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- #607485 - FRONTOTEMPORAL DEMENTIA 2; FTD2
- OMIM
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<span class="h4">#607485</span>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/607485"><strong>Clinical Synopsis</strong></a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<div><a href="https://clinicaltrials.gov/search?cond=FRONTOTEMPORAL DEMENTIA" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100070" title="Progressive non-fluent aphasia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Progressive non-fluent aph…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Frontotemporal dementia</a></div>
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</div>
</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">
<span class="panel-title">
<span class="small">
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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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</a>
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</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0060672" 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/607485" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0060672" 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>
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</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.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ICD10CM:</strong> G31.01<br />
<strong>ORPHA:</strong> 100070, 282<br />
<strong>DO:</strong> 0060672<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>
607485
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
FRONTOTEMPORAL DEMENTIA 2; FTD2
</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">
FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED<br />
FTLD-TDP, GRN-RELATED<br />
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, GRN-RELATED<br />
FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS; FTLDU<br />
FRONTOTEMPORAL DEMENTIA, UBIQUITIN-POSITIVE; FTDU<br />
DEMENTIA, HEREDITARY DYSPHASIC DISINHIBITION; HDDD<br />
APHASIA, PRIMARY PROGRESSIVE; PPA
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/638?start=-3&limit=10&highlight=638">
17q21.31
</a>
</span>
</td>
<td>
<span class="mim-font">
Aphasia, primary progressive
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607485"> 607485 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
GRN
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/138945"> 138945 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/638?start=-3&limit=10&highlight=638">
17q21.31
</a>
</span>
</td>
<td>
<span class="mim-font">
Frontotemporal dementia 2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607485"> 607485 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
GRN
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/138945"> 138945 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/607485" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<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/607485" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/607485" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
Autosomal recessive (uncommon) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Progressive visual impairment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839364&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839364</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000529" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000529</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000529" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000529</a>]</span><br /> -
Retinitis pigmentosa <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28835009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28835009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.52</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035334</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000510</a>]</span><br /> -
Blindness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0456909&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0456909</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</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">
- Cognitive impairment, gradual onset <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3551964&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3551964</a>]</span><br /> -
Frontotemporal dementia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230270009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230270009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G31.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G31.01</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G31.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G31.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/331.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">331.11</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/331.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">331.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338451&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338451</a>, <a href="https://bioportal.bioontology.org/search?q=C0236642&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0236642</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002145" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002145</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002145" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002145</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 /> -
Progressive language deterioration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843793&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843793</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007064" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007064</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007064" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007064</a>]</span><br /> -
Dysphasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20301004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20301004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/229746007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">229746007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R47.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R47.02</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0973461&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0973461</a>, <a href="https://bioportal.bioontology.org/search?q=C0454651&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0454651</a>]</span><br /> -
Speech hesitancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843794&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843794</a>]</span><br /> -
Perseveration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44515000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44515000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0233651&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0233651</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030223" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030223</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030223" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030223</a>]</span><br /> -
Dysnomia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/10325006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">10325006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003113&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003113</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030784" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030784</a>]</span><br /> -
Reading comprehension deficits <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847616&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847616</a>]</span><br /> -
Nonfluent aphasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/229654003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">229654003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/328681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">328681008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003550&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003550</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002427" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002427</a>]</span><br /> -
Mutism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88052002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88052002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026884</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002300</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002300</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 /> -
Parkinsonism (later) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843796&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843796</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32798002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32798002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G20.C" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G20.C</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001300" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001300</a>]</span><br /> -
Motor neuron disease (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37340000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37340000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G12.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G12.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G12.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G12.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/335.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">335.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085084&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085084</a>]</span><br /> -
Cerebral cortical atrophy, especially frontal lobes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843797&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843797</a>]</span><br /> -
Enlarged lateral ventricles <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856409&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856409</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006956</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006956</a>]</span><br /> -
Ubiquitin-positive cytoplasmic and intranuclear neuronal inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3551965&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3551965</a>]</span><br /> -
Amyloid plaques may be present <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3551966&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3551966</a>]</span><br /> -
Neurofibrillary tangles may be present <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1842042&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1842042</a>]</span><br /> -
No Pick bodies or Lewy bodies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3551967&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3551967</a>]</span><br /> -
No tau pathology <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969696&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969696</a>]</span><br /> -
Cortical and brainstem neuronal loss <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843799&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843799</a>]</span><br /> -
Astrocytic gliosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843800&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843800</a>]</span><br /> -
Nonspecific spongiform degeneration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843801&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843801</a>]</span><br /> -
Microvacuolation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3551968&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3551968</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
Repetitive compulsive behavior <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969697</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008762</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008762</a>]</span><br /> -
Disinhibition <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247977003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247977003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66347000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66347000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40662008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40662008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F63.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/312.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">312.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021122&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021122</a>, <a href="https://bioportal.bioontology.org/search?q=C0234410&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234410</a>, <a href="https://bioportal.bioontology.org/search?q=C0424296&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424296</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:5200029" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:5200029</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000734</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000734</a>]</span><br /> -
Apathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20602000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20602000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0436596&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0436596</a>, <a href="https://bioportal.bioontology.org/search?q=C0085632&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085632</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000741" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000741</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000741" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000741</a>]</span><br /> -
Agitation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24199005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24199005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085631</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000713</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000713</a>]</span><br /> -
Hypersexuality <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73744004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73744004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0312420&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0312420</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030214</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:5200321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:5200321</a>]</span><br /> -
Hyperphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/58424009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">58424009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267023007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267023007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020505</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002591" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002591</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002591" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002591</a>]</span><br /> -
Hyperorality <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838320&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838320</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000710" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000710</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000710" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000710</a>]</span><br /> -
Inappropriate behavior <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/112082005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">112082005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0233522&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0233522</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000719</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000719</a>]</span><br /> -
Hallucinations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7011001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7011001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R44.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R44.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018524&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018524</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000738" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000738</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000738" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000738</a>]</span><br /> -
Restlessness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/162221009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">162221009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47295007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47295007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24199005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24199005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887612</a>, <a href="https://bioportal.bioontology.org/search?q=C0085631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085631</a>, <a href="https://bioportal.bioontology.org/search?q=C3887611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887611</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000713</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000711" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000711</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000711" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000711</a>]</span><br />
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- Decreased serum and plasma progranulin levels<br />
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- Adult onset <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span><br /> -
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the granulin gene (GRN, <a href="/entry/138945#0001">138945.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that frontotemporal dementia-2 (FTD2) is caused by mutation in the GRN gene (<a href="/entry/138945">138945</a>) on chromosome 17q21. Most affected individuals have heterozygous loss-of-function mutations, although rare patients may have biallelic presumably hypomorphic mutations.</p><p>Biallelic mutations in the GRN gene cause CLN11 (<a href="/entry/614706">614706</a>).</p>
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<strong>Description</strong>
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<p>Frontotemporal dementia-2 (FTD2) is a neurodegenerative disorder characterized by adult onset of progressive cognitive decline which shows variable phenotypic expression but most commonly presents as behavioral changes with executive dysfunction (bvFTD) and/or language deterioration. The age at onset for individuals with heterozygous GRN mutations ranges from 40 to 85 years. Gestural apraxia, parkinsonism, visual loss, and visual hallucinations are present in 25 to 40% of patients. Other variations of the phenotype have been referred to as 'dysphasic disinhibition dementia,' 'primary progressive aphasia' (PPA), or 'corticobasal degeneration.' Some patients may present with a clinical diagnosis of Alzheimer disease (AD; <a href="/entry/104300">104300</a>) or Parkinson disease (PD; <a href="/entry/168600">168600</a>), features of which are part of the phenotypic spectrum of this disorder. Most GRN mutations are null and lead to haploinsufficiency. Rare individuals with biallelic, likely hypomorphic mutations have been reported (<a href="#7" class="mim-tip-reference" title="Brouwers, N., Nuytemans, K., van der Zee, J., Gijselinck, I., Engelborghs, S., Theuns, J., Kumar-Singh, S., Pickut, B. A., Pals, P., Dermaut, B., Bogaerts, V., De Pooter, T., and 14 others. &lt;strong&gt;Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family.&lt;/strong&gt; Arch. Neurol. 64: 1436-1446, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17923627/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17923627&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.10.1436&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="17923627">Brouwers et al., 2007</a>; <a href="#22" class="mim-tip-reference" title="Huey, E. D., Grafman, J., Wassermann, E. M., Pietrini, P., Tierney, M. C., Ghetti, B., Spina, S., Baker, M., Hutton, M., Elder, J. W., Berger, S. L., Heflin, K. A., Hardy, J., Momeni, P. &lt;strong&gt;Characteristics of frontotemporal dementia patients with a progranulin mutation.&lt;/strong&gt; Ann. Neurol. 60: 374-380, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16983677/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16983677&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20969&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="16983677">Huey et al., 2006</a>; <a href="#37" class="mim-tip-reference" title="Mukherjee, O., Pastor, P., Cairns, N. J., Chakraverty, S., Kauwe, J. S. K., Shears, S., Behrens, M. I., Budde, J., Hinrichs, A. L., Norton, J., Levitch, D., Taylor-Reinwald, L., Gitcho, M., Tu, P.-H., Grinberg, L. T., Liscic, R. M., Armendariz, J., Morris, J. C., Goate, A. M. &lt;strong&gt;HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.&lt;/strong&gt; Ann. Neurol. 60: 314-322, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16983685/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16983685&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16983685[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20963&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="16983685">Mukherjee et al., 2006</a>; <a href="#34" class="mim-tip-reference" title="Mesulam, M., Johnson, N., Krefft, T. A., Gass, J. M., Cannon, A. D., Adamson, J. L., Bigio, E. H., Weintraub, S., Dickson, D. W., Hutton, M. L., Graff-Radford, N. R. &lt;strong&gt;Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.&lt;/strong&gt; Arch. Neurol. 64: 43-47, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17210807/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17210807&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.1.43&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="17210807">Mesulam et al., 2007</a>; <a href="#23" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. &lt;strong&gt;Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.&lt;/strong&gt; Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31855245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31855245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awz377&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="31855245">Huin et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16983677+17923627+17210807+16983685+31855245" 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>See also FTD1 (<a href="/entry/600274">600274</a>), caused by mutation in the MAPT gene (<a href="/entry/157140">157140</a>), which is also on chromosome 17q21.</p><p><strong><em>Genetic Heterogeneity of FTLD-TDP</em></strong></p><p>
The specific presence of TDP43 (TARDBP; <a href="/entry/605078">605078</a>)-positive inclusions on neuropathologic examination defines a genetically heterogeneous group of dementias known collectively as 'FTLD-TDP.' FTLD-TDP is a neuropathologic diagnosis; only about 20% of patients with this neuropathologic diagnosis have GRN mutations (review by <a href="#49" class="mim-tip-reference" title="Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., and 88 others. &lt;strong&gt;Common variants at 7p21 are associated with fronto-temporal lobar degeneration with TDP-43 inclusions.&lt;/strong&gt; Nature Genet. 42: 234-239, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20154673/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20154673&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20154673[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.536&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="20154673">Van Deerlin et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20154673" 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>TDP43-positive inclusions also occur in ALS10 (<a href="/entry/612069">612069</a>), caused by mutation in the TARDBP gene (<a href="/entry/605078">605078</a>); IBMPFD (<a href="/entry/167320">167320</a>), caused by mutation in the VCP gene (<a href="/entry/601023">601023</a>); and FTDALS (<a href="/entry/105550">105550</a>), caused by mutation in the C9ORF72 gene (<a href="/entry/614260">614260</a>).</p><p><a href="#32" class="mim-tip-reference" title="Mackenzie, I. R. A., Rademakers, R. &lt;strong&gt;The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments.&lt;/strong&gt; Neurogenetics 8: 237-248, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17805587/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17805587&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-007-0102-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17805587">Mackenzie and Rademakers (2007)</a> provided a detailed review of the molecular genetics of FTLD, with special emphasis on FTLDU. <a href="#8" class="mim-tip-reference" title="Cairns, N. J., Ghoshal, N. &lt;strong&gt;FUS: a new actor on the frontotemporal lobar degeneration stage.&lt;/strong&gt; Neurology 74: 354-356, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20124200/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20124200&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181ce5dd6&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="20124200">Cairns and Ghoshal (2010)</a> reviewed the molecular pathology and genetic heterogeneity of FTLD, including FTLD-TDP, and also noted that FTLDU is now referred to as FTLD-TDP. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20124200+17805587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an Ohio family of Bavarian origin, <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a> described a distinct disease entity, which they termed 'hereditary dysphasic dementia,' in 10 of 16 members who lived past the age of 60. Over 3 generations, the disease was inherited as an autosomal dominant trait; male-to-male transmission was observed. The clinical characteristics included progressive cognitive deficits with memory loss and personality changes, severe dysphasic disturbances leading to mutism, and hyperphagia. <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a> suggested that the kindred reported by <a href="#27" class="mim-tip-reference" title="Kim, R. C., Collins, G. H., Parisi, J. E., Wright, A. W., Chu, Y. B. &lt;strong&gt;Familial dementia of adult onset with pathological findings of a &#x27;non-specific&#x27; nature.&lt;/strong&gt; Brain 104: 61-78, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7470845/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7470845&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/104.1.61&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7470845">Kim et al. (1981)</a> had the same disorder. This was a family of Italian extraction in which 4 of 10 members of a single generation developed dementia, dysphasia, and, in some cases, parkinsonian signs and bulimia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6497355+7470845" 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="Froelich, S., Basun, H., Forsell, C., Lilius, L., Axelman, K., Andreadis, A., Lannfelt, L. &lt;strong&gt;Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.&lt;/strong&gt; Am. J. Med. Genet. 74: 380-385, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9259373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9259373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19970725)74:4&lt;380::aid-ajmg8&gt;3.0.co;2-t&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="9259373">Froelich et al. (1997)</a> and <a href="#3" class="mim-tip-reference" title="Basun, H., Almkvist, O., Axelman, K., Brun, A., Campbell, T. A., Collinge, J., Forsell, C., Froelich, S., Wahlund, L.-O., Wetterberg, L., Lannfelt, L. &lt;strong&gt;Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.&lt;/strong&gt; Arch. Neurol. 54: 539-544, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9152110/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9152110&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1997.00550170021010&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="9152110">Basun et al. (1997)</a> reported a large Swedish family with rapidly progressive FTD inherited in an autosomal dominant pattern. The mean age at onset was 51 years, and mean disease duration was 3 years. Four patients were described in detail. Two patients presented with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia with akinesia and muscular rigidity, and 1 patient developed reckless driving and personality changes. All developed loss of spontaneous speech, and 3 had emotional bluntness. Cerebral perfusion was decreased in the frontal areas in all patients. Postmortem examination showed frontal lobe degeneration with spongy changes and gliosis. <a href="#47" class="mim-tip-reference" title="Skoglund, L., Brundin, R., Olofsson, T., Kalimo, H., Ingvast, S., Blom, E. S., Giedraitis, V., Ingelsson, M., Lannfelt, L., Basun, H., Glaser, A. &lt;strong&gt;Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation.&lt;/strong&gt; Neurogenetics 10: 27-34, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18855025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18855025&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-008-0155-z&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="18855025">Skoglund et al. (2009)</a> reported follow-up of the Swedish family reported by <a href="#16" class="mim-tip-reference" title="Froelich, S., Basun, H., Forsell, C., Lilius, L., Axelman, K., Andreadis, A., Lannfelt, L. &lt;strong&gt;Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.&lt;/strong&gt; Am. J. Med. Genet. 74: 380-385, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9259373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9259373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19970725)74:4&lt;380::aid-ajmg8&gt;3.0.co;2-t&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="9259373">Froelich et al. (1997)</a> and <a href="#3" class="mim-tip-reference" title="Basun, H., Almkvist, O., Axelman, K., Brun, A., Campbell, T. A., Collinge, J., Forsell, C., Froelich, S., Wahlund, L.-O., Wetterberg, L., Lannfelt, L. &lt;strong&gt;Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.&lt;/strong&gt; Arch. Neurol. 54: 539-544, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9152110/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9152110&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1997.00550170021010&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="9152110">Basun et al. (1997)</a> and added 6 additional affected individuals. These additional patients presented with personality and behavioral changes (2), language impairment (2), and memory impairment (2). Although there was a large variation of the initial symptoms in this family, the common pattern of clinical features included rapid disease progression and ultimately nonfluent aphasia with loss of spontaneous speech patients. Limb ataxia and parkinsonism were uncommon symptoms, and there was no motor neuron disease, although dysphagia was seen in 3 patients. Neuropathologic examination revealed frontotemporal neurodegeneration with ubiquitin and TDP43 immunoreactive intraneuronal inclusions. Molecular analysis identified a frameshift mutation in the GRN gene (<a href="/entry/138945#0016">138945.0016</a>) that resulted in functional haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9152110+9259373+18855025" 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="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a> studied a kindred with the same manifestations as those in the kindred reported by <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a> and renamed the disorder hereditary dysphasic disinhibition dementia (HDDD). For both kindreds, the mean age of disease onset was approximately 60 years. The range of duration of disease was 5 to 11 years in the kindred reported by <a href="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a> and 4 to 22 years in the kindred reported by <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a>. Early manifestations included gradual onset with progressive memory loss and other cognitive deficits. There were more abnormalities of language earlier in the course of disease, frequently as the initial symptom, than are typically seen in the dementia of Alzheimer disease (AD; <a href="/entry/104300">104300</a>). These included hesitancy of speech, reduction in spontaneous output, diminished fluency, and dysnomia progressing to auditory and reading-comprehension deficits, and eventual mutism. Behavioral and personality changes were occasional in the kindred reported by <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a> and more notable in the kindred reported by <a href="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a>, sometimes occurring as the initial symptoms. Disinhibition, hypersexuality, bulimia, inappropriate behavior, and unaccustomed excessive alcohol consumption was present in some patients in both kindreds. Also in both families, parkinsonian features frequently developed, usually at a later stage of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6497355+9633693" 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="Kertesz, A., Kawarai, T., Rogaeva, E., St. George-Hyslop, P., Poorkaj, P., Bird, T. D., Munoz, D. G. &lt;strong&gt;Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.&lt;/strong&gt; Neurology 54: 818-827, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10690970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10690970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.4.818&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="10690970">Kertesz et al. (2000)</a> reported a family with a highly penetrant form of autosomal dominant frontotemporal dementia, or 'clinical Pick disease.' Age at onset ranged from 38 to 44 years, with a rapid progression. Affected members had similar clinical features characterized by social withdrawal, lack of motivation, inappropriate behavior, disinhibition, and perseveration. Strikingly similar features were hyperorality and stealing. <a href="#26" class="mim-tip-reference" title="Kertesz, A., Kawarai, T., Rogaeva, E., St. George-Hyslop, P., Poorkaj, P., Bird, T. D., Munoz, D. G. &lt;strong&gt;Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.&lt;/strong&gt; Neurology 54: 818-827, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10690970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10690970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.4.818&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="10690970">Kertesz et al. (2000)</a> noted the similarities to Kluver-Bucy syndrome. Neuropsychologic examination indicated inattention, word-finding difficulties, and disorganization of memories. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10690970" 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="#45" class="mim-tip-reference" title="Rosso, S. M., Kamphorst, W., de Graaf, B., Willemsen, R., Ravid, R., Niermeijer, M. F., Spillantini, M. G., Heutink, P., van Swieten, J. C. &lt;strong&gt;Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22.&lt;/strong&gt; Brain 124: 1948-1957, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11571213/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11571213&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/124.10.1948&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="11571213">Rosso et al. (2001)</a> reported a large Dutch family, previously reported by <a href="#21" class="mim-tip-reference" title="Heutink, P., Stevens, M., Rizzu, P., Bakker, E., Kros, J. M., Tibben, A., Niermeijer, M. F., van Duijn, C. M., Oostra, B. A., van Swieten, J. C. &lt;strong&gt;Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families.&lt;/strong&gt; Ann. Neurol. 41: 150-159, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9029063/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9029063&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410410205&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="9029063">Heutink et al. (1997)</a> with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 17q21-q22 (lod score of 3.46), but without mutations in the tau gene (MAPT; <a href="/entry/157140">157140</a>). Mean age at onset was 61 years, with loss of initiative and decreased spontaneous speech as the most predominant presenting symptoms. Other features included agitation and restlessness, language difficulties, and hyperorality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11571213+9029063" 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="#28" class="mim-tip-reference" title="Krefft, T. A., Graff-Radford, N. R., Dickson, D. W., Baker, M., Castellani, R. J. &lt;strong&gt;Familial primary progressive aphasia.&lt;/strong&gt; Alzheimer Dis. Assoc. Disord. 17: 106-112, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12794388/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12794388&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00002093-200304000-00009&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="12794388">Krefft et al. (2003)</a> reported 3 sibs with classic primary progressive aphasia, defined as an isolated progressive language dysfunction. Onset of word-finding and naming difficulties occurred at ages 60, 61, and 65 years, respectively. All showed left frontotemporal atrophy. The eldest sib had mild right motor impairment, including hemiparesis and mild tremor, and died mute and bedridden 12 years after onset. A younger brother had behavioral changes, and a younger sister had significant parkinsonism, cortical release signs, and dementia. She died 4 years after onset, and postmortem neuropathologic examination showed marked cortical thinning with neuronal loss, gliosis, spongiosis, and ubiquitin-positive inclusions within cortical neurons. Other features included hippocampal sclerosis and Lewy bodies in the substantia nigra, which may have represented a concurrent pathologic process. Genetic analysis excluded common mutations in the MAPT gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794388" 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="#34" class="mim-tip-reference" title="Mesulam, M., Johnson, N., Krefft, T. A., Gass, J. M., Cannon, A. D., Adamson, J. L., Bigio, E. H., Weintraub, S., Dickson, D. W., Hutton, M. L., Graff-Radford, N. R. &lt;strong&gt;Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.&lt;/strong&gt; Arch. Neurol. 64: 43-47, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17210807/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17210807&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.1.43&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="17210807">Mesulam et al. (2007)</a> reported 2 sisters with a typical presentation of primary progressive aphasia. The phenotype was an isolated aphasia beginning at ages 65 and 62 years, respectively, without other features. There was rapid progression of aphasia to complete mutism within 2 to 3 years. One sister developed a right-sided tremor, clumsiness, rigidity, and impaired motor function. Genetic analysis identified a heterozygous mutation in the GRN gene (R493X; <a href="/entry/138945#0009">138945.0009</a>) in both sisters. <a href="#19" class="mim-tip-reference" title="Gliebus, G., Bigio, E. H., Gasho, K., Mishra, M., Caplan, D., Mesulam, M.-M., Geula, C. &lt;strong&gt;Asymmetric TDP-43 distribution in primary progressive aphasia with progranulin mutation.&lt;/strong&gt; Neurology 74: 1607-1610, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20479359/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20479359&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181df0a1b&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="20479359">Gliebus et al. (2010)</a> reported neuropathologic findings of 1 of the sisters with PPA reported by <a href="#34" class="mim-tip-reference" title="Mesulam, M., Johnson, N., Krefft, T. A., Gass, J. M., Cannon, A. D., Adamson, J. L., Bigio, E. H., Weintraub, S., Dickson, D. W., Hutton, M. L., Graff-Radford, N. R. &lt;strong&gt;Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.&lt;/strong&gt; Arch. Neurol. 64: 43-47, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17210807/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17210807&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.1.43&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="17210807">Mesulam et al. (2007)</a>. She died at the age of 67 years, 5 years after onset. She had significantly more neuronal intranuclear and cytoplasmic TDP43-positive inclusions and dystrophic neurites in the left inferior parietal lobule and superior temporal gyrus compared to the right, consistent with involvement of language areas of the brain. The findings illustrated a concordance between the aphasic phenotype in this patient and pathologic involvement of the language-related regions of the brain rather than memory-related regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20479359+17210807" 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 retrospective study, <a href="#50" class="mim-tip-reference" title="Van Deerlin, V. M., Wood, E. M., Moore, P., Yuan, W., Forman, M. S., Clark, C. M., Neumann, M., Kwong, L. K., Trojanowski, J. Q., Lee, V. M.-Y., Grossman, M. &lt;strong&gt;Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations.&lt;/strong&gt; Arch. Neurol. 64: 1148-1153, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17698705/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17698705&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.8.1148&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="17698705">Van Deerlin et al. (2007)</a> compared the clinical features of 9 patients with FTLDU and GRN mutations to 19 patients with the same pathologic diagnosis of FTLDU but without GRN mutations. Family history was significantly more common in those with mutations. Although both patient groups had social and personality deficits, neuropsychologic testing showed that those with a GRN mutation had a significant recognition memory deficit, whereas those without a GRN mutation had a significant language deficit. <a href="#50" class="mim-tip-reference" title="Van Deerlin, V. M., Wood, E. M., Moore, P., Yuan, W., Forman, M. S., Clark, C. M., Neumann, M., Kwong, L. K., Trojanowski, J. Q., Lee, V. M.-Y., Grossman, M. &lt;strong&gt;Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations.&lt;/strong&gt; Arch. Neurol. 64: 1148-1153, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17698705/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17698705&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.8.1148&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="17698705">Van Deerlin et al. (2007)</a> concluded that patients with a GRN mutation differ clinically from those with the same pathologic diagnosis but no GRN mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698705" 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="#42" class="mim-tip-reference" title="Rogalski, E., Johnson, N., Weintraub, S., Mesulam, M. &lt;strong&gt;Increased frequency of learning disability in patients with primary progressive aphasia and their first-degree relatives.&lt;/strong&gt; Arch. Neurol. 