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<title>
Entry
- #607822 - ALZHEIMER DISEASE 3; AD3
- OMIM
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<span class="h4">#607822</span>
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<a href="/clinicalSynopsis/607822"><strong>Clinical Synopsis</strong></a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(ALZHEIMER DISEASE) OR (PSEN1 OR APOE)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=631&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1161/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
<div><a href="https://medlineplus.gov/genetics/condition/alzheimers-disease" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607822[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1020" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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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>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0110042" 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/607822" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/results?search_type=advanced&omia_id=000033,002493" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0110042" 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>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:607822" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<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.">
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</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> 1020<br />
<strong>DO:</strong> 0110042<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>
607822
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
ALZHEIMER DISEASE 3; AD3
</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">
ALZHEIMER DISEASE 3, EARLY-ONSET<br />
ALZHEIMER DISEASE, FAMILIAL, 3
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND UNUSUAL PLAQUES, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND APRAXIA, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/361?start=-3&limit=10&highlight=361">
14q24.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Alzheimer disease, type 3, with or without spastic paraparesis
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607822"> 607822 </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">
PSEN1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/104311"> 104311 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/803?start=-3&limit=10&highlight=803">
19q13.32
</a>
</span>
</td>
<td>
<span class="mim-font">
{?Alzheimer disease, protection against, due to APOE3-Christchurch}
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
</span>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607822"> 607822 </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">
APOE
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/107741"> 107741 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/607822" 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')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/607822" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/607822" 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> 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">
- 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 />
</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">
- Alzheimer disease, early-onset <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G30.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G30.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0750901&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750901</a>]</span><br /> -
Dementia, progressive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
Memory loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386807006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386807006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48167000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48167000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R41.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R41.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.93" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.93</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002622&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002622</a>, <a href="https://bioportal.bioontology.org/search?q=C0751295&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751295</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002354" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002354</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002354" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002354</a>]</span><br /> -
Loss of language ability <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843016&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843016</a>]</span><br /> -
Gait disturbances <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 /> -
Spastic quadriparesis <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 /> -
Myoclonus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17450006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17450006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/333.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">333.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027066&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027066</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span><br /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
Extrapyramidal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43378000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43378000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span><br /> -
Hyperreflexia in lower limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836696&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836696</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002395" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002395</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002395" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002395</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 /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Apraxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68345001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68345001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/6950007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">6950007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R48.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R48.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003635</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002186" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002186</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002186" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002186</a>]</span><br /> -
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
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 /> -
Constructional apraxia (in a subset of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53863007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53863007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76251002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76251002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2243023&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2243023</a>]</span><br /> -
Visuospatial agnosia (in a subset of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/285758006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">285758006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0563622&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0563622</a>]</span><br /> -
Optic ataxia (in a subset of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1231201006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1231201006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4703584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4703584</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031868" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031868</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031868" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031868</a>]</span><br /> -
Cortical and subcortical regions involved <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843020&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843020</a>]</span><br /> -
Neurofibrillary tangles <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85775002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85775002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085400&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085400</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002185" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002185</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002185" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002185</a>]</span><br /> -
Amyloid plaques <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38551001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38551001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2936349&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2936349</a>, <a href="https://bioportal.bioontology.org/search?q=C0333463&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0333463</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100256</a>]</span><br /> -
Eosinophilic 'cotton wool' plaques without dense congophilic core in various brain regions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843021&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843021</a>]</span><br /> -
Cortical atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551583</a>, <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>]</span><br />
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<em> Behavioral Psychiatric Manifestations </em>
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- Loss of attention <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843022&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843022</a>]</span><br /> -
Loss of executive functions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843023&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843023</a>]</span><br /> -
Behavioral changes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/315244000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">315244000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0542299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0542299</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000708</a>]</span><br /> -
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 /> -
Social withdrawal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/105411000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">105411000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424095&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424095</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Onset in late twenties to thirties<br /> -
A subset of patients have a 'visual variant'<br /> -
Rapidly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838681&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838681</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003678" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003678</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003678" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003678</a>]</span><br /> -
Severe phenotype <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8116006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8116006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363778006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363778006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0031437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031437</a>, <a href="https://bioportal.bioontology.org/search?q=C1285572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1285572</a>]</span><br /> -
Later onset has been reported<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the presenilin-1 gene (PSEN1, <a href="/entry/104311#0001">104311.0001</a>)<br />
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<p>A number sign (#) is used with this entry because early-onset familial Alzheimer disease-3 (AD3) is caused by heterozygous mutation in the presenilin-1 gene (PSEN1; <a href="/entry/104311">104311</a>) on chromosome 14q24.</p><p>For a phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see <a href="/entry/104300">104300</a>.</p>
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<strong>Clinical Features</strong>
