cohen, O. S., Raininko, R., Melberg, A., Dahl, N.
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[Full Text: https://doi.org/10.1007/s10048-010-0269-y]
</p>
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Schwankhaus, J. D., Katz, D. A., Eldridge, R., Schlesinger, S., McFarland, H.
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Sundblom, J., Melberg, A., Kalimo, H., Smits, A., Raininko, R.
<strong>MR imaging characteristics and neuropathology of the spinal cord in adult-onset autosomal dominant leukodystrophy with autonomic symptoms.</strong>
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</p>
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<p class="mim-text-font">
Terlizzi, R., Calandra-Buonaura, G., Zanigni, S., Barletta, G., Capellari, S., Guaraldi, P., Donadio, V., Cason, E., Contin, M., Poda, R., Tonon, C., Sambati, L., Gallassi, R., Liguori, R., Lodi, R., Cortelli, P.
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</li>
<li>
<p class="mim-text-font">
Zerbin-Rudin, E., Peiffer, J.
<strong>Ein genetischer Beitrag zur Frage der Spaetform der Pelizaeus-Merzbacherschen Krankheit.</strong>
Humangenetik 1: 107-122, 1964.
[PubMed: 5869474]
[Full Text: https://doi.org/10.1007/BF00389627]
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Cassandra L. Kniffin - updated : 01/16/2025<br>Cassandra L. Kniffin - updated : 02/12/2021<br>Cassandra L. Kniffin - updated : 7/8/2015<br>Cassandra L. Kniffin - updated : 12/29/2014<br>Cassandra L. Kniffin - updated : 10/24/2013<br>Cassandra L. Kniffin - updated : 6/5/2012<br>Cassandra L. Kniffin - updated : 12/2/2008<br>Victor A. McKusick - updated : 10/27/2006<br>Cassandra L. Kniffin - updated : 5/3/2006<br>George E. Tiller - updated : 4/26/2000
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