65: 244-248, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18268195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18268195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2007.34&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="18268195">Rogalski et al. (2008)</a> observed a significantly higher frequency of self-reported learning disabilities among 108 PPA probands (14.8%) and their first-degree relatives (29.6%) compared to 84 individuals with the behavioral variant of FTD (7.1%) and their relatives (14.3%), 154 individuals with AD (4.5%) and their relatives (10.4%), and 353 controls (1.4%) and their relatives (6.8%). PPA patients and PPA family members reported deficits specifically in the area of language, suggesting that individuals who develop PPA may have an antecedent selective vulnerability in the anatomic brain regions that underlie language. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18268195" 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="#44" class="mim-tip-reference" title="Rohrer, J. D., Warren, J. D., Omar, R., Mead, S., Beck, J., Revesz, T., Holton, J., Stevens, J. M., Al-Sarraj, S., Pickering-Brown, S. M., Hardy, J., Cox, N. C., Collinge, J., Warrington, E. K., Rossor, M. N. &lt;strong&gt;Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene.&lt;/strong&gt; Arch. Neurol. 65: 506-513, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18413474/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18413474&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18413474[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/10.1001/archneur.65.4.506&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="18413474">Rohrer et al. (2008)</a> reported a large British kindred with FTLDU associated with a mutation in the GRN gene (<a href="/entry/138945#0005">138945.0005</a>). The average age at disease onset was 57.8 years. All patients had clinical and radiographic features of frontotemporal lobar degeneration with behavioral changes and language deficits. Nonfluent aphasia was present in 2 patients, and 3 became mute several years into the illness. Most also had features suggestive of parietal lobe involvement, including dyscalculia, visuoperceptual/visuospatial dysfunction, and limb apraxia. Brain imaging showed extension of the atrophy to the parietal lobe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413474" 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="#35" class="mim-tip-reference" title="Moreno, F., Indakoetxea, B., Barandiaran, M., Alzualde, A., Gabilondo, A., Estanga, A., Ruiz, J., Ruibal, M., Bergareche, A., Marti-Masso, J. F., Lopez de Munain, A. &lt;strong&gt;&#x27;Frontotemporoparietal&#x27; dementia: clinical phenotype associated with the c.709-1G-A PGRN mutation.&lt;/strong&gt; Neurology 73: 1367-1374, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19858458/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19858458&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181bd82a7&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="19858458">Moreno et al. (2009)</a> reported the clinical features of 21 patients of Basque origin with FTD caused by the same heterozygous mutation in the GRN gene (<a href="/entry/138945#0019">138945.0019</a>). The mean age at onset was 59.2 years (range, 42 to 71 years), and 4 of 21 patients died after a mean duration of 4.75 years. Overall, 14 (66.7%) had a diagnosis of behavioral variant FTD, 10 (47.6%) had a diagnosis of corticobasal degeneration, and 7 (33.3%) had a diagnosis of progressive nonfluent aphasia. None developed signs of motor neuron disease/ALS, but 8 with corticobasal degeneration had motor signs, including limb rigidity or apraxia and myoclonus. The most prominent behavioral symptoms were apathy, impulsivity, disinhibition, and bulimia, suggesting involvement of the medial frontal and orbitofrontal cortex. Dysgraphia, dyscalculia, apraxia, and hemineglect suggested parietal dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19858458" 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="#25" class="mim-tip-reference" title="Kelley, B. J., Haidar, W., Boeve, B. F., Baker, M., Shiung, M., Knopman, D. S., Rademakers, R., Hutton, M., Adamson, J., Kuntz, K. M., Dickson, D. W., Parisi, J. E., Smith, G. E., Petersen, R. C. &lt;strong&gt;Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin.&lt;/strong&gt; Arch. Neurol. 67: 171-177, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142525/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142525&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20142525[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/10.1001/archneurol.2010.113&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="20142525">Kelley et al. (2010)</a> reported a large family with autosomal dominant inheritance of FTLD associated with a heterozygous mutation in the GRN gene (154delA; <a href="/entry/138945#0017">138945.0017</a>). Of 10 affected individuals, 6 presented with early amnestic symptoms resulting in initial clinical diagnoses of Alzheimer disease or amnestic mild cognitive impairment, and 3 with frontotemporal dementia; 1 had nonspecific dementia. Neuropathologic examination of 6 individuals showed FTLD with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions, even in those with an AD diagnosis. The mean age at onset was younger in the third generation (60.7 years) than in the second generation (75.8 years). <a href="#25" class="mim-tip-reference" title="Kelley, B. J., Haidar, W., Boeve, B. F., Baker, M., Shiung, M., Knopman, D. S., Rademakers, R., Hutton, M., Adamson, J., Kuntz, K. M., Dickson, D. W., Parisi, J. E., Smith, G. E., Petersen, R. C. &lt;strong&gt;Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin.&lt;/strong&gt; Arch. Neurol. 67: 171-177, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142525/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142525&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20142525[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/10.1001/archneurol.2010.113&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="20142525">Kelley et al. (2010)</a> noted that the presentation in some individuals with GRN-related FTLD may include Alzheimer disease-like clinical features, particularly anterograde amnesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142525" 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 an international collaborative study comparing clinical features of 97 unrelated patients with FTLD due to GRN mutations and 453 patients with FTLD who did not have GRN mutations, <a href="#9" class="mim-tip-reference" title="Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M., Bing, S., Grossman, M., Schellenberg, G. D., Hatanpaa, K. J., Weiner, M. F., White, C. L., III, and 43 others. &lt;strong&gt;Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.&lt;/strong&gt; Arch. Neurol. 68: 488-497, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21482928/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21482928&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21482928[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/10.1001/archneurol.2011.53&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="21482928">Chen-Plotkin et al. (2011)</a> found clinical differences between the 2 groups. Those with GRN mutations had a younger age at disease onset (median age 58.0 vs 61.0 years), younger age at death (median age 65.5 vs 69.0 years), and less motor neuron disease (5.4% vs 26.3%). Clinical diagnoses of Parkinson disease, corticobasal syndrome, and progressive supranuclear palsy were more common in GRN mutation carriers (5.3% vs 1.3%), and more patients with GRN mutations presented with aphasia. Fifty different mutations were identified, with the most common being R493X (<a href="/entry/138945#0009">138945.0009</a>), found in 18.6% of GRN cases. The A9D mutation (<a href="/entry/138945#0008">138945.0008</a>) was found in 6.2% of cases and associated with an even younger age at onset (51.0 years) and more parkinsonian features compared to those with other GRN mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21482928" 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>Biallelic GRN Mutations</em></strong></p><p>
<a href="#23" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. &lt;strong&gt;Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.&lt;/strong&gt; Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31855245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31855245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awz377&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="31855245">Huin et al. (2020)</a> reported 4 patients from 2 unrelated French families with FTD2 associated with homozygous mutations in the GRN gene. A 56-year-old woman (family FTD-1042) presented with visual hallucinations, followed by progressive language and behavioral abnormalities, including compulsive shopping, stereotyped behaviors, aggression, and hyperphagia, consistent with executive dysfunction. She rapidly became mute and was diagnosed with behavioral variant FTD (bvFTD). Physical examination showed an akinetic-rigid syndrome, pyramidal spasticity of all limbs, and right extensor plantar responses. Brain imaging showed cortico/subcortical atrophy with right temporal lobe involvement. Plasma progranulin was decreased to about half of normal values. Parental information was not available. Her 2 asymptomatic children, who were heterozygous for the mutation, had low plasma progranulin levels, but not as low as their affected mother. In a second family (family FTDP-N12/1611), 3 French brothers had a progressive neurodegenerative disorder characterized by visual impairment and retinitis pigmentosa resulting in blindness, cognitive deterioration with behavioral disorders, including disinhibition, impulsivity, emotional lability, and apathy, consistent with executive dysfunction, and loss of autonomy. Two had visual hallucinations. One brother (P1) also had atypical parkinsonism, including upper limb tremor, postural instability, impaired gait, hypophonia, dysarthria, and freezing. The 2 other brothers did not have movement disorders. Brain imaging showed cortical atrophy with normal cerebellum. Plasma progranulin, measured in 2, was undetectable. Two died in their sixties. Family history revealed that their father had dementia and died at age 66, the mother had Parkinson disease and died at age 83, and 2 maternal aunts had dementia at age 65. Consanguinity was possible. None of the patients had epilepsy or cerebellar ataxia. Genetic studies identified homozygous mutations in the GRN gene in each family: a splice site mutation (<a href="/entry/138945#0023">138945.0023</a>) and a frameshift (<a href="/entry/138945#0024">138945.0024</a>). Aside from the 2 sibs in 1 family, additional family segregation studies could not be performed. <a href="#23" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. &lt;strong&gt;Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.&lt;/strong&gt; Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31855245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31855245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awz377&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="31855245">Huin et al. (2020)</a> noted that both mutations had been detected in the heterozygous state in patients with autosomal dominant FTD2, suggesting the presence of additional modifying factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" 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>Neuropathologic Findings</em></strong></p><p>
<a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a> reported that complete neuropathologic examination of 4 of their patients showed asymmetric focal cerebral atrophy (characteristic of Pick disease), neuritic plaques (characteristic of Alzheimer disease), and depletion of neurons in the pigmented nuclei of the brainstem (characteristic of paralysis agitans). There was also cortical neuronal loss, nonspecific spongiform degeneration of the external layers of cerebral cortex, and reactive gliosis. Pick cells and Pick bodies were absent, and in 1 patient, Lewy bodies were present in nigral neurons. Transmissibility studies were negative. <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a> concluded that this is a distinct entity but 'may be best considered as part of a Pick-Alzheimer spectrum of cortical neuronal degenerations.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6497355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Behrens, M. I., Mukherjee, O., Tu, P., Liscic, R. M., Grinberg, L. T., Carter, D., Paulsmeyer, K., Taylor-Reinwald, L., Gitcho, M., Norton, J. B., Chakraverty, S., Goate, A. M., Morris, J. C., Cairns, N. J. &lt;strong&gt;Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.&lt;/strong&gt; Alzheimer Dis. Assoc. Disord. 21: 1-7, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17334266/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17334266&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/WAD.0b013e31803083f2&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="17334266">Behrens et al. (2007)</a> provided neuropathologic analysis of another member of the family reported by <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a>. She had a disease course similar to that of other family members, with onset at age 62 years of personality changes and disinhibition, followed by nonfluent dysphasia and memory loss that progressed to mutism and total dependence, with death at age 84. There was severe generalized brain atrophy. Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in the frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and neurofibrillary tangles in the parietal and occipital cortices. The case met neuropathologic criteria for both FTLD-U and Alzheimer disease. No Pick bodies were present. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6497355+17334266" 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>Neuropathologic examination of affected members of a family by <a href="#26" class="mim-tip-reference" title="Kertesz, A., Kawarai, T., Rogaeva, E., St. George-Hyslop, P., Poorkaj, P., Bird, T. D., Munoz, D. G. &lt;strong&gt;Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.&lt;/strong&gt; Neurology 54: 818-827, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10690970/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10690970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.54.4.818&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="10690970">Kertesz et al. (2000)</a> showed severe hippocampal atrophy, frontal lobe atrophy, loss of pigmented neurons in the substantia nigra, and ubiquitin-positive inclusions that were not immunoreactive to tau or alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>). The authors referred to these inclusions as ITSNU. No mutations in the MAPT gene were detected. Neuropathologic examination of affected members of a family by <a href="#45" class="mim-tip-reference" title="Rosso, S. M., Kamphorst, W., de Graaf, B., Willemsen, R., Ravid, R., Niermeijer, M. F., Spillantini, M. G., Heutink, P., van Swieten, J. C. &lt;strong&gt;Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22.