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<p><a href="#6" class="mim-tip-reference" title="Campion, D., Brice, A., Hannequin, D., Tardieu, S., Dubois, B., Calenda, A., Brun, E., Penet, C., Tayot, J., Martinez, M., Bellis, M., Mallet, J., Agid, Y., Clerget-Darpoux, F. &lt;strong&gt;A large pedigree with early-onset Alzheimer&#x27;s disease: clinical, neuropathologic, and genetic characterization.&lt;/strong&gt; Neurology 45: 80-85, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7824141/&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;7824141&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.45.1.80&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="7824141">Campion et al. (1995)</a> studied a large pedigree that included 34 subjects with early-onset progressive dementia with mean age at onset at 46 plus or minus 3.5 years and mean age at death at 52.6. Myoclonus and extrapyramidal signs were common; seizures were present in all affected subjects. There were neuropathologic changes typical of Alzheimer disease in the 2 brains examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7824141" 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="#14" class="mim-tip-reference" title="Lopera, F., Ardilla, A., Martinez, A., Madrigal, L., Arango-Viana, J. C., Lemere, C. A., Arango-Lasprilla, J. C., Hincapie, L., Arcos-Burgos, M., Ossa, J. E., Behrens, I. M., Norton, J., Lendon, C., Goate, A. M., Ruiz-Linares, A., Rosselli, M., Kosik, K. S. &lt;strong&gt;Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation.&lt;/strong&gt; JAMA 277: 793-799, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9052708/&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;9052708&lt;/a&gt;]" pmid="9052708">Lopera et al. (1997)</a> described a large pedigree with early-onset Alzheimer disease from a community based in Antioquia, Colombia. Affected patients had a mean age at onset of 46.8 years (range, 34 to 62 years) with an average interval of 8 years until death. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentations were memory loss followed by behavioral and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9052708" 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="#12" class="mim-tip-reference" title="Hull, M., Fiebich, B. L., Dykierek, P., Schmidtke, K., Nitzsche, E., Orszagh, M., Deuschl, G., Moser, E., Schumacher, M., Lucking, C., Berger, M., Bauer, J. &lt;strong&gt;Early-onset Alzheimer&#x27;s disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139.&lt;/strong&gt; Europ. Arch. Psychiat. Clin. Neurosci. 248: 123-129, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9728730/&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;9728730&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004060050028&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="9728730">Hull et al. (1998)</a> described a German family with early-onset Alzheimer disease with a mutation in the PSEN1 gene. From the age of 43 years, the proband had complained of deficits in short-term memory. Relatives had noticed his symptoms even earlier and dated the onset of deficits to age 38 years when he showed increasing interruptions during speech followed by social withdrawal. There was a strong family history of dementia. Through 3 generations the onset of dementia in this family was between 42 and 45 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9728730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Rippon, G. A., Crook, R., Baker, M., Halvorsen, E., Chin, S., Hutton, M., Houlden, H., Hardy, J., Lynch, T. &lt;strong&gt;Presenilin 1 mutation in an African American family presenting with atypical Alzheimer dementia.&lt;/strong&gt; Arch. Neurol. 60: 884-888, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12810495/&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;12810495&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.60.6.884&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="12810495">Rippon et al. (2003)</a> reported an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade. Two brothers presented with personality changes, labile mood, language difficulties, psychosis, primitive reflexes consistent with frontotemporal dementia (<a href="/entry/600274">600274</a>), but also were found to have memory impairment and neuropathologic findings diagnostic of AD. Both brothers had a mutation in the PSEN1 gene (<a href="/entry/104311#0006">104311.0006</a>). Their father reportedly had died in his sixth decade with a similar illness. The authors commented on the atypical clinical presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12810495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Godbolt, A. K., Beck, J. A., Collinge, J., Garrard, P., Warren, J. D., Fox, N. C., Rossor, M. N. &lt;strong&gt;A presenilin 1 R278I mutation presenting with language impairment.&lt;/strong&gt; Neurology 63: 1702-1704, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15534260/&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;15534260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000143060.98164.1a&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="15534260">Godbolt et al. (2004)</a> reported 2 sibs with early-onset Alzheimer disease confirmed by genetic analysis (<a href="/entry/104311#0030">104311.0030</a>). Both patients presented at around age 50 with difficulty in word finding and impaired frontal executive function, but with relative preservation of memory. The sister exhibited dysfluent speech with phonemic paraphasias, dysgraphia, and dyspraxia. She later developed mutism, generalized rigidity, myoclonus of the upper limbs, dystonic posturing of the right hand, and shuffling gait. The brother exhibited impaired repetition of sentences and polysyllabic words, nominal dysphasia, dysgraphia, and dyscalculia. MRI of both patients showed multiple foci of white matter signal changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534260" 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="#3" class="mim-tip-reference" title="Ataka, S., Tomiyama, T., Takuma, H., Yamashita, T., Shimada, H., Tsutada, T., Kawabata, K., Mori, H., Miki, T. &lt;strong&gt;A novel presenilin-1 mutation (leu85pro) in early-onset Alzheimer disease with spastic paraparesis.&lt;/strong&gt; Arch. Neurol. 61: 1773-1776, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15534188/&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;15534188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.61.11.1773&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="15534188">Ataka et al. (2004)</a> reported a Japanese patient with onset of memory impairment and difficulty driving a car at age 26. Neuropsychologic testing showed that he had visual constructional apraxia, visuospatial agnosia, and optic ataxia, consistent with the 'visual variant' of AD in which there is a visuospatial cognitive deficit. The patient was heterozygous for a PSEN1 mutation (<a href="/entry/104311#0031">104311.0031</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Halliday, G. M., Song, Y. J. C., Lepar, G., Brooks, W. S., Kwok, J. B., Kersaitis, C., Gregory, G., Shepherd, C. E., Rahimi, F., Schofield, P. R., Kril, J. J. &lt;strong&gt;Pick bodies in a family with presenilin-1 Alzheimer&#x27;s disease.&lt;/strong&gt; Ann. Neurol. 57: 139-143, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15622541/&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;15622541&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20366&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="15622541">Halliday et al. (2005)</a> reported 2 sibs with early-onset FAD and mutation (M146L; <a href="/entry/104311#0001">104311.0001</a>) in the PSEN1 gene. Family history suggested that their father was also affected. Neuropathologic examination of both patients showed numerous cortical plaques and neurofibrillary tangles, consistent with AD. In addition, both cases showed ballooned neurons and numerous tau (MAPT; <a href="/entry/157140">157140</a>)-immunoreactive Pick bodies in upper frontotemporal cortical layers and in the hippocampal dentate gyrus. <a href="#11" class="mim-tip-reference" title="Halliday, G. M., Song, Y. J. C., Lepar, G., Brooks, W. S., Kwok, J. B., Kersaitis, C., Gregory, G., Shepherd, C. E., Rahimi, F., Schofield, P. R., Kril, J. J. &lt;strong&gt;Pick bodies in a family with presenilin-1 Alzheimer&#x27;s disease.&lt;/strong&gt; Ann. Neurol. 57: 139-143, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15622541/&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;15622541&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20366&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="15622541">Halliday et al. (2005)</a> suggested that the M146L mutation may specifically predispose to both AD and Pick pathology by affecting multiple intracellular pathways involving tau phosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15622541" 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="#13" class="mim-tip-reference" title="Leverenz, J. B., Fishel, M. A., Peskind, E. R., Montine, T. J., Nochlin, D., Steinbart, E., Raskind, M. A., Schellenberg, G. D., Bird, T. D., Tsuang, D. &lt;strong&gt;Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype.&lt;/strong&gt; Arch. Neurol. 63: 370-376, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16533963/&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;16533963&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.63.3.370&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="16533963">Leverenz et al. (2006)</a> found that 24 (96%) of 25 patients with AD3 had Lewy body pathology in the amygdala. Most patients also had Lewy body pathology in other brain regions, including the cingulate gyrus and neocortex, although there was variability. AD patients with PSEN1 mutations had more frequent Lewy body pathology compared to AD patients with PSEN2 (<a href="/entry/600759">600759</a>) mutations. There was no clinical correlation between age at onset or disease severity onset and Lewy body pathology in either group, although those with longer disease duration tended to have more Lewy body pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16533963" 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="#23" class="mim-tip-reference" title="Piccini, A., Zanusso, G., Borghi, R., Noviello, C., Monaco, S., Russo, R., Damonte, G., Armirotti, A., Gelati, M., Giordano, R., Zambenedetti, P., Russo, C., Ghetti, B., Tabaton, M. &lt;strong&gt;Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype.&lt;/strong&gt; Arch. Neurol. 64: 738-745, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17502474/&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;17502474&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.5.738&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="17502474">Piccini et al. (2007)</a> reported a patient who presented at age 28 years with delusions and lower limb jerks accompanied by intentional myoclonus and cerebellar ataxia. He had rapid progression with global impairment of all cognitive functions and became bedridden, anarthric, and incontinent by age 33. He died of bronchopneumonia at age 35. Postmortem examination showed severe beta-amyloid deposition in the cerebral and cerebellar cortices, amyloid angiopathy, and severe loss of Purkinje cells and fibers in the cerebellum. Neurofibrillary tangles were also present. Genetic analysis revealed a heterozygous mutation in the PSEN1 gene (S170F; <a href="/entry/104311#0036">104311.0036</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17502474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>FAD with spastic paraparesis and unusual plaques</em></strong></p><p>
In a family with onset of AD in the early forties reported by the <a href="#1" class="mim-tip-reference" title="Alzheimer&#x27;s Disease Collaborative Group. &lt;strong&gt;The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.&lt;/strong&gt; Nature Genet. 11: 219-222, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7550356/&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;7550356&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1095-219&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="7550356">Alzheimer's Disease Collaborative Group (1995)</a>, <a href="#21" class="mim-tip-reference" title="O&#x27;Riordan, S., McMonagle, P., Janssen, J. C., Fox, N. C., Farrell, M., Collinge, J., Rossor, M. N., Hutchinson, M. &lt;strong&gt;Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities.&lt;/strong&gt; Neurology 59: 1108-1110, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12370477/&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;12370477&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.59.7.1108&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="12370477">O'Riordan et al. (2002)</a> described an atypical disease pattern in 3 additional members from the third generation. One had cognitive impairment, spastic paraparesis, and white matter abnormalities on MRI. One of his sibs developed dementia and myoclonus and had white matter abnormalities on MRI. Another sib had ophthalmoplegia, spastic-ataxic quadriparesis, and cotton-wool plaques with amyloid angiopathy on brain biopsy (MRI was not performed). The authors suggested that the MRI findings may reflect an ischemic leukoencephalopathy due to amyloid angiopathy affecting meningocortical vessels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7550356+12370477" 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="#7" class="mim-tip-reference" title="Crook, R., Verkkoniemi, A., Perez-Tur, J., Mehta N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H., Ylikoski, R., Poyhonen, M., Kucera, S., Haltia, M. &lt;strong&gt;A variant of Alzheimer&#x27;s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.&lt;/strong&gt; Nature Med. 4: 452-455, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9546792/&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;9546792&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm0498-452&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="9546792">Crook et al. (1998)</a> reported a Finnish pedigree with 17 affected individuals of both sexes in 3 generations suffering from a novel variant of Alzheimer disease characterized by progressive dementia that was in most cases preceded by spastic paraparesis. Neuropathologic investigations showed numerous distinct, large, round, and eosinophilic plaques, as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton-wool balls and were immunoreactive for A-beta, but lacked a congophilic dense core or marked plaque-related neuritic pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9546792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Matsubara-Tsutsui, M., Yasuda, M., Yamagata, H., Nomura, T., Taguchi, K., Kohara, K., Miyoshi, K., Miki, T. &lt;strong&gt;Molecular evidence of presenilin 1 mutation in familial early onset dementia.&lt;/strong&gt; Am. J. Med. Genet. 114: 292-298, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11920851/&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;11920851&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10250&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="11920851">Matsubara-Tsutsui et al. (2002)</a> reported a Japanese family in which 6 individuals in 2 generations were affected with presenile dementia preceded by spastic gait. Detailed information was available in 1 patient who had disease onset at age 35 with spasticity, motor apraxia, and cognitive decline. Neuropathologic examination was not done. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11920851" 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="#27" class="mim-tip-reference" title="Rogaeva, E., Bergeron, C., Sato, C., Moliaka, I., Kawarai, T., Toulina, A., Song, Y.-Q., Kolesnikova, T., Orlacchio, A., Bernardi, G., St. George-Hyslop, P. H. &lt;strong&gt;PS1 Alzheimer&#x27;s disease family with spastic paraplegia: the search for a gene modifier.&lt;/strong&gt; Neurology 61: 1005-1007, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14557582/&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;14557582&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.61.7.1005&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="14557582">Rogaeva et al. (2003)</a> reported the neuropathologic findings of a patient with FAD and spastic paraplegia with onset at 52 years of age. The brain had severe cortical atrophy with neuronal loss, as well as atrophy of the caudate, hippocampus, amygdala, and entorhinal cortex. The substantia nigra was pale, depopulated, and had rare tangles and Lewy bodies. Neurofibrillary tangles and amyloid plaques with a cotton-wool appearance were identified. Consistent with spastic paraplegia, the spinal cord was smaller than usual and flattened in its anteroposterior dimension, and there was degeneration of the corticospinal tracts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557582" 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="#17" class="mim-tip-reference" title="Moretti, P., Lieberman, A. P., Wilde, E. A., Giordani, B. I., Kluin, K. J., Koeppe, R. A., Minoshima, S., Kuhl, D. E., Seltzer, W. K., Foster, N. L. &lt;strong&gt;Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.&lt;/strong&gt; Neurology 62: 1865-1868, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15159497/&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;15159497&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000126447.91111.a1&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="15159497">Moretti et al. (2004)</a> reported 2 sibs with early-onset dementia and spastic paraparesis. Their father, paternal grandfather, and paternal great-grandfather reportedly died in their thirties of a dementing illness associated with severe progressive gait impairment. The proband developed memory problems at age 28 years. At age 31, he had mild bilateral limb apraxia, dystonia, mild dementia, and hypometabolism of the temporoparietal association cortex on PET scan. By age 34, he was profoundly demented, with dysarthria, dysphagia, and spasticity of the arms and legs. Postmortem examination showed moderate brain atrophy with amyloid plaques and neurofibrillary tangles consistent with AD throughout the neocortex, limbic regions, and striatum, as well as large eosinophilic cotton-wool plaques. His sister had a similar disease course. <a href="#17" class="mim-tip-reference" title="Moretti, P., Lieberman, A. P., Wilde, E. A., Giordani, B. I., Kluin, K. J., Koeppe, R. A., Minoshima, S., Kuhl, D. E., Seltzer, W. K., Foster, N. L. &lt;strong&gt;Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.&lt;/strong&gt; Neurology 62: 1865-1868, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15159497/&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;15159497&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000126447.91111.a1&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="15159497">Moretti et al. (2004)</a> identified a heterozygous 6-bp insertion in the PSEN1 gene (<a href="/entry/104311#0029">104311.0029</a>) in both sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159497" 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="#15" class="mim-tip-reference" title="Marrosu, M. G., Floris, G., Costa, G., Schirru, L., Spinicci, G., Cherchi, M. V., Mura, M., Mascia, M. G., Cocco, E. &lt;strong&gt;Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation.&lt;/strong&gt; Neurology 66: 108-111, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401857/&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;16401857&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000191360.08881.12&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="16401857">Marrosu et al. (2006)</a> reported a family in which 4 members had memory loss and personality changes ranging in onset from 32 to 45 years of age followed by a rapidly progressive disease course resulting in dementia, spastic tetraparesis, and anarthria in the most severely affected patients. Brain imaging showed multiple white matter lesions reminiscent of those seen in multiple sclerosis (see <a href="/entry/126200">126200</a>). Genetic analysis confirmed a heterozygous mutation in the PSEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#32" class="mim-tip-reference" title="St. George-Hyslop, P., Haines, J., Rogaev, E., Mortilla, M., Vaula, G., Pericak-Vance, M., Foncin, J.-F., Montesi, M., Bruni, A., Sorbi, S., Rainero, I., Pinessi, L., Pollen, D., Polinsky, R., Nee, L., Kennedy, J., Macciardi, F., Rogaeva, E., Liang, Y., Alexandrova, N., Lukiw, W., Schlumpf, K., Tanzi, R., Tsuda, T., Farrer, L., Cantu, J.-M., Duara, R., Amaducci, L., Bergamini, L., Gusella, J., Roses, A., Crapper McLachlan, D. &lt;strong&gt;Genetic evidence for a novel familial Alzheimer&#x27;s disease locus on chromosome 14.&lt;/strong&gt; Nature Genet. 2: 330-334, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1303289/&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;1303289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1292-330&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="1303289">St. George-Hyslop et al. (1992)</a>, <a href="#33" class="mim-tip-reference" title="Van Broeckhoven, C., Backhovens, H., Cruts, M., De Winter, G., Bruyland, M., Cras, P., Martin, J.-J. &lt;strong&gt;Mapping of a gene predisposing to early-onset Alzheimer&#x27;s disease to chromosome 14q24.3.&lt;/strong&gt; Nature Genet. 2: 335-339, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1303290/&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;1303290&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1292-335&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1303290">Van Broeckhoven et al. (1992)</a>, and <a href="#18" class="mim-tip-reference" title="Mullan, M., Houlden, H., Windelspecht, M., Fidani, L., Lombardi, C., Diaz, P., Rossor, M., Crook, R., Hardy, J., Duff, K., Crawford, F. &lt;strong&gt;A locus for familial early-onset Alzheimer&#x27;s disease on the long arm of chromosome 14, proximal to the alpha-1-antichymotrypsin gene.&lt;/strong&gt; Nature Genet. 2: 340-342, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1303291/&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;1303291&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1292-340&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="1303291">Mullan et al. (1992)</a> presented evidence of linkage of early-onset FAD to chromosome 14q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1303291+1303290+1303289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Belgian families with early-onset autosomal dominant AD, <a href="#34" class="mim-tip-reference" title="Van Broeckhoven, C., Genthe, A. M., Vandenberghe, A., Horsthemke, B., Backhovens, H., Raeymaekers, P., Van Hul, W., Wehnert, A., Gheuens, J., Cras, P., Bruyland, M., Martin, J. J., Salbaum, M., Multhaup, G., Masters, C. L., Beyreuther, K., Gurling, H. M. D., Mullan, M. J., Holland, A., Barton, A., Irving, N., Williamson, R., Richards, S. J., Hardy, J. A. &lt;strong&gt;Failure of familial Alzheimer&#x27;s disease to segregate with the A4-amyloid gene in several European families.&lt;/strong&gt; Nature 329: 153-155, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3306405/&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;3306405&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/329153a0&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="3306405">Van Broeckhoven et al. (1987)</a> excluded linkage to the APP locus on chromosome 21q. One pedigree contained 36 patients in 6 generations, and the second had 22 patients spanning 5 generations. By linkage analysis of the 2 Belgian families studied by <a href="#34" class="mim-tip-reference" title="Van Broeckhoven, C., Genthe, A. M., Vandenberghe, A., Horsthemke, B., Backhovens, H., Raeymaekers, P., Van Hul, W., Wehnert, A., Gheuens, J., Cras, P., Bruyland, M., Martin, J. J., Salbaum, M., Multhaup, G., Masters, C. L., Beyreuther, K., Gurling, H. M. D., Mullan, M. J., Holland, A., Barton, A., Irving, N., Williamson, R., Richards, S. J., Hardy, J. A. &lt;strong&gt;Failure of familial Alzheimer&#x27;s disease to segregate with the A4-amyloid gene in several European families.&lt;/strong&gt; Nature 329: 153-155, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3306405/&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;3306405&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/329153a0&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="3306405">Van Broeckhoven et al. (1987)</a>, <a href="#33" class="mim-tip-reference" title="Van Broeckhoven, C., Backhovens, H., Cruts, M., De Winter, G., Bruyland, M., Cras, P., Martin, J.-J. &lt;strong&gt;Mapping of a gene predisposing to early-onset Alzheimer&#x27;s disease to chromosome 14q24.3.&lt;/strong&gt; Nature Genet. 2: 335-339, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1303290/&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;1303290&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1292-335&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1303290">Van Broeckhoven et al. (1992)</a> found linkage to chromosome 14q. They narrowed the candidate region to an 8.9-cM area between D14S42 and D14S53, flanking D14S43 on both sides. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3306405+1303290" 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="#18" class="mim-tip-reference" title="Mullan, M., Houlden, H., Windelspecht, M., Fidani, L., Lombardi, C., Diaz, P., Rossor, M., Crook, R., Hardy, J., Duff, K., Crawford, F. &lt;strong&gt;A locus for familial early-onset Alzheimer&#x27;s disease on the long arm of chromosome 14, proximal to the alpha-1-antichymotrypsin gene.&lt;/strong&gt; Nature Genet. 2: 340-342, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1303291/&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;1303291&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1292-340&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="1303291">Mullan et al. (1992)</a> placed the gene proximal to that for alpha-1-antichymotrypsin (AACT; <a href="/entry/107280">107280</a>), thus excluding AACT, which is a component of plaque cores and a protease inhibitor, as a possible candidate gene for AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 9 non-Volga German kindreds with autosomal dominant AD, <a href="#28" class="mim-tip-reference" title="Schellenberg, G. D., Bird, T. D., Wijsman, E. M., Orr, H. T., Anderson, L., Nemens, E., White, J. A., Bonnycastle, L., Weber, J. L., Alonso, M. E., Potter, H., Heston, L. L., Martin, G. M. &lt;strong&gt;Genetic linkage evidence for a familial Alzheimer&#x27;s disease locus on chromosome 14.&lt;/strong&gt; Science 258: 668-671, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1411576/&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;1411576&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1411576&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="1411576">Schellenberg et al. (1992)</a> found linkage to chromosome 14: a total lod score of 9.15 at theta = 0.01 was obtained with the marker D14S43 at 14q24.3. A single early-onset family yielded a lod score of 4.89 (theta = 0.0). When no assumptions were made about age-dependent penetrance, significant results were still obtained (maximum lod = 5.94 at theta = 0.0) despite the loss of power. Results for several Volga German families were either negative or nonsignificant for markers in this region of chromosome 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1411576" 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="#29" class="mim-tip-reference" title="Schellenberg, G. D., Payami, H., Wijsman, E. M., Orr, H. T., Goddard, K. A. B., Anderson, L., Nemens, E., White, J. A., Alonso, M. E., Ball, M. J., Kaye, J., Morris, J. C., Chui, H., Sadovnick, A. D., Heston, L. L., Martin, G. M., Bird, T. D. &lt;strong&gt;Chromosome 14 and late-onset familial Alzheimer disease (FAD).&lt;/strong&gt; Am. J. Hum. Genet. 53: 619-628, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8352272/&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;8352272&lt;/a&gt;]" pmid="8352272">Schellenberg et al. (1993)</a> explored the role of chromosome 14 in late-onset FAD. They studied 49 families with a mean age of onset of 60 years or more. No evidence of linkage was obtained, and strong evidence against linkage to chromosome 3 markers was found. Evidence of linkage to D14S52 was found for a subgroup of families of intermediate age of onset, namely, older than 60 but less than 70 years of age. They concluded that the chromosome 14 locus was not responsible for Alzheimer disease in most late-onset FAD kindreds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8352272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 large early-onset FAD pedigrees, <a href="#20" class="mim-tip-reference" title="Nechiporuk, A., Fain, P., Kort, E., Nee, L. E., Frommelt, E., Polinsky, R. J., Korenberg, J. R., Pulst, S.-M. &lt;strong&gt;Linkage of familial Alzheimer disease to chromosome 14 in two large early-onset pedigrees: effects of marker allele frequencies on lod scores.&lt;/strong&gt; Am. J. Med. Genet. 48: 63-66, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8357039/&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;8357039&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320480113&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="8357039">Nechiporuk et al. (1993)</a> found tight linkage to D14S43 and D14S53. In a large pedigree with early-onset FAD, <a href="#6" class="mim-tip-reference" title="Campion, D., Brice, A., Hannequin, D., Tardieu, S., Dubois, B., Calenda, A., Brun, E., Penet, C., Tayot, J., Martinez, M., Bellis, M., Mallet, J., Agid, Y., Clerget-Darpoux, F. &lt;strong&gt;A large pedigree with early-onset Alzheimer&#x27;s disease: clinical, neuropathologic, and genetic characterization.&lt;/strong&gt; Neurology 45: 80-85, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7824141/&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;7824141&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.45.1.80&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="7824141">Campion et al. (1995)</a> observed a lod score of 5.48 at a recombination fraction of theta = 0.0 with the genetic marker D14S43, confirming the location of the responsible gene on chromosome 14q24.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7824141+8357039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><a href="#30" class="mim-tip-reference" title="Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.-F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R. J., Wasco, W., Da Silva, H. A. R., Haines, J. L., Pericak-Vance, M. A., Tanzi, R. E., Roses, A. D., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. &lt;strong&gt;Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer&#x27;s disease.&lt;/strong&gt; Nature 375: 754-760, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7596406/&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;7596406&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/375754a0&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="7596406">Sherrington et al. (1995)</a> identified 5 different missense mutations in the PSEN1 gene that cosegregated with early-onset familial Alzheimer disease type 3 (<a href="/entry/104311#0001">104311.0001</a>-<a href="/entry/104311#0005">104311.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7596406" 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="#14" class="mim-tip-reference" title="Lopera, F., Ardilla, A., Martinez, A., Madrigal, L., Arango-Viana, J. C., Lemere, C. A., Arango-Lasprilla, J. C., Hincapie, L., Arcos-Burgos, M., Ossa, J. E., Behrens, I. M., Norton, J., Lendon, C., Goate, A. M., Ruiz-Linares, A., Rosselli, M., Kosik, K. S. &lt;strong&gt;Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation.&lt;/strong&gt; JAMA 277: 793-799, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9052708/&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;9052708&lt;/a&gt;]" pmid="9052708">Lopera et al. (1997)</a> stated that affected members of a large Colombian kindred with early-onset AD had a glu280-to-ala mutation in the PSEN1 gene (E280A; <a href="/entry/104311#0009">104311.0009</a>). Some members of this kindred additionally carry alleles of APOE (<a href="/entry/107741">107741</a>) that may influence age of onset or severity of the AD phenotype; see below. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9052708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 24 of 31 families with early-onset AD, <a href="#25" class="mim-tip-reference" title="Raux, G., Guyant-Marechal, L., Martin, C., Bou, J., Penet, C., Brice, A., Hannequin, D., Frebourg, T., Campion, D. &lt;strong&gt;Molecular diagnosis of autosomal dominant early onset Alzheimer&#x27;s disease: an update. (Letter)&lt;/strong&gt; J. Med. Genet. 42: 793-795, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16033913/&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;16033913&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.033456&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="16033913">Raux et al. (2005)</a> identified mutations in the PSEN1 gene. The mean age of disease onset was 41.7 years. Combined with earlier studies, the authors estimated that 66% of families with early-onset AD are attributable to mutations in the PSEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16033913" 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="#5" class="mim-tip-reference" title="Bruni, A. C., Bernardi, L., Colao, R., Rubino, E., Smirne, N., Frangipane, F., Terni, B., Curcio, S. A. M., Mirabelli, M., Clodomiro, A., Di Lorenzo, R., Maletta, R., and 23 others. &lt;strong&gt;Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.&lt;/strong&gt; Neurology 74: 798-806, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20164095/&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;20164095&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20164095[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181d52785&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="20164095">Bruni et al. (2010)</a> identified an AD3 family from Naples, Italy, with the PSEN1 M146L mutation (<a href="/entry/104311#0001">104311.0001</a>). The 40-year-old proband showed memory loss with attention and planning deficits. Six other family members spanning 4 generations had developed dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20164095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifiers of AD Age of Onset and Severity</em></strong></p><p>
By genotype analysis of 109 carriers of the E280A PSEN1 mutation, including 52 individuals with AD, <a href="#22" class="mim-tip-reference" title="Pastor, P., Roe, C. M., Villegas, A., Bedoya, G., Chakraverty, S., Garcia, G., Tirado, V., Norton, J., Rios, S., Martinez, M., Kosik, K. S., Lopera, F., Goate, A. M. &lt;strong&gt;Apolipoprotein E-epsilon-4 modifies Alzheimer&#x27;s disease onset in an E280A PS1 kindred.&lt;/strong&gt; Ann. Neurol. 54: 163-169, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12891668/&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;12891668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10636&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="12891668">Pastor et al. (2003)</a> found that those with at least 1 APOE4 (see <a href="/entry/107741">107741</a>) allele were more likely to develop AD at an earlier age than those without an APOE4 allele, indicating an epistatic effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12891668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a member of the kindred reported by <a href="#14" class="mim-tip-reference" title="Lopera, F., Ardilla, A., Martinez, A., Madrigal, L., Arango-Viana, J. C., Lemere, C. A., Arango-Lasprilla, J. C., Hincapie, L., Arcos-Burgos, M., Ossa, J. E., Behrens, I. M., Norton, J., Lendon, C., Goate, A. M., Ruiz-Linares, A., Rosselli, M., Kosik, K. S. &lt;strong&gt;Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation.&lt;/strong&gt; JAMA 277: 793-799, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9052708/&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;9052708&lt;/a&gt;]" pmid="9052708">Lopera et al. (1997)</a> who carried the E280A mutation but who did not develop mild cognitive impairment until her seventies, <a href="#2" class="mim-tip-reference" title="Arboleda-Velasquez, J. F., Lopera, F., O&#x27;Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., Leyton-Cifuentes, D., Chen, K., and 32 others. &lt;strong&gt;Resistance to autosomal dominant Alzheimer&#x27;s disease in an APOE3 Christchurch homozygote: a case report.&lt;/strong&gt; Nature Med. 25: 1680-1683, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31686034/&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;31686034&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31686034[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41591-019-0611-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31686034">Arboleda-Velasquez et al. (2019)</a> detected homozygosity for an arginine-to-serine substitution at amino acid 136 (R136S) on the APOE3 allele of APOE (<a href="/entry/107741#0034">107741.0034</a>). The R136S mutation in APOE is known as the Christchurch mutation; the authors referred to the APOE allele in this individual as APOE3ch. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31686034+9052708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Quiroz, Y. T., Aguillon, D., Aguirre-Acevedo, D. C., Vasquez, D., Zuluaga, Y., Baena, A. Y., Madrigal, L., Hincapie, L., Sanchez, J. S., Langella, S., Posada-Duque, R., Littau, J. L., and 18 others. &lt;strong&gt;APOE3 Christchurch heterozygosity and autosomal dominant Alzheimer&#x27;s disease.&lt;/strong&gt; New Eng. J. Med. 390: 2156-2164, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/38899694/&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;38899694&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2308583&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="38899694">Quiroz et al. (2024)</a> analyzed data from 27 participants with 1 copy of the APOE3 Ch variant among 1,077 carriers of the PSEN1 E280A variant in a kindred of over 6,000 individuals with autosomal dominant Alzheimer disease from Antioquia, Colombia, to estimate the age at onset of cognitive impairment and dementia in this group as compared to persons without the APOE3 Ch variant. Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% CI, 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age of onset was 47 years (95% CI, 47 to 49). Both age of onset of mild cognitive impairment and dementia were delayed in those with the APOE3 Ch variant. In 2 participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer disease. In 1 of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Autopsy material obtained from 4 individuals with the APOE3 Ch and PSEN1 E280A variants showed greater amyloid plaque burden and a relatively limited tau burden as compared with that seen in material obtained from those who had the PSEN1 E280A variant but not the APOE3 Ch variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38899694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>FAD with Spastic Paraparesis and Unusual Plaques</em></strong></p><p>
In a family with FAD with onset in the early forties, <a href="#21" class="mim-tip-reference" title="O&#x27;Riordan, S., McMonagle, P., Janssen, J. C., Fox, N. C., Farrell, M., Collinge, J., Rossor, M. N., Hutchinson, M. &lt;strong&gt;Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities.&lt;/strong&gt; Neurology 59: 1108-1110, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12370477/&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;12370477&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.59.7.1108&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="12370477">O'Riordan et al. (2002)</a> identified a mutation in the PSEN1 gene (E280G; <a href="/entry/104311#0010">104311.0010</a>). Three additional members with the same mutation also had spastic paraparesis and unusual plaques. In a patient with FAD, spastic paraplegia, and cotton-wool plaques, <a href="#27" class="mim-tip-reference" title="Rogaeva, E., Bergeron, C., Sato, C., Moliaka, I., Kawarai, T., Toulina, A., Song, Y.-Q., Kolesnikova, T., Orlacchio, A., Bernardi, G., St. George-Hyslop, P. H. &lt;strong&gt;PS1 Alzheimer&#x27;s disease family with spastic paraplegia: the search for a gene modifier.&lt;/strong&gt; Neurology 61: 1005-1007, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14557582/&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;14557582&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.61.7.1005&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="14557582">Rogaeva et al. (2003)</a> identified the E280G mutation. The authors noted that the E280G mutation had been found in patients with classic FAD, suggesting that genetic modifiers may exist. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12370477+14557582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Finnish family with FAD with spastic paraparesis and unusual plaques, <a href="#7" class="mim-tip-reference" title="Crook, R., Verkkoniemi, A., Perez-Tur, J., Mehta N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H., Ylikoski, R., Poyhonen, M., Kucera, S., Haltia, M. &lt;strong&gt;A variant of Alzheimer&#x27;s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.&lt;/strong&gt; Nature Med. 4: 452-455, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9546792/&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;9546792&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm0498-452&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="9546792">Crook et al. (1998)</a> identified a mutation in the PSEN1 gene that caused deletion of exon 9 (<a href="/entry/104311#0012">104311.0012</a>). They stated that it was the only known structural mutation in the PSEN1 gene; previously identified mutations had been missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9546792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese patient with early-onset FAD, spasticity, and apraxia, <a href="#16" class="mim-tip-reference" title="Matsubara-Tsutsui, M., Yasuda, M., Yamagata, H., Nomura, T., Taguchi, K., Kohara, K., Miyoshi, K., Miki, T. &lt;strong&gt;Molecular evidence of presenilin 1 mutation in familial early onset dementia.&lt;/strong&gt; Am. J. Med. Genet. 114: 292-298, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11920851/&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;11920851&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10250&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="11920851">Matsubara-Tsutsui et al. (2002)</a> identified a mutation in the PSEN1 gene (<a href="/entry/104311#0022">104311.0022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11920851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