&lt;/strong&gt; Brain 124: 1948-1957, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11571213/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11571213&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/124.10.1948&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="11571213">Rosso et al. (2001)</a> also showed ubiquitin-positive inclusions that were not immunoreactive to tau or alpha-synuclein. There were no abnormalities in tau isoform distribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11571213+10690970" 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>Four affected members of the large Canadian family reported by <a href="#33" class="mim-tip-reference" title="Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M. &lt;strong&gt;A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.&lt;/strong&gt; Brain 129: 853-867, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401619/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16401619&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh724&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="16401619">Mackenzie et al. (2006)</a> had undergone postmortem examination. In all cases cerebral atrophy was moderate to severe and was largely restricted to the frontal lobe. There was often mild atrophy at the head of the caudate nucleus and some loss of pigmentation of the substantia nigra. Microscopic examination of the neocortex showed nonspecific chronic degenerative changes including neuronal loss and gliosis with an anterior-to-posterior anatomic gradient of severity. Apart from a small number of neurofibrillary tangles identified in 1 family member, no other pathology was identified with silver stains, or immunohistochemistry for tau, alpha-synuclein, or nonphosphorylated or phosphorylated neurofilament; specifically, there were no senile plaques, Pick bodies, Lewy bodies, glial inclusions, or achromatic neurons. In contrast, ubiquitin-immunoreactive neurites and neuronal cytoplasmic inclusions were present in the superficial laminae of the frontal and temporal neocortex in all cases. Discrete dense ubiquitin-immunoreactive neuronal intranuclear inclusions were identified in all 4 cases and had a similar anatomic distribution to the dense neuronal cytoplasmic inclusions, being most numerous in the frontal neocortex and striatum and less common in the dentate granule cells, globus pallidus, and thalamus. The number of neuronal intranuclear inclusions varied between the anatomic regions, and they were always much less numerous than the neuronal cytoplasmic inclusions. All neuronal intranuclear inclusions were reactive to SUMO1 in addition to ubiquitin, and a proportion was positive for PML, suggesting to <a href="#33" class="mim-tip-reference" title="Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M. &lt;strong&gt;A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.&lt;/strong&gt; Brain 129: 853-867, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401619/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16401619&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh724&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="16401619">Mackenzie et al. (2006)</a> that these inclusions form in the nuclear body and providing a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401619" 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="#39" class="mim-tip-reference" title="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.&lt;/strong&gt; Science 314: 130-133, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17023659/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17023659&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1134108&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17023659">Neumann et al. (2006)</a> identified TDP43 (<a href="/entry/605078">605078</a>) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration and amyotrophic lateral sclerosis (see <a href="/entry/105400">105400</a>). Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. <a href="#39" class="mim-tip-reference" title="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.&lt;/strong&gt; Science 314: 130-133, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17023659/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17023659&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1134108&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17023659">Neumann et al. (2006)</a> concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17023659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Mukherjee, O., Pastor, P., Cairns, N. J., Chakraverty, S., Kauwe, J. S. K., Shears, S., Behrens, M. I., Budde, J., Hinrichs, A. L., Norton, J., Levitch, D., Taylor-Reinwald, L., Gitcho, M., Tu, P.-H., Grinberg, L. T., Liscic, R. M., Armendariz, J., Morris, J. C., Goate, A. M. &lt;strong&gt;HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.&lt;/strong&gt; Ann. Neurol. 60: 314-322, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16983685/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16983685&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16983685[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20963&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="16983685">Mukherjee et al. (2006)</a> described additional neuropathologic findings of 8 affected individuals from the family reported by <a href="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a>. Atrophy varied from moderate to severe and was most pronounced in the frontal lobe, with lesser degrees of atrophy in the temporal and parietal lobes. All cases had severe cortical neuronal loss, status spongiosus, and reactive astrocytosis. The hippocampus was less atrophied and showed less neuronal loss than is usually seen in Alzheimer disease. Immunohistochemical analysis showed ubiquitin-positive, tau-negative, neuronal cytoplasmic inclusions; dystrophic neurites; and neuronal intranuclear inclusions in 7 of 8 cases. Further studies showed that progranulin was not a component of any of the pathologic inclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16983685+9633693" 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="Forman, M. S., Farmer, J., Johnson, J. K., Clark, C. M., Arnold, S. E., Coslett, H. B., Chatterjee, A., Hurtig, H. I., Karlawish, J. H., Rosen, H. J., Van Deerlin, V., Lee, V. M.-Y., Miller, B. L., Trojanowski, J. Q., Grossman, M. &lt;strong&gt;Frontotemporal dementia: clinicopathological correlations.&lt;/strong&gt; Ann. Neurol. 59: 952-962, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16718704/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16718704&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16718704[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20873&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="16718704">Forman et al. (2006)</a> performed a clinicopathologic assessment of 124 patients with either a clinical or pathologic diagnosis of frontotemporal dementia. Neuropathologic examination showed that 46% had a tauopathy, 29% had FTLD with ubiquitin inclusions, and 17% had findings consistent with Alzheimer disease. Patients with FTLD with ubiquitin inclusions were more likely to present with social and language dysfunction; tauopathies were more commonly associated with an extrapyramidal disorder; and AD was associated with greater deficits in memory and executive function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16718704" 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="Davion, S., Johnson, N., Weintraub, S., Mesulam, M.-M., Engberg, A., Mishra, M., Baker, M., Adamson, J., Hutton, M., Rademakers, R., Bigio, E. H. &lt;strong&gt;Clinicopathologic correlation in PGRN mutations.&lt;/strong&gt; Neurology 69: 1113-1121, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17522386/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17522386&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17522386[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/10.1212/01.wnl.0000267701.58488.69&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="17522386">Davion et al. (2007)</a> found that 4 of 9 patients with a pathologic diagnosis of FTLDU had mutations in the GRN gene (<a href="/entry/138945#0009">138945.0009</a>; <a href="/entry/138945#0012">138945.0012</a>; <a href="/entry/138945#0013">138945.0013</a>). Two presented with frontotemporal dementia and 2 with primary progressive aphasia. Neuropathologic examination of all 9 cases showed that those with the GRN mutations had more frequent ubiquitinated neuronal cytoplasmic and intranuclear inclusions in the frontal lobe, temporal lobe, and striatum than those without GRN mutations, who had more neurocytoplasmic inclusions in the dentate gyrus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17522386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Grossman, M., Wood, E. M., Moore, P., Neumann, M., Kwong, L., Forman, M. S., Clark, C. M., McCluskey, L. F., Miller, B. L., Lee, V. M.-Y., Trojanowski, J. Q. &lt;strong&gt;TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions.&lt;/strong&gt; Arch. Neurol. 64: 1449-1454, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17923628/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17923628&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.10.1449&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="17923628">Grossman et al. (2007)</a> noted that several subtypes of FTLDU had been characterized based on neuropathologic localization of TDP43-positive ubiquitin inclusions. In a retrospective review of 23 patients, the authors found notable clinical differences between the subtypes. Only 4 of the 23 patients had mutations in the GRN gene; this was a pathologic study. Patients with numerous TDP43-positive neuronal intracytoplasmic inclusions had shorter survival; patients with numerous TDP43-positive neurites had difficulty with object naming; and patients with TDP43-positive neuronal intranuclear inclusions had substantial executive deficits. Different anatomical distributions of ubiquitin pathologic features in FTLDU subgroups were consistent with their cognitive deficits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17923628" 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="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#13" class="mim-tip-reference" title="Finch, N., Baker, M., Crook, R., Swanson, K., Kuntz, K., Surtees, R., Bisceglio, G., Rovelet-Lecrux, A., Boeve, B., Petersen, R. C., Dickson, D. W., Younkin, S. G., Deramecourt, V., Crook, J., Graff-Radford, N. R., Rademakers, R. &lt;strong&gt;Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.&lt;/strong&gt; Brain 132: 583-591, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19158106/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19158106&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19158106[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awn352&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="19158106">Finch et al. (2009)</a> used ELISA analysis to measure plasma GRN levels in a consecutive series of 207 patients with FTLD, 70 control individuals, 72 early-onset probable Alzheimer disease patients, and 9 symptomatic and 18 asymptomatic relatives of GRN mutation carriers. All 8 FTLD patients with GRN loss-of-function mutations showed significantly reduced plasma GRN levels of about one-third of the levels found in non-GRN carriers and controls individuals (p less than 0.001). There was no overlap in the distribution of plasma GRN levels between the 8 GRN mutation carriers (range, 53-94 ng/ml) and 191 non-GRN mutation carriers (range, 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. ELISA analysis also identified 1 (1.4%) probable AD patient who carried a GRN mutation. The ELISA technique only identified full-length GRN, but not GRN fragments. The study demonstrated that ELISA analysis of plasma GRN can detect asymptomatic carriers of pathogenic GRN mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158106" 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 cohort of 244 Portuguese individuals with neurodegenerative dementias, including FTLD-related disorders and Alzheimer disease, <a href="#1" class="mim-tip-reference" title="Almeida, M. R., Baldeiras, I., Ribeiro, M. H., Santiago, B., Machado, C., Massano, J., Guimaraes, J., Resende Oliveira, C., Santana, I. &lt;strong&gt;Progranulin peripheral levels as a screening tool for the identification of subjects with progranulin mutations in a Portuguese cohort.&lt;/strong&gt; Neurodegener. Dis. 13: 214-223, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24022032/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24022032&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000352022&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="24022032">Almeida et al. (2014)</a> found that serum/plasma levels of progranulin accurately detected all 7 individuals with heterozygous loss-of-function mutations in the GRN gene. In these 7 individuals, serum/plasma progranulin levels were reduced by about one-third compared to controls, which corresponded well with heterozygous null GRN mutations leading to haploinsufficiency. There was no relationship between serum progranulin levels and age of symptom onset. Both their novel ELISA assay and a kit from Adipogen measuring serum/plasma progranulin levels yielded a sensitivity and specificity of 100% for identification of individuals with null GRN mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24022032" 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>To evaluate whether aminoglycosides could facilitate the readthrough of nonsense mutations in the GRN gene, <a href="#29" class="mim-tip-reference" title="Kuang, L., Hashimoto, K., Huang, E. J., Gentry, M. S., Zhu, H. &lt;strong&gt;Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.&lt;/strong&gt; Hum. Molec. Genet. 29: 624-634, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31913476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31913476&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31913476[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddz280&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="31913476">Kuang et al. (2020)</a> transfected N2A cells with plasmids with wildtype GRN or one of 3 mutations associated with FTD (R493X, <a href="/entry/138945#0009">138945.0009</a>; Q125X <a href="/entry/138945#0002">138945.0002</a>; or Y229X), and tested the readthrough effects of 11 aminoglycosides and a clinically approved readthrough small molecule, PTC124. Both G418 and gentamicin induced the readthrough of GRN with the R493X mutation, but not the other GRN mutants, in a time- and dose-dependent manner. G418 had a stronger effect on readthrough than gentamicin. The readthrough product of the R493X GRN mutant had similar subcellular localization as wildtype GRN. Based on these findings, <a href="#29" class="mim-tip-reference" title="Kuang, L., Hashimoto, K., Huang, E. J., Gentry, M. S., Zhu, H. &lt;strong&gt;Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.&lt;/strong&gt; Hum. Molec. Genet. 29: 624-634, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31913476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31913476&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31913476[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddz280&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="31913476">Kuang et al. (2020)</a> suggested that readthrough-promoting therapies could provide a potential avenue of treatment in individuals with FTD due to a nonsense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31913476" 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>The transmission pattern of FTD2 in the family reported by <a href="#11" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. &lt;strong&gt;Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.&lt;/strong&gt; Nature 442: 920-924, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862115/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862115&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05017&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="16862115">Cruts et al. (2006)</a> and <a href="#51" class="mim-tip-reference" title="van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lubke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., Dermaut, B. &lt;strong&gt;A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.&lt;/strong&gt; Brain 129: 841-852, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16495329/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16495329&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awl029&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="16495329">van der Zee et al. (2006)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16495329+16862115" 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>The transmission pattern of FTD2 in family FTPD-N12/16 reported by <a href="#23" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. &lt;strong&gt;Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.&lt;/strong&gt; Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31855245/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31855245&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awz377&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="31855245">Huin et al. (2020)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" 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="mapping" class="mim-anchor"></a>
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<p><a href="#16" class="mim-tip-reference" title="Froelich, S., Basun, H., Forsell, C., Lilius, L., Axelman, K., Andreadis, A., Lannfelt, L. &lt;strong&gt;Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.&lt;/strong&gt; Am. J. Med. Genet. 74: 380-385, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9259373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9259373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19970725)74:4&lt;380::aid-ajmg8&gt;3.0.co;2-t&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="9259373">Froelich et al. (1997)</a> mapped FTD in a large Swedish family to chromosome 17. Probable linkage to chromosome 17q12-q21 was found, with a maximum 2-point lod score of 2.76 at theta = 0.0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Sequencing analysis excluded mutations in the MAPT gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By linkage analysis, <a href="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a> demonstrated linkage of the disorder in their kindred to chromosome 17q21-q22, with a maximum lod score of 3.68 at 0.0 recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9633693" 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="#40" class="mim-tip-reference" title="Rademakers, R., Cruts, M., Dermaut, B., Sleegers, K., Rosso, S. M., Van den Broeck, M., Backhovens, H., van Swieten, J., van Duijn, C. M., Van Broeckhoven, C. &lt;strong&gt;Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.&lt;/strong&gt; Molec. Psychiat. 7: 1064-1074, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12476321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12476321&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.mp.4001198&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="12476321">Rademakers et al. (2002)</a> reported the results of a genomewide search in a 4-generation pedigree with autosomal dominant early-onset dementia (mean age of onset 64.9 years, range 53 to 79 years). In this family they excluded mutations in Alzheimer disease genes, mutations in the prion protein gene (PRNP; <a href="/entry/176640">176640</a>), and exons 9 through 13 of the MAPT gene. <a href="#40" class="mim-tip-reference" title="Rademakers, R., Cruts, M., Dermaut, B., Sleegers, K., Rosso, S. M., Van den Broeck, M., Backhovens, H., van Swieten, J., van Duijn, C. M., Van Broeckhoven, C. &lt;strong&gt;Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.&lt;/strong&gt; Molec. Psychiat. 7: 1064-1074, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12476321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12476321&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.mp.4001198&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="12476321">Rademakers et al. (2002)</a> obtained conclusive linkage with chromosome 17q21 markers with a maximum multipoint lod score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Clinical and neuropathologic follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia characterized by dense ubiquitin-positive neuronal inclusions that were tau-negative. Extensive mutation analysis of MAPT identified 38 sequence variants in exons, introns, untranslated regions, and the 5-prime regulatory sequence; however, none occurred within the disease haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12476321" 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="#33" class="mim-tip-reference" title="Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M. &lt;strong&gt;A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.&lt;/strong&gt; Brain 129: 853-867, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401619/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16401619&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh724&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="16401619">Mackenzie et al. (2006)</a> reported a large Canadian family with autosomal dominant FTD linked to chromosome 17q21 with a maximum multipoint lod score of 3.911 containing MAPT. They could not identify point mutations in MAPT by direct sequencing or any gross MAPT gene alterations using fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Molecular Genetics</strong>
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<p><a href="#54" class="mim-tip-reference" title="Zhukareva, V., Vogelsberg-Ragaglia, V., Van Deerlin, V. M. D., Bruce, J., Shuck, T., Grossman, M., Clark, C. M., Arnold, S. E., Masliah, E., Galasko, D., Trojanowski, J. Q., Lee, V. M.-Y. &lt;strong&gt;Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia.&lt;/strong&gt; Ann. Neurol. 49: 165-175, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11220736/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11220736&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1531-8249(20010201)49:2&lt;165::aid-ana36&gt;3.0.co;2-3&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="11220736">Zhukareva et al. (2001)</a> stated that no tau gene mutation had been detected in the family reported by <a href="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a> in which linkage to 17q21-q22 had been established. However, they identified a loss of tau protein by Western blot analysis of protein extracts from brain regions both with and without neuronal degeneration, and concluded that, functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9633693+11220736" 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 series of 98 genealogically unrelated Belgian patients with frontotemporal lobar degeneration (FTLD), <a href="#51" class="mim-tip-reference" title="van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lubke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., Dermaut, B. &lt;strong&gt;A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.&lt;/strong&gt; Brain 129: 841-852, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16495329/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16495329&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awl029&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="16495329">van der Zee et al. (2006)</a> identified an ancestral 8-cM MAPT-containing haplotype in 2 patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 (maximum summed lod score of 5.28 at D17S931). Interestingly, the same DR2/DR8 ancestral haplotype was observed in 5 additional familial FTLD patients, indicating a founder effect. In the FTLD series, the DR2/DR8 ancestral haplotype explained 7% (7 of 98) of FTLD and 17% (7 of 42) of familial FTLD and was 7 times more frequent than MAPT mutations (1 of 98, or 1%). Clinically, DR2/DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in 1 carrier the neuropathologic diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, <a href="#51" class="mim-tip-reference" title="van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lubke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., Dermaut, B. &lt;strong&gt;A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.&lt;/strong&gt; Brain 129: 841-852, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16495329/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16495329&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awl029&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="16495329">van der Zee et al. (2006)</a> concluded that their results strongly suggested that the DR2/DR8 founder haplotype in 17q21 harbors a tau-negative FTLD-causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16495329" 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="#2" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. &lt;strong&gt;Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.&lt;/strong&gt; Nature 442: 916-919, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862116/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862116&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05016&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="16862116">Baker et al. (2006)</a> identified a frameshift mutation in exon 1 of the progranulin gene (<a href="/entry/138945#0005">138945.0005</a>) in family UBC17 reported by <a href="#33" class="mim-tip-reference" title="Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M. &lt;strong&gt;A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.&lt;/strong&gt; Brain 129: 853-867, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16401619/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16401619&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh724&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="16401619">Mackenzie et al. (2006)</a>. <a href="#2" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. &lt;strong&gt;Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.&lt;/strong&gt; Nature 442: 916-919, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862116/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862116&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05016&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="16862116">Baker et al. (2006)</a> then sequenced GRN in affected individuals from an additional 41 families with clinical and pathologic features consistent with tau-negative FTD. This analysis identified an additional 7 GRN mutations in 8 families, each predicted to cause premature termination of the coding sequence. The mutations included 4 nonsense mutations, 2 frameshift mutations, and a mutation at the 5-prime site of exon 8. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16401619+16862116" 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="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. &lt;strong&gt;Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.&lt;/strong&gt; Nature 442: 920-924, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862115/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862115&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05017&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="16862115">Cruts et al. (2006)</a> independently found mutation in progranulin in a Belgian founder family reported by <a href="#51" class="mim-tip-reference" title="van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lubke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., Dermaut, B. &lt;strong&gt;A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.&lt;/strong&gt; Brain 129: 841-852, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16495329/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16495329&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awl029&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="16495329">van der Zee et al. (2006)</a>: a mutation in the splice donor site of intron 0, indicating loss of mutant transcript by nuclear degradation (<a href="/entry/138945#0001">138945.0001</a>). <a href="#11" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. &lt;strong&gt;Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.&lt;/strong&gt; Nature 442: 920-924, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862115/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862115&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05017&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="16862115">Cruts et al. (2006)</a> also found a mutation of the initiating methionine and found that GRN haploinsufficiency leads to neurodegeneration because of reduced GRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, GRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of GRN in FTD pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16495329+16862115" 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>Both <a href="#2" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. &lt;strong&gt;Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.