<a href="#8" class="mim-tip-reference" title="Dolzhanskaya, N., Gonzalez, M. A., Sperziani, F., Stefl, S., Messing, J., Wen, G. Y., Alexov, E., Zuchner, S., Velinov, M. &lt;strong&gt;A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease.&lt;/strong&gt; J. Alzheimers Dis. 39: 23-27, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24121961/&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;24121961&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24121961[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/10.3233/JAD-131340&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="24121961">Dolzhanskaya et al. (2014)</a> reported 3 brothers with early-onset Alzheimer disease with spastic paraparesis and unusually rapid progression. The boys' father and paternal grandmother were reportedly similarly affected. The brothers had onset of progressive dementia and ataxia between ages 29 and 32 years; 2 died at age 32 and the other died at age 36. The proband presented with memory deficits and ataxia, and later developed dysarthria and spastic paraparesis. Electron microscopy of a skin biopsy showed lipofuscin-containing phagocytic cells and distinct curvilinear lysosomal inclusion bodies, suggestive of neuronal ceroid lipofuscinosis. Neuropathologic examination showed changes consistent with Alzheimer disease, including neuritic and amyloid-containing plaques and neurofibrillary tangles. Additional findings included Hirano bodies and granulovacuolar degeneration in the hippocampus. The proband was originally ascertained from a cohort of patients clinically thought to have autosomal dominant adult-onset neuronal ceroid lipofuscinosis (CLN4B; <a href="/entry/162350">162350</a>) who were negative for mutations in the DNAJC5 gene (<a href="/entry/611203">611203</a>). Whole-exome sequencing of the proband identified a heterozygous mutation in the PSEN1 gene (L381F; <a href="/entry/104311#0039">104311.0039</a>) that segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24121961" 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="populationGenetics" class="mim-anchor"></a>
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<span id="mimPopulationGeneticsToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Population Genetics</strong>
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<p><a href="#35" class="mim-tip-reference" title="Yescas, P., Huertas-Vazquez, A., Villarreal-Molina, M. T., Rasmussen, A., Tusie-Luna, M. T., Lopez, M., Canizales-Quinteros, S., Alonso, M. E. &lt;strong&gt;Founder effect for the ala431glu mutation of the presenilin 1 gene causing early-onset Alzheimer&#x27;s disease in Mexican families.&lt;/strong&gt; Neurogenetics 7: 195-200, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16628450/&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;16628450&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-006-0043-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16628450">Yescas et al. (2006)</a> identified a heterozygous mutation in the PSEN1 gene (A431E; <a href="/entry/104311#0033">104311.0033</a>) in affected members of 9 Mexican families with early-onset Alzheimer disease, All families were from the state of Jalisco in western Mexico, and haplotype analysis indicated a founder effect. The A431E mutation was found in 19 (32%) of 60 apparently unaffected family members, suggesting either a presymptomatic state or reduced penetrance. <a href="#19" class="mim-tip-reference" title="Murrell, J., Ghetti, B., Cochran, E., Macias-Islas, M. A., Medina, L., Varpetian, A., Cummings, J. L., Mendez, M. F., Kawas, C., Chui, H., Ringman, J. M. &lt;strong&gt;The A431E mutation in PSEN1 causing familial Alzheimer&#x27;s disease originating in Jalisco state, Mexico: an additional fifteen families. (Letter)&lt;/strong&gt; Neurogenetics 7: 277-279, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16897084/&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;16897084&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-006-0053-1&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="16897084">Murrell et al. (2006)</a> found the A431E mutation in 20 individuals with AD3 from 15 families identified in Guadalajara, southern California, and Chicago. Age at disease onset ranged from 33 to 44 years, and spasticity was a common clinical feature. Fourteen families were of Mexican mestizo descent, and of these families, 9 traced the illness to ancestors from the state of Jalisco in Mexico. The remaining proband had a more remote Mexican ancestry. The findings further supported a founder effect for the A431E mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16628450+16897084" 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="#5" class="mim-tip-reference" title="Bruni, A. C., Bernardi, L., Colao, R., Rubino, E., Smirne, N., Frangipane, F., Terni, B., Curcio, S. A. M., Mirabelli, M., Clodomiro, A., Di Lorenzo, R., Maletta, R., and 23 others. &lt;strong&gt;Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.&lt;/strong&gt; Neurology 74: 798-806, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20164095/&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;20164095&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20164095[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181d52785&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="20164095">Bruni et al. (2010)</a> retrospectively identified 7 articles reporting AD3 families with the PSEN1 M146L mutation (<a href="/entry/104311#0001">104311.0001</a>), including those reported by <a href="#31" class="mim-tip-reference" title="Sorbi, S., Nacmias, B., Forleo, P., Piacentini, S., Sherrington, R., Rogaev, E., St George Hyslop, P., Amaducci, L. &lt;strong&gt;Missense mutation of S182 gene in Italian families with early-onset Alzheimer&#x27;s disease. (Letter)&lt;/strong&gt; Lancet 346: 439-440, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7623584/&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;7623584&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(95)92809-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7623584">Sorbi et al. (1995)</a> and <a href="#11" class="mim-tip-reference" title="Halliday, G. M., Song, Y. J. C., Lepar, G., Brooks, W. S., Kwok, J. B., Kersaitis, C., Gregory, G., Shepherd, C. E., Rahimi, F., Schofield, P. R., Kril, J. J. &lt;strong&gt;Pick bodies in a family with presenilin-1 Alzheimer&#x27;s disease.&lt;/strong&gt; Ann. Neurol. 57: 139-143, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15622541/&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;15622541&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20366&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="15622541">Halliday et al. (2005)</a>. They also reviewed the Calabrian families reported by <a href="#30" class="mim-tip-reference" title="Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.-F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R. J., Wasco, W., Da Silva, H. A. R., Haines, J. L., Pericak-Vance, M. A., Tanzi, R. E., Roses, A. D., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. &lt;strong&gt;Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer&#x27;s disease.&lt;/strong&gt; Nature 375: 754-760, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7596406/&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;7596406&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/375754a0&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="7596406">Sherrington et al. (1995)</a>. The reconstituted Calabrian families, a family from Naples, and the Australian family comprised 148 affected individuals, and a genealogic link from the 17th century was established with all the patients with the M146L mutation. The ancestral mutation originated from southern Italy. Phenotypic cluster analysis applied to 50 patients at onset and during the first 2 years identified 4 subgroups: 2 with a cognitive onset (58%), including memory loss or disorientation, and 2 with a behavioral onset (42%), including apathy, depression, and executive dysfunction. Neuropathologic examination of 2 patients showed substantial beta-amyloid and phosphorylated tau immunoreactivity throughout the cortex, deep brain regions, and brainstem, consistent with AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15622541+7623584+20164095+7596406" 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="history" class="mim-anchor"></a>
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<strong>History</strong>
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<p>Early-onset Alzheimer disease with spastic paraparesis was first reported by <a href="#4" class="mim-tip-reference" title="Barrett, A. M. &lt;strong&gt;A case of Alzheimer&#x27;s disease with unusual neurological disturbances.&lt;/strong&gt; J. Nerv. Ment. Dis. 4: 361-374, 1913."None>Barrett (1913)</a>.</p><p><a href="#9" class="mim-tip-reference" title="Ettinger, S., Weksler, M. E., Zhou, X., Blass, J., Szabo, P. &lt;strong&gt;Chromosomal fragility associated with familial Alzheimer&#x27;s disease.&lt;/strong&gt; Ann. Neurol. 36: 190-199, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8053655/&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;8053655&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410360211&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="8053655">Ettinger et al. (1994)</a> proposed that familial Alzheimer disease is associated with chromosomal instability and breakage at nonrandom sites. Using a novel gene cotransfer technique involving X-linked markers, they found decreased cotransfer of markers in FAD fibroblasts compared to controls, suggesting increased chromosomal breakage. The authors hypothesized a role for the trifunctional protein C(1)-THF synthase (<a href="/entry/172460">172460</a>), which maps to 14q24, in the generation of chromosomal instability in FAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8053655" 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="references"class="mim-anchor"></a>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="{Alzheimer&#x27;s Disease Collaborative Group}1995" class="mim-anchor"></a>
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Alzheimer's Disease Collaborative Group.
<strong>The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.</strong>
Nature Genet. 11: 219-222, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550356</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550356" 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/ng1095-219" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Arboleda-Velasquez2019" class="mim-anchor"></a>
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Arboleda-Velasquez, J. F., Lopera, F., O'Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., Leyton-Cifuentes, D., Chen, K., and 32 others.
<strong>Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.</strong>
Nature Med. 25: 1680-1683, 2019.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31686034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31686034</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31686034[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=31686034" 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/s41591-019-0611-3" target="_blank">Full Text</a>]
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<a id="Ataka2004" class="mim-anchor"></a>
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Ataka, S., Tomiyama, T., Takuma, H., Yamashita, T., Shimada, H., Tsutada, T., Kawabata, K., Mori, H., Miki, T.
<strong>A novel presenilin-1 mutation (leu85pro) in early-onset Alzheimer disease with spastic paraparesis.</strong>
Arch. Neurol. 61: 1773-1776, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534188" 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.61.11.1773" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="Barrett1913" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Barrett, A. M.
<strong>A case of Alzheimer's disease with unusual neurological disturbances.</strong>
J. Nerv. Ment. Dis. 4: 361-374, 1913.
</p>
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<a id="5" class="mim-anchor"></a>
<a id="Bruni2010" class="mim-anchor"></a>
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Bruni, A. C., Bernardi, L., Colao, R., Rubino, E., Smirne, N., Frangipane, F., Terni, B., Curcio, S. A. M., Mirabelli, M., Clodomiro, A., Di Lorenzo, R., Maletta, R., and 23 others.
<strong>Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.</strong>
Neurology 74: 798-806, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20164095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20164095</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20164095[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=20164095" 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.0b013e3181d52785" target="_blank">Full Text</a>]
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<a id="Campion1995" class="mim-anchor"></a>
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Campion, D., Brice, A., Hannequin, D., Tardieu, S., Dubois, B., Calenda, A., Brun, E., Penet, C., Tayot, J., Martinez, M., Bellis, M., Mallet, J., Agid, Y., Clerget-Darpoux, F.
<strong>A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization.</strong>
Neurology 45: 80-85, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7824141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7824141</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7824141" 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.45.1.80" target="_blank">Full Text</a>]
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<a id="Crook1998" class="mim-anchor"></a>
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<p class="mim-text-font">
Crook, R., Verkkoniemi, A., Perez-Tur, J., Mehta N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H., Ylikoski, R., Poyhonen, M., Kucera, S., Haltia, M.
<strong>A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.</strong>
Nature Med. 4: 452-455, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9546792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9546792</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9546792" 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/nm0498-452" target="_blank">Full Text</a>]
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<a id="Dolzhanskaya2014" class="mim-anchor"></a>
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Dolzhanskaya, N., Gonzalez, M. A., Sperziani, F., Stefl, S., Messing, J., Wen, G. Y., Alexov, E., Zuchner, S., Velinov, M.