&lt;/strong&gt; Nature 442: 916-919, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862116/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862116&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05016&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="16862116">Baker et al. (2006)</a> and <a href="#11" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. &lt;strong&gt;Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.&lt;/strong&gt; Nature 442: 920-924, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16862115/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16862115&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05017&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="16862115">Cruts et al. (2006)</a> found a premature termination mutation in the Dutch family reported by <a href="#40" class="mim-tip-reference" title="Rademakers, R., Cruts, M., Dermaut, B., Sleegers, K., Rosso, S. M., Van den Broeck, M., Backhovens, H., van Swieten, J., van Duijn, C. M., Van Broeckhoven, C. &lt;strong&gt;Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.&lt;/strong&gt; Molec. Psychiat. 7: 1064-1074, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12476321/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12476321&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.mp.4001198&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="12476321">Rademakers et al. (2002)</a> (<a href="/entry/138945#0002">138945.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862116+16862115+12476321" 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 the family with HDDD originally reported by <a href="#31" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. &lt;strong&gt;Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.&lt;/strong&gt; Neurology 50: 1546-1555, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9633693/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9633693&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.50.6.1546&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="9633693">Lendon et al. (1998)</a>, <a href="#37" class="mim-tip-reference" title="Mukherjee, O., Pastor, P., Cairns, N. J., Chakraverty, S., Kauwe, J. S. K., Shears, S., Behrens, M. I., Budde, J., Hinrichs, A. L., Norton, J., Levitch, D., Taylor-Reinwald, L., Gitcho, M., Tu, P.-H., Grinberg, L. T., Liscic, R. M., Armendariz, J., Morris, J. C., Goate, A. M. &lt;strong&gt;HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.&lt;/strong&gt; Ann. Neurol. 60: 314-322, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16983685/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16983685&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16983685[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20963&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="16983685">Mukherjee et al. (2006)</a> identified a heterozygous mutation in the GRN gene (A9D; <a href="/entry/138945#0008">138945.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16983685+9633693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Huey, E. D., Grafman, J., Wassermann, E. M., Pietrini, P., Tierney, M. C., Ghetti, B., Spina, S., Baker, M., Hutton, M., Elder, J. W., Berger, S. L., Heflin, K. A., Hardy, J., Momeni, P. &lt;strong&gt;Characteristics of frontotemporal dementia patients with a progranulin mutation.&lt;/strong&gt; Ann. Neurol. 60: 374-380, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16983677/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16983677&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20969&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="16983677">Huey et al. (2006)</a> identified a nonsense mutation in the GRN gene (R493X; <a href="/entry/138945#0009">138945.0009</a>) in 3 unrelated patients with rapidly progressive frontotemporal dementia. All had predominantly behavioral symptoms, and 2 families showed mild parkinsonism. Brain imaging of 2 patients showed frontotemporal atrophy and hypometabolism with a right-sided predominance. In the patients with primary progressive aphasia reported by <a href="#28" class="mim-tip-reference" title="Krefft, T. A., Graff-Radford, N. R., Dickson, D. W., Baker, M., Castellani, R. J. &lt;strong&gt;Familial primary progressive aphasia.&lt;/strong&gt; Alzheimer Dis. Assoc. Disord. 17: 106-112, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12794388/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12794388&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00002093-200304000-00009&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="12794388">Krefft et al. (2003)</a>, <a href="#34" class="mim-tip-reference" title="Mesulam, M., Johnson, N., Krefft, T. A., Gass, J. M., Cannon, A. D., Adamson, J. L., Bigio, E. H., Weintraub, S., Dickson, D. W., Hutton, M. L., Graff-Radford, N. R. &lt;strong&gt;Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.&lt;/strong&gt; Arch. Neurol. 64: 43-47, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17210807/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17210807&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.64.1.43&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="17210807">Mesulam et al. (2007)</a> identified a heterozygous R493X mutation in the GRN gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17210807+16983677+12794388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Le Ber, I., van der Zee, J., Hannequin, D., Gijselinck, I., Campion, D., Puel, M., Laquerriere, A., De Pooter, T., Camuzat, A., Van den Broeck, M., Dubois, B., Sellal, F., and 13 others. &lt;strong&gt;Progranulin null mutations in both sporadic and familial frontotemporal dementia.&lt;/strong&gt; Hum. Mutat. 28: 846-855, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436289/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20520&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="17436289">Le Ber et al. (2007)</a> identified 9 novel null mutations in the GRN gene in 10 (4.8%) of 210 unrelated patients with frontotemporal dementia. The frequency was 12.8% (5 of 39) in familial cases and 3.2% (5 of 158) in sporadic cases. The phenotype was heterogeneous with age at onset ranging from 45 to 74 years and frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%). No GRN mutations were identified in 43 patients with a dementia and motor neuron disease. <a href="#30" class="mim-tip-reference" title="Le Ber, I., van der Zee, J., Hannequin, D., Gijselinck, I., Campion, D., Puel, M., Laquerriere, A., De Pooter, T., Camuzat, A., Van den Broeck, M., Dubois, B., Sellal, F., and 13 others. &lt;strong&gt;Progranulin null mutations in both sporadic and familial frontotemporal dementia.&lt;/strong&gt; Hum. Mutat. 28: 846-855, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436289/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20520&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="17436289">Le Ber et al. (2007)</a> stated that 31 GRN mutations had been identified in patients worldwide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436289" 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 the family originally reported by <a href="#36" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. &lt;strong&gt;Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.&lt;/strong&gt; Ann. Neurol. 16: 455-466, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6497355/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6497355&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410160407&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="6497355">Morris et al. (1984)</a>, <a href="#38" class="mim-tip-reference" title="Mukherjee, O., Wang, J., Gitcho, M., Chakraverty, S., Taylor-Reinwald, L., Shears, S., Kauwe, J. S. K., Norton, J., Levitch, D., Bigio, E. H., Hatanpaa, K. J., White, C. L., Morris, J. C., Cairns, N. J., Goate, A. &lt;strong&gt;Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia.&lt;/strong&gt; Hum. Mutat. 29: 512-521, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18183624/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18183624&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18183624[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20681&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="18183624">Mukherjee et al. (2008)</a> identified a heterozygous mutation in the GRN gene (<a href="/entry/138945#0014">138945.0014</a>). Affected members of another family with the disorder were found to carry the same mutation, and haplotype analysis indicated a founder effect. Western blot analysis showed a 50% reduction in GRN protein compared to controls, suggesting haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6497355+18183624" 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="#6" class="mim-tip-reference" title="Borroni, B., Archetti, S., Alberici, A., Agosti, C., Gennarelli, M., Bigni, B., Bonvicini, C., Ferrari, M., Bellelli, G., Galimberti, D., Scarpini, E., Di Lorenzo, D., Caimi, L., Caltagirone, C., Di Luca, M., Padovani, A. &lt;strong&gt;Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series.&lt;/strong&gt; Neurogenetics 9: 197-205, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18392865/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18392865&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-008-0127-3&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="18392865">Borroni et al. (2008)</a> identified a pathogenic mutation in the GRN gene (<a href="/entry/138945#0015">138945.0015</a>) in 4 (1.64%) of 243 unrelated Italian patients with a clinical diagnosis of FTLD. Two female patients were diagnosed with the behavioral variant of frontotemporal dementia, and 2 males with progressive nonfluent aphasia. The estimated age at onset ranged from 53 to 64 years, and all showed evidence of hypoperfusion of the frontotemporal brain regions. Three of the 4 had a family history of the disorder. Considering all patients in the study with a well-known family history for dementia, the frequency of this mutation was 6% (4 of 84). Haplotype analysis indicated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18392865" 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="Gijselinck, I., Van Broeckhoven, C., Cruts, M. &lt;strong&gt;Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update.&lt;/strong&gt; Hum. Mutat. 29: 1373-1386, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18543312/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18543312&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20785&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="18543312">Gijselinck et al. (2008)</a> provided a detailed review of granulin mutations associated with frontotemporal lobar degeneration. They noted that 63 heterozygous loss-of-function mutations had been identified in 163 families worldwide, representing about 5 to 10% of FTLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18543312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Seelaar, H., Kamphorst, W., Rosso, S. M., Azmani, A., Masdjedi, R., de Koning, I., Maat-Kievit, J. A., Anar, B., Donker Kaat, L., Breedveld, G. J., Dooijes, D., Rosemuller, J. M., Bronner, I. F., Rizzu, P., van Swieten, J. C. &lt;strong&gt;Distinct genetic forms of frontotemporal dementia.&lt;/strong&gt; Neurology 71: 1220-1226, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18703462/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18703462&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000319702.37497.72&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="18703462">Seelaar et al. (2008)</a> found a family history consistent with autosomal dominant inheritance in 98 (27%) of 364 probands with frontotemporal dementia. Among the familial cases, mutations in the GRN and MAPT gene were identified in 6% and 11%, respectively. Those with GRN mutations had a higher mean age at onset (61.8 years) compared to those with MAPT mutations (52.4). Neuropathologic findings, when available, were consistent with genetic analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18703462" 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 population-based study of 59 patients with pathologically confirmed FTLDU and 433 controls, <a href="#41" class="mim-tip-reference" title="Rademakers, R., Eriksen, J. L., Baker, M., Robinson, T., Ahmed, Z., Lincoln, S. J., Finch, N., Rutherford, N. J., Crook, R. J., Josephs, K. A., Boeve, B. F., Knopman, D. S., and 10 others. &lt;strong&gt;Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.&lt;/strong&gt; Hum. Molec. Genet. 17: 3631-3642, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18723524/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18723524&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18723524[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn257&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="18723524">Rademakers et al. (2008)</a> identified a C-to-T SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5848</a>; <a href="/entry/138945#0018">138945.0018</a>) in the 3-prime untranslated region of the GRN gene that conferred increased risk for the development of FTLDU when present in the homozygous state. Functional studies showed that the minor T allele increased binding of MIR659, a translation suppressor, providing a novel mechanism for loss of GRN function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18723524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 225 patients with a diagnosis of FTLD, <a href="#43" class="mim-tip-reference" title="Rohrer, J. D., Guerreiro, R., Vandrovcova, J., Uphill, J., Reiman, D., Beck, J., Isaacs, A. M., Authier, A., Ferrari, R., Fox, N. C., Mackenzie, I. R. A., Warren, J. D., de Silva, R., Holton, J., Revesz, T., Hardy, J., Mead, S., Rossor, M. N. &lt;strong&gt;The heritability and genetics of frontotemporal lobar degeneration.