<strong>A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease.</strong>
J. Alzheimers Dis. 39: 23-27, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24121961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24121961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24121961[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=24121961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.3233/JAD-131340" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Ettinger1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ettinger, S., Weksler, M. E., Zhou, X., Blass, J., Szabo, P.
<strong>Chromosomal fragility associated with familial Alzheimer's disease.</strong>
Ann. Neurol. 36: 190-199, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8053655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8053655</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8053655" 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.410360211" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Godbolt2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Godbolt, A. K., Beck, J. A., Collinge, J., Garrard, P., Warren, J. D., Fox, N. C., Rossor, M. N.
<strong>A presenilin 1 R278I mutation presenting with language impairment.</strong>
Neurology 63: 1702-1704, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534260</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000143060.98164.1a" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Halliday2005" class="mim-anchor"></a>
<div class="">
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Halliday, G. M., Song, Y. J. C., Lepar, G., Brooks, W. S., Kwok, J. B., Kersaitis, C., Gregory, G., Shepherd, C. E., Rahimi, F., Schofield, P. R., Kril, J. J.
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[<a href="https://doi.org/10.1002/ana.20366" target="_blank">Full Text</a>]
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Hull, M., Fiebich, B. L., Dykierek, P., Schmidtke, K., Nitzsche, E., Orszagh, M., Deuschl, G., Moser, E., Schumacher, M., Lucking, C., Berger, M., Bauer, J.
<strong>Early-onset Alzheimer's disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139.</strong>
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[<a href="https://doi.org/10.1007/s004060050028" target="_blank">Full Text</a>]
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Leverenz, J. B., Fishel, M. A., Peskind, E. R., Montine, T. J., Nochlin, D., Steinbart, E., Raskind, M. A., Schellenberg, G. D., Bird, T. D., Tsuang, D.
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[<a href="https://doi.org/10.1001/archneur.63.3.370" target="_blank">Full Text</a>]
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Lopera, F., Ardilla, A., Martinez, A., Madrigal, L., Arango-Viana, J. C., Lemere, C. A., Arango-Lasprilla, J. C., Hincapie, L., Arcos-Burgos, M., Ossa, J. E., Behrens, I. M., Norton, J., Lendon, C., Goate, A. M., Ruiz-Linares, A., Rosselli, M., Kosik, K. S.
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[<a href="https://doi.org/10.1212/01.wnl.0000191360.08881.12" target="_blank">Full Text</a>]
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<strong>Molecular evidence of presenilin 1 mutation in familial early onset dementia.</strong>
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[<a href="https://doi.org/10.1002/ajmg.10250" target="_blank">Full Text</a>]
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Moretti, P., Lieberman, A. P., Wilde, E. A., Giordani, B. I., Kluin, K. J., Koeppe, R. A., Minoshima, S., Kuhl, D. E., Seltzer, W. K., Foster, N. L.
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[<a href="https://doi.org/10.1212/01.wnl.0000126447.91111.a1" target="_blank">Full Text</a>]
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Mullan, M., Houlden, H., Windelspecht, M., Fidani, L., Lombardi, C., Diaz, P., Rossor, M., Crook, R., Hardy, J., Duff, K., Crawford, F.
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[<a href="https://doi.org/10.1038/ng1292-340" target="_blank">Full Text</a>]
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Murrell, J., Ghetti, B., Cochran, E., Macias-Islas, M. A., Medina, L., Varpetian, A., Cummings, J. L., Mendez, M. F., Kawas, C., Chui, H., Ringman, J. M.
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[<a href="https://doi.org/10.1007/s10048-006-0053-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320480113" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.59.7.1108" target="_blank">Full Text</a>]
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Pastor, P., Roe, C. M., Villegas, A., Bedoya, G., Chakraverty, S., Garcia, G., Tirado, V., Norton, J., Rios, S., Martinez, M., Kosik, K. S., Lopera, F., Goate, A. M.
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[<a href="https://doi.org/10.1002/ana.10636" target="_blank">Full Text</a>]
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Piccini, A., Zanusso, G., Borghi, R., Noviello, C., Monaco, S., Russo, R., Damonte, G., Armirotti, A., Gelati, M., Giordano, R., Zambenedetti, P., Russo, C., Ghetti, B., Tabaton, M.
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[<a href="https://doi.org/10.1001/archneur.64.5.738" target="_blank">Full Text</a>]
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Quiroz, Y. T., Aguillon, D., Aguirre-Acevedo, D. C., Vasquez, D., Zuluaga, Y., Baena, A. Y., Madrigal, L., Hincapie, L., Sanchez, J. S., Langella, S., Posada-Duque, R., Littau, J. L., and 18 others.
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[<a href="https://doi.org/10.1136/jmg.2005.033456" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.60.6.884" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.61.7.1005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1411576" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/375754a0" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7623584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7623584</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7623584" 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/s0140-6736(95)92809-x" target="_blank">Full Text</a>]
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<a id="St. George-Hyslop1992" class="mim-anchor"></a>
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St. George-Hyslop, P., Haines, J., Rogaev, E., Mortilla, M., Vaula, G., Pericak-Vance, M., Foncin, J.-F., Montesi, M., Bruni, A., Sorbi, S., Rainero, I., Pinessi, L., Pollen, D., Polinsky, R., Nee, L., Kennedy, J., Macciardi, F., Rogaeva, E., Liang, Y., Alexandrova, N., Lukiw, W., Schlumpf, K., Tanzi, R., Tsuda, T., Farrer, L., Cantu, J.-M., Duara, R., Amaducci, L., Bergamini, L., Gusella, J., Roses, A., Crapper McLachlan, D.
<strong>Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14.</strong>
Nature Genet. 2: 330-334, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303289</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303289" 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/ng1292-330" target="_blank">Full Text</a>]
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<a id="Van Broeckhoven1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Van Broeckhoven, C., Backhovens, H., Cruts, M., De Winter, G., Bruyland, M., Cras, P., Martin, J.-J.
<strong>Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3.</strong>
Nature Genet. 2: 335-339, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303290" 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/ng1292-335" target="_blank">Full Text</a>]
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<a id="34" class="mim-anchor"></a>
<a id="Van Broeckhoven1987" class="mim-anchor"></a>
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<p class="mim-text-font">
Van Broeckhoven, C., Genthe, A. M., Vandenberghe, A., Horsthemke, B., Backhovens, H., Raeymaekers, P., Van Hul, W., Wehnert, A., Gheuens, J., Cras, P., Bruyland, M., Martin, J. J., Salbaum, M., Multhaup, G., Masters, C. L., Beyreuther, K., Gurling, H. M. D., Mullan, M. J., Holland, A., Barton, A., Irving, N., Williamson, R., Richards, S. J., Hardy, J. A.
<strong>Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families.</strong>
Nature 329: 153-155, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3306405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3306405</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3306405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/329153a0" target="_blank">Full Text</a>]
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<a id="Yescas2006" class="mim-anchor"></a>
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Yescas, P., Huertas-Vazquez, A., Villarreal-Molina, M. T., Rasmussen, A., Tusie-Luna, M. T., Lopez, M., Canizales-Quinteros, S., Alonso, M. E.
<strong>Founder effect for the ala431glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families.</strong>
Neurogenetics 7: 195-200, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16628450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16628450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16628450" 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/s10048-006-0043-3" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 09/25/2024
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Ada Hamosh - updated : 11/22/2019<br>Cassandra L. Kniffin - updated : 3/12/2014<br>Cassandra L. Kniffin - updated : 4/15/2008<br>Cassandra L. Kniffin - updated : 2/19/2007<br>Cassandra L. Kniffin - updated : 12/6/2006<br>Cassandra L. Kniffin - updated : 8/29/2006<br>Cassandra L. Kniffin - updated : 4/7/2006<br>Cassandra L. Kniffin - updated : 12/28/2005<br>Cassandra L. Kniffin - updated : 11/3/2005<br>Cassandra L. Kniffin - updated : 7/25/2005<br>Cassandra L. Kniffin - updated : 6/17/2005<br>Cassandra L. Kniffin - updated : 5/13/2005<br>Cassandra L. Kniffin - updated : 2/18/2005<br>Cassandra L. Kniffin - updated : 2/6/2004<br>Cassandra L. Kniffin - updated : 1/7/2004<br>Cassandra L. Kniffin - updated : 8/8/2003
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Cassandra L. Kniffin : 5/23/2003
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alopez : 09/25/2024
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carol : 02/09/2022<br>carol : 11/25/2019<br>alopez : 11/22/2019<br>carol : 02/21/2017<br>carol : 03/20/2014<br>mcolton : 3/18/2014<br>ckniffin : 3/12/2014<br>terry : 6/3/2009<br>wwang : 4/17/2008<br>ckniffin : 4/15/2008<br>alopez : 6/4/2007<br>wwang : 2/22/2007<br>ckniffin : 2/19/2007<br>wwang : 12/7/2006<br>ckniffin : 12/6/2006<br>wwang : 9/7/2006<br>ckniffin : 8/29/2006<br>wwang : 4/11/2006<br>ckniffin : 4/7/2006<br>carol : 2/10/2006<br>ckniffin : 12/28/2005<br>terry : 12/20/2005<br>ckniffin : 12/19/2005<br>ckniffin : 12/19/2005<br>wwang : 11/10/2005<br>ckniffin : 11/3/2005<br>wwang : 7/26/2005<br>ckniffin : 7/25/2005<br>ckniffin : 6/17/2005<br>wwang : 5/27/2005<br>ckniffin : 5/13/2005<br>ckniffin : 5/12/2005<br>wwang : 2/23/2005<br>ckniffin : 2/18/2005<br>ckniffin : 2/18/2005<br>tkritzer : 2/18/2004<br>ckniffin : 2/6/2004<br>tkritzer : 1/14/2004<br>ckniffin : 1/7/2004<br>ckniffin : 8/8/2003<br>ckniffin : 5/29/2003<br>ckniffin : 5/29/2003<br>carol : 5/28/2003<br>ckniffin : 5/27/2003
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<h3>
<span class="mim-font">
<strong>#</strong> 607822
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<span class="mim-font">
ALZHEIMER DISEASE 3; AD3
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<em>Alternative titles; symbols</em>
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ALZHEIMER DISEASE 3, EARLY-ONSET<br />
ALZHEIMER DISEASE, FAMILIAL, 3
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Other entities represented in this entry:
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ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND UNUSUAL PLAQUES, INCLUDED
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ALZHEIMER DISEASE, FAMILIAL, 3, WITH SPASTIC PARAPARESIS AND APRAXIA, INCLUDED
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<strong>ORPHA:</strong> 1020; &nbsp;
<strong>DO:</strong> 0110042; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
14q24.2
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Alzheimer disease, type 3, with or without spastic paraparesis
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607822
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Autosomal dominant
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3
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PSEN1
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104311
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19q13.32
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<span class="mim-font">
{?Alzheimer disease, protection against, due to APOE3-Christchurch}
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607822
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Autosomal dominant
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3
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APOE
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107741
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because early-onset familial Alzheimer disease-3 (AD3) is caused by heterozygous mutation in the presenilin-1 gene (PSEN1; 104311) on chromosome 14q24.</p><p>For a phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300.</p>
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<strong>Clinical Features</strong>
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<p>Campion et al. (1995) studied a large pedigree that included 34 subjects with early-onset progressive dementia with mean age at onset at 46 plus or minus 3.5 years and mean age at death at 52.6. Myoclonus and extrapyramidal signs were common; seizures were present in all affected subjects. There were neuropathologic changes typical of Alzheimer disease in the 2 brains examined. </p><p>Lopera et al. (1997) described a large pedigree with early-onset Alzheimer disease from a community based in Antioquia, Colombia. Affected patients had a mean age at onset of 46.8 years (range, 34 to 62 years) with an average interval of 8 years until death. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentations were memory loss followed by behavioral and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. </p><p>Hull et al. (1998) described a German family with early-onset Alzheimer disease with a mutation in the PSEN1 gene. From the age of 43 years, the proband had complained of deficits in short-term memory. Relatives had noticed his symptoms even earlier and dated the onset of deficits to age 38 years when he showed increasing interruptions during speech followed by social withdrawal. There was a strong family history of dementia. Through 3 generations the onset of dementia in this family was between 42 and 45 years. </p><p>Rippon et al. (2003) reported an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade. Two brothers presented with personality changes, labile mood, language difficulties, psychosis, primitive reflexes consistent with frontotemporal dementia (600274), but also were found to have memory impairment and neuropathologic findings diagnostic of AD. Both brothers had a mutation in the PSEN1 gene (104311.0006). Their father reportedly had died in his sixth decade with a similar illness. The authors commented on the atypical clinical presentation. </p><p>Godbolt et al. (2004) reported 2 sibs with early-onset Alzheimer disease confirmed by genetic analysis (104311.0030). Both patients presented at around age 50 with difficulty in word finding and impaired frontal executive function, but with relative preservation of memory. The sister exhibited dysfluent speech with phonemic paraphasias, dysgraphia, and dyspraxia. She later developed mutism, generalized rigidity, myoclonus of the upper limbs, dystonic posturing of the right hand, and shuffling gait. The brother exhibited impaired repetition of sentences and polysyllabic words, nominal dysphasia, dysgraphia, and dyscalculia. MRI of both patients showed multiple foci of white matter signal changes. </p><p>Ataka et al. (2004) reported a Japanese patient with onset of memory impairment and difficulty driving a car at age 26. Neuropsychologic testing showed that he had visual constructional apraxia, visuospatial agnosia, and optic ataxia, consistent with the 'visual variant' of AD in which there is a visuospatial cognitive deficit. The patient was heterozygous for a PSEN1 mutation (104311.0031). </p><p>Halliday et al. (2005) reported 2 sibs with early-onset FAD and mutation (M146L; 104311.0001) in the PSEN1 gene. Family history suggested that their father was also affected. Neuropathologic examination of both patients showed numerous cortical plaques and neurofibrillary tangles, consistent with AD. In addition, both cases showed ballooned neurons and numerous tau (MAPT; 157140)-immunoreactive Pick bodies in upper frontotemporal cortical layers and in the hippocampal dentate gyrus. Halliday et al. (2005) suggested that the M146L mutation may specifically predispose to both AD and Pick pathology by affecting multiple intracellular pathways involving tau phosphorylation. </p><p>Leverenz et al. (2006) found that 24 (96%) of 25 patients with AD3 had Lewy body pathology in the amygdala. Most patients also had Lewy body pathology in other brain regions, including the cingulate gyrus and neocortex, although there was variability. AD patients with PSEN1 mutations had more frequent Lewy body pathology compared to AD patients with PSEN2 (600759) mutations. There was no clinical correlation between age at onset or disease severity onset and Lewy body pathology in either group, although those with longer disease duration tended to have more Lewy body pathology. </p><p>Piccini et al. (2007) reported a patient who presented at age 28 years with delusions and lower limb jerks accompanied by intentional myoclonus and cerebellar ataxia. He had rapid progression with global impairment of all cognitive functions and became bedridden, anarthric, and incontinent by age 33. He died of bronchopneumonia at age 35. Postmortem examination showed severe beta-amyloid deposition in the cerebral and cerebellar cortices, amyloid angiopathy, and severe loss of Purkinje cells and fibers in the cerebellum. Neurofibrillary tangles were also present. Genetic analysis revealed a heterozygous mutation in the PSEN1 gene (S170F; 104311.0036). </p><p><strong><em>FAD with spastic paraparesis and unusual plaques</em></strong></p><p>
In a family with onset of AD in the early forties reported by the Alzheimer's Disease Collaborative Group (1995), O'Riordan et al. (2002) described an atypical disease pattern in 3 additional members from the third generation. One had cognitive impairment, spastic paraparesis, and white matter abnormalities on MRI. One of his sibs developed dementia and myoclonus and had white matter abnormalities on MRI. Another sib had ophthalmoplegia, spastic-ataxic quadriparesis, and cotton-wool plaques with amyloid angiopathy on brain biopsy (MRI was not performed). The authors suggested that the MRI findings may reflect an ischemic leukoencephalopathy due to amyloid angiopathy affecting meningocortical vessels. </p><p>Crook et al. (1998) reported a Finnish pedigree with 17 affected individuals of both sexes in 3 generations suffering from a novel variant of Alzheimer disease characterized by progressive dementia that was in most cases preceded by spastic paraparesis. Neuropathologic investigations showed numerous distinct, large, round, and eosinophilic plaques, as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton-wool balls and were immunoreactive for A-beta, but lacked a congophilic dense core or marked plaque-related neuritic pathology. </p><p>Matsubara-Tsutsui et al. (2002) reported a Japanese family in which 6 individuals in 2 generations were affected with presenile dementia preceded by spastic gait. Detailed information was available in 1 patient who had disease onset at age 35 with spasticity, motor apraxia, and cognitive decline. Neuropathologic examination was not done. </p><p>Rogaeva et al. (2003) reported the neuropathologic findings of a patient with FAD and spastic paraplegia with onset at 52 years of age. The brain had severe cortical atrophy with neuronal loss, as well as atrophy of the caudate, hippocampus, amygdala, and entorhinal cortex. The substantia nigra was pale, depopulated, and had rare tangles and Lewy bodies. Neurofibrillary tangles and amyloid plaques with a cotton-wool appearance were identified. Consistent with spastic paraplegia, the spinal cord was smaller than usual and flattened in its anteroposterior dimension, and there was degeneration of the corticospinal tracts. </p><p>Moretti et al. (2004) reported 2 sibs with early-onset dementia and spastic paraparesis. Their father, paternal grandfather, and paternal great-grandfather reportedly died in their thirties of a dementing illness associated with severe progressive gait impairment. The proband developed memory problems at age 28 years. At age 31, he had mild bilateral limb apraxia, dystonia, mild dementia, and hypometabolism of the temporoparietal association cortex on PET scan. By age 34, he was profoundly demented, with dysarthria, dysphagia, and spasticity of the arms and legs. Postmortem examination showed moderate brain atrophy with amyloid plaques and neurofibrillary tangles consistent with AD throughout the neocortex, limbic regions, and striatum, as well as large eosinophilic cotton-wool plaques. His sister had a similar disease course. Moretti et al. (2004) identified a heterozygous 6-bp insertion in the PSEN1 gene (104311.0029) in both sibs. </p><p>Marrosu et al. (2006) reported a family in which 4 members had memory loss and personality changes ranging in onset from 32 to 45 years of age followed by a rapidly progressive disease course resulting in dementia, spastic tetraparesis, and anarthria in the most severely affected patients. Brain imaging showed multiple white matter lesions reminiscent of those seen in multiple sclerosis (see 126200). Genetic analysis confirmed a heterozygous mutation in the PSEN1 gene. </p>