&lt;/strong&gt; Neurology 73: 1451-1456, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19884572/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19884572&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181bf997a&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="19884572">Rohrer et al. (2009)</a> found that 41.8% had some family history of the disorder, although only 10.2% had a clear autosomal dominant history. Those with the behavioral variant of the disorder were more likely to have a positive family history than those with the language syndromes. Mutations in the MAPT and GRN genes were found in 8.9% and 8.4% of the cohort, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19884572" 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="Benussi, L., Ghidoni, R., Pegoiani, E., Moretti, D. V., Zanetti, O., Binetti, G. &lt;strong&gt;Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.&lt;/strong&gt; Neurobiol. Dis 33: 379-385, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19101631/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19101631&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nbd.2008.11.008&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="19101631">Benussi et al. (2009)</a> found the heterozygous c.813delCACT mutation in the GRN gene (Thr272SerfsTer10; <a href="/entry/138945#0015">138945.0015</a>) in 22 (15%) of 151 Italian patients with a clinical diagnosis of neurodegenerative frontotemporal dementia-related disorders, indicating that it is one of the most common GRN mutations. GRN mutation carriers had variable clinical diagnoses, including corticobasal degeneration syndrome, FTD with motorneuron disease, behavioral variant FTD, primary progressive aphasia, and Lewy body dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19101631" 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="#53" class="mim-tip-reference" title="Yu, C.-E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., Galloway, N. M., Feldman, H., Woltjer, R., Miller, C. A., Wood, E. M., Grossman, M., and 13 others. &lt;strong&gt;The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.&lt;/strong&gt; Arch. Neurol. 67: 161-170, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142524/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142524&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20142524[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/10.1001/archneurol.2009.328&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="20142524">Yu et al. (2010)</a> reported the results of a large collaborative study of GRN mutations involving 8 academic centers. Twenty-four pathogenic GRN mutations, including 8 novel mutations, were found among 434 patients with various forms of cognitive neurodegenerative diseases. Approximately 55% of the patients with FTD for whom information was available had a family history of the disorder. Overall, the frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases. The frequency was 21.4% (9 of 42) in those with a pathologically confirmed diagnosis of FTLD-U; 16.0% (28 of 175) of FTD-spectrum cases with a family history; and 56.2% (9 of 16) of FTLD-U with a family history. The authors noted that GRN mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases, such as Pick disease (<a href="/entry/172700">172700</a>) or progressive supranuclear palsy (PSNP1; <a href="/entry/601104">601104</a>). In addition, GRN mutations were not found in patients with ALS (<a href="/entry/105400">105400</a>) or multiple system atrophy (MSA; <a href="/entry/146500">146500</a>) in whom TDP43 deposits were a neuropathologic feature. <a href="#53" class="mim-tip-reference" title="Yu, C.-E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., Galloway, N. M., Feldman, H., Woltjer, R., Miller, C. A., Wood, E. M., Grossman, M., and 13 others. &lt;strong&gt;The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.&lt;/strong&gt; Arch. Neurol. 67: 161-170, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142524/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142524&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20142524[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/10.1001/archneurol.2009.328&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="20142524">Yu et al. (2010)</a> concluded that haploinsufficiency of GRN is the predominant mechanism leading to FTD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142524" 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="#52" class="mim-tip-reference" title="Yang, W., Deng, B., Huang, Y., Liu, J., Huang, Z., Chang, Z., Zhu, S., Chan, L.-L., Chaudhuri, K. R., Tan, E.-K., Wang, Q. &lt;strong&gt;Two heterozygous progranulin mutations in progressive supranuclear palsy.&lt;/strong&gt; Brain 144: e27, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33844830/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;33844830&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awaa428&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="33844830">Yang et al. (2021)</a> reported a 65-year-old Chinese man who presented with bradykinesia, rigidity, and postural instability, which was later complicated by supranuclear gaze palsy, dysarthria, and dysphagia. Brain MRI showed mild generalized cortical atrophy, midbrain atrophy and the 'hummingbird' sign. He was diagnosed clinically with progressive supranuclear palsy (PSP). Genetic studies showed 2 heterozygous missense variants in the GRN gene (Q249E and T268P), which were on the same chromosome, presumably in cis, although the paper stated they were in trans. Expression of the variants in HEK293 cells resulted in decreased stability of the mutant protein and decreased secretion of progranulin by about 50% compared to controls. He had no family history of a neurologic disorder and family members were not available for study. <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Durr, A., Le Ber, I. &lt;strong&gt;Reply: Two heterozygous progranulin mutations in progressive supranuclear palsy.&lt;/strong&gt; Brain 144: e28, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33428710/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;33428710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awaa456&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="33428710">Huin et al. (2021)</a> cast doubt on the pathogenicity of the variants reported by <a href="#52" class="mim-tip-reference" title="Yang, W., Deng, B., Huang, Y., Liu, J., Huang, Z., Chang, Z., Zhu, S., Chan, L.-L., Chaudhuri, K. R., Tan, E.-K., Wang, Q. &lt;strong&gt;Two heterozygous progranulin mutations in progressive supranuclear palsy.&lt;/strong&gt; Brain 144: e27, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33844830/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;33844830&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awaa428&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="33844830">Yang et al. (2021)</a> in a patient who presented with PSP. <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Durr, A., Le Ber, I. &lt;strong&gt;Reply: Two heterozygous progranulin mutations in progressive supranuclear palsy.&lt;/strong&gt; Brain 144: e28, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33428710/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;33428710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awaa456&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="33428710">Huin et al. (2021)</a> noted that family members were not assessed, plasma progranulin levels were not measured in the patient, and there was not convincing evidence that the mutations occurred in trans. <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Durr, A., Le Ber, I. &lt;strong&gt;Reply: Two heterozygous progranulin mutations in progressive supranuclear palsy.&lt;/strong&gt; Brain 144: e28, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/33428710/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;33428710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awaa456&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="33428710">Huin et al. (2021)</a> suggested that the Q294E and T268P changes should be classified as 'variants of uncertain significance' (VUS). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33844830+33428710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Modifiers</em></strong></p><p>
<a href="#49" class="mim-tip-reference" title="Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., and 88 others. &lt;strong&gt;Common variants at 7p21 are associated with fronto-temporal lobar degeneration with TDP-43 inclusions.&lt;/strong&gt; Nature Genet. 42: 234-239, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20154673/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20154673&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20154673[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.536&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="20154673">Van Deerlin et al. (2010)</a> performed a genomewide association study of 515 individuals with FTLD-TDP and 2,509 controls from 45 clinical centers representing 11 countries. Eighty-nine (17.7%) of the patients had mutations in the GRN gene, and 23% had accompanying motor neuron disease. A significant association was found between FTLD-TDP and 12 SNPs in strong linkage disequilibrium (LD) within a 68-kb interval spanning the TMEM106B gene (<a href="/entry/613413">613413</a>) on chromosome 7p21.3. The most significant association was with a T-to-C transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a>) located 6.9-kb downstream of TMEM106B (odds ratio of 0.61; p = 1.08 x 10(-11)). The findings were replicated in a cohort of 89 patients, including 10 (13.5%) with GRN mutations. When stratified by GRN mutation status, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a> still showed a significant association with FTLD-TDP, both in those with and without GRN mutations (p = 1.34 x 10(-9) and 6.90 x 10(-7), respectively). Further studies showed the T risk allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a> was significantly correlated with increased TMEM106B protein and mRNA expression in lymphoblastoid cell lines. Brain tissue from 18 patients with FTLD-TDP showed increased TMEM106B expression compared to controls, and this expression correlated with presence of the T risk allele; these results were found in both GRN-positive and GRN-negative individuals. The results were compatible with a model in which mutations in GRN may act upstream of TMEM106B expression in increasing the risk for FTLD-TDP. <a href="#49" class="mim-tip-reference" title="Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., and 88 others. &lt;strong&gt;Common variants at 7p21 are associated with fronto-temporal lobar degeneration with TDP-43 inclusions.&lt;/strong&gt; Nature Genet. 42: 234-239, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20154673/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20154673&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20154673[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.536&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="20154673">Van Deerlin et al. (2010)</a> concluded that a locus on chromosome 7p21.3, most likely reflecting variants affecting expression of the TMEM106B gene, represents a genetic risk factor for the development of FTLD-TDP, both in patients with and without GRN mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20154673" 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="Finch, N., Carrasquillo, M. M., Baker, M., Rutherford, N. J., Coppola, G., DeJesus-Hernandez, M., Crook, R., Hunter, T., Ghidoni, R., Benussi, L., Crook, J., Finger, E., and 27 others. &lt;strong&gt;TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers.&lt;/strong&gt; Neurology 76: 467-474, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21178100/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21178100&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31820a0e3b&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="21178100">Finch et al. (2011)</a> found a significant association between SNPs in the TMEM106B gene and disease penetrance in patients with FTLD due to GRN mutations. In a group of 78 GRN mutation-positive patients, there was a highly significant decrease in the frequency of homozygous carriers of the minor alleles of 3 SNPs, with the strongest results for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a> (CC genotype frequency of 2.6% in patients vs 19.1% in controls, p = 0.009). Only 2 patients were homozygous for these SNPs, and both showed later disease onset compared to other patients. There was also a significant association between the minor alleles of these SNPs and increased plasma GRN protein levels in controls and increased GRN mRNA levels in patients and controls. There was an inverse correlation between TMEM106B levels and GRN levels. Sequencing of the TMEM106B gene identified a coding variant (thr185-to-ser, T185S, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3173615;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3173615</a>) that was in linkage disequilibrium with 2 of the other SNPs. <a href="#14" class="mim-tip-reference" title="Finch, N., Carrasquillo, M. M., Baker, M., Rutherford, N. J., Coppola, G., DeJesus-Hernandez, M., Crook, R., Hunter, T., Ghidoni, R., Benussi, L., Crook, J., Finger, E., and 27 others. &lt;strong&gt;TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers.&lt;/strong&gt; Neurology 76: 467-474, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21178100/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21178100&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31820a0e3b&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="21178100">Finch et al. (2011)</a> noted that haploinsufficiency for GRN is associated with disease development, and postulated that variation in TMEM106B may alter GRN levels, thus influencing disease penetrance in mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21178100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 50 GRN mutation carriers from 4 families with FTLD, <a href="#10" class="mim-tip-reference" title="Cruchaga, C., Graff, C., Chiang, H.-H., Wang, J., Hinrichs, A. L., Spiegel, N., Bertelsen, S., Mayo, K., Norton, J. B., Morris, J. C., Goate, A. &lt;strong&gt;Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels.&lt;/strong&gt; Arch. Neurol. 68: 581-586, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21220649/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21220649&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2010.350&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="21220649">Cruchaga et al. (2011)</a> found a significant association between the A risk allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a> and earlier age at onset: those homozygous for the risk A allele had a median onset 13 years earlier than those heterozygous and homozygous for the minor G allele (p = 9.9 x 10(-7)). There was also an association between the risk allele and decreased GRN plasma levels in both