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<h4>
<span class="mim-font">
<strong>Mapping</strong>
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<p>St. George-Hyslop et al. (1992), Van Broeckhoven et al. (1992), and Mullan et al. (1992) presented evidence of linkage of early-onset FAD to chromosome 14q. </p><p>In 2 Belgian families with early-onset autosomal dominant AD, Van Broeckhoven et al. (1987) excluded linkage to the APP locus on chromosome 21q. One pedigree contained 36 patients in 6 generations, and the second had 22 patients spanning 5 generations. By linkage analysis of the 2 Belgian families studied by Van Broeckhoven et al. (1987), Van Broeckhoven et al. (1992) found linkage to chromosome 14q. They narrowed the candidate region to an 8.9-cM area between D14S42 and D14S53, flanking D14S43 on both sides. </p><p>Mullan et al. (1992) placed the gene proximal to that for alpha-1-antichymotrypsin (AACT; 107280), thus excluding AACT, which is a component of plaque cores and a protease inhibitor, as a possible candidate gene for AD. </p><p>In 9 non-Volga German kindreds with autosomal dominant AD, Schellenberg et al. (1992) found linkage to chromosome 14: a total lod score of 9.15 at theta = 0.01 was obtained with the marker D14S43 at 14q24.3. A single early-onset family yielded a lod score of 4.89 (theta = 0.0). When no assumptions were made about age-dependent penetrance, significant results were still obtained (maximum lod = 5.94 at theta = 0.0) despite the loss of power. Results for several Volga German families were either negative or nonsignificant for markers in this region of chromosome 14. </p><p>Schellenberg et al. (1993) explored the role of chromosome 14 in late-onset FAD. They studied 49 families with a mean age of onset of 60 years or more. No evidence of linkage was obtained, and strong evidence against linkage to chromosome 3 markers was found. Evidence of linkage to D14S52 was found for a subgroup of families of intermediate age of onset, namely, older than 60 but less than 70 years of age. They concluded that the chromosome 14 locus was not responsible for Alzheimer disease in most late-onset FAD kindreds. </p><p>In 2 large early-onset FAD pedigrees, Nechiporuk et al. (1993) found tight linkage to D14S43 and D14S53. In a large pedigree with early-onset FAD, Campion et al. (1995) observed a lod score of 5.48 at a recombination fraction of theta = 0.0 with the genetic marker D14S43, confirming the location of the responsible gene on chromosome 14q24.3. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
<p>Sherrington et al. (1995) identified 5 different missense mutations in the PSEN1 gene that cosegregated with early-onset familial Alzheimer disease type 3 (104311.0001-104311.0005). </p><p>Lopera et al. (1997) stated that affected members of a large Colombian kindred with early-onset AD had a glu280-to-ala mutation in the PSEN1 gene (E280A; 104311.0009). Some members of this kindred additionally carry alleles of APOE (107741) that may influence age of onset or severity of the AD phenotype; see below. </p><p>In affected members of 24 of 31 families with early-onset AD, Raux et al. (2005) identified mutations in the PSEN1 gene. The mean age of disease onset was 41.7 years. Combined with earlier studies, the authors estimated that 66% of families with early-onset AD are attributable to mutations in the PSEN1 gene. </p><p>Bruni et al. (2010) identified an AD3 family from Naples, Italy, with the PSEN1 M146L mutation (104311.0001). The 40-year-old proband showed memory loss with attention and planning deficits. Six other family members spanning 4 generations had developed dementia. </p><p><strong><em>Modifiers of AD Age of Onset and Severity</em></strong></p><p>
By genotype analysis of 109 carriers of the E280A PSEN1 mutation, including 52 individuals with AD, Pastor et al. (2003) found that those with at least 1 APOE4 (see 107741) allele were more likely to develop AD at an earlier age than those without an APOE4 allele, indicating an epistatic effect. </p><p>In a member of the kindred reported by Lopera et al. (1997) who carried the E280A mutation but who did not develop mild cognitive impairment until her seventies, Arboleda-Velasquez et al. (2019) detected homozygosity for an arginine-to-serine substitution at amino acid 136 (R136S) on the APOE3 allele of APOE (107741.0034). The R136S mutation in APOE is known as the Christchurch mutation; the authors referred to the APOE allele in this individual as APOE3ch. </p><p>Quiroz et al. (2024) analyzed data from 27 participants with 1 copy of the APOE3 Ch variant among 1,077 carriers of the PSEN1 E280A variant in a kindred of over 6,000 individuals with autosomal dominant Alzheimer disease from Antioquia, Colombia, to estimate the age at onset of cognitive impairment and dementia in this group as compared to persons without the APOE3 Ch variant. Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% CI, 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age of onset was 47 years (95% CI, 47 to 49). Both age of onset of mild cognitive impairment and dementia were delayed in those with the APOE3 Ch variant. In 2 participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer disease. In 1 of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Autopsy material obtained from 4 individuals with the APOE3 Ch and PSEN1 E280A variants showed greater amyloid plaque burden and a relatively limited tau burden as compared with that seen in material obtained from those who had the PSEN1 E280A variant but not the APOE3 Ch variant. </p><p><strong><em>FAD with Spastic Paraparesis and Unusual Plaques</em></strong></p><p>
In a family with FAD with onset in the early forties, O'Riordan et al. (2002) identified a mutation in the PSEN1 gene (E280G; 104311.0010). Three additional members with the same mutation also had spastic paraparesis and unusual plaques. In a patient with FAD, spastic paraplegia, and cotton-wool plaques, Rogaeva et al. (2003) identified the E280G mutation. The authors noted that the E280G mutation had been found in patients with classic FAD, suggesting that genetic modifiers may exist. </p><p>In a Finnish family with FAD with spastic paraparesis and unusual plaques, Crook et al. (1998) identified a mutation in the PSEN1 gene that caused deletion of exon 9 (104311.0012). They stated that it was the only known structural mutation in the PSEN1 gene; previously identified mutations had been missense mutations. </p><p>In a Japanese patient with early-onset FAD, spasticity, and apraxia, Matsubara-Tsutsui et al. (2002) identified a mutation in the PSEN1 gene (104311.0022). </p><p><strong><em>Clinical Variability</em></strong></p><p>
Dolzhanskaya et al. (2014) reported 3 brothers with early-onset Alzheimer disease with spastic paraparesis and unusually rapid progression. The boys' father and paternal grandmother were reportedly similarly affected. The brothers had onset of progressive dementia and ataxia between ages 29 and 32 years; 2 died at age 32 and the other died at age 36. The proband presented with memory deficits and ataxia, and later developed dysarthria and spastic paraparesis. Electron microscopy of a skin biopsy showed lipofuscin-containing phagocytic cells and distinct curvilinear lysosomal inclusion bodies, suggestive of neuronal ceroid lipofuscinosis. Neuropathologic examination showed changes consistent with Alzheimer disease, including neuritic and amyloid-containing plaques and neurofibrillary tangles. Additional findings included Hirano bodies and granulovacuolar degeneration in the hippocampus. The proband was originally ascertained from a cohort of patients clinically thought to have autosomal dominant adult-onset neuronal ceroid lipofuscinosis (CLN4B; 162350) who were negative for mutations in the DNAJC5 gene (611203). Whole-exome sequencing of the proband identified a heterozygous mutation in the PSEN1 gene (L381F; 104311.0039) that segregated with the disorder in the family. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Yescas et al. (2006) identified a heterozygous mutation in the PSEN1 gene (A431E; 104311.0033) in affected members of 9 Mexican families with early-onset Alzheimer disease, All families were from the state of Jalisco in western Mexico, and haplotype analysis indicated a founder effect. The A431E mutation was found in 19 (32%) of 60 apparently unaffected family members, suggesting either a presymptomatic state or reduced penetrance. Murrell et al. (2006) found the A431E mutation in 20 individuals with AD3 from 15 families identified in Guadalajara, southern California, and Chicago. Age at disease onset ranged from 33 to 44 years, and spasticity was a common clinical feature. Fourteen families were of Mexican mestizo descent, and of these families, 9 traced the illness to ancestors from the state of Jalisco in Mexico. The remaining proband had a more remote Mexican ancestry. The findings further supported a founder effect for the A431E mutation. </p><p>Bruni et al. (2010) retrospectively identified 7 articles reporting AD3 families with the PSEN1 M146L mutation (104311.0001), including those reported by Sorbi et al. (1995) and Halliday et al. (2005). They also reviewed the Calabrian families reported by Sherrington et al. (1995). The reconstituted Calabrian families, a family from Naples, and the Australian family comprised 148 affected individuals, and a genealogic link from the 17th century was established with all the patients with the M146L mutation. The ancestral mutation originated from southern Italy. Phenotypic cluster analysis applied to 50 patients at onset and during the first 2 years identified 4 subgroups: 2 with a cognitive onset (58%), including memory loss or disorientation, and 2 with a behavioral onset (42%), including apathy, depression, and executive dysfunction. Neuropathologic examination of 2 patients showed substantial beta-amyloid and phosphorylated tau immunoreactivity throughout the cortex, deep brain regions, and brainstem, consistent with AD. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Early-onset Alzheimer disease with spastic paraparesis was first reported by Barrett (1913).</p><p>Ettinger et al. (1994) proposed that familial Alzheimer disease is associated with chromosomal instability and breakage at nonrandom sites. Using a novel gene cotransfer technique involving X-linked markers, they found decreased cotransfer of markers in FAD fibroblasts compared to controls, suggesting increased chromosomal breakage. The authors hypothesized a role for the trifunctional protein C(1)-THF synthase (172460), which maps to 14q24, in the generation of chromosomal instability in FAD. </p>
</span>
<div>
<br />
</div>
</div>
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<p class="mim-text-font">
Van Broeckhoven, C., Backhovens, H., Cruts, M., De Winter, G., Bruyland, M., Cras, P., Martin, J.-J.
<strong>Mapping of a gene predisposing to early-onset Alzheimer&#x27;s disease to chromosome 14q24.3.</strong>
Nature Genet. 2: 335-339, 1992.
[PubMed: 1303290]
[Full Text: https://doi.org/10.1038/ng1292-335]
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Van Broeckhoven, C., Genthe, A. M., Vandenberghe, A., Horsthemke, B., Backhovens, H., Raeymaekers, P., Van Hul, W., Wehnert, A., Gheuens, J., Cras, P., Bruyland, M., Martin, J. J., Salbaum, M., Multhaup, G., Masters, C. L., Beyreuther, K., Gurling, H. M. D., Mullan, M. J., Holland, A., Barton, A., Irving, N., Williamson, R., Richards, S. J., Hardy, J. A.
<strong>Failure of familial Alzheimer&#x27;s disease to segregate with the A4-amyloid gene in several European families.</strong>
Nature 329: 153-155, 1987.
[PubMed: 3306405]
[Full Text: https://doi.org/10.1038/329153a0]
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Yescas, P., Huertas-Vazquez, A., Villarreal-Molina, M. T., Rasmussen, A., Tusie-Luna, M. T., Lopez, M., Canizales-Quinteros, S., Alonso, M. E.
<strong>Founder effect for the ala431glu mutation of the presenilin 1 gene causing early-onset Alzheimer&#x27;s disease in Mexican families.</strong>
Neurogenetics 7: 195-200, 2006.
[PubMed: 16628450]
[Full Text: https://doi.org/10.1007/s10048-006-0043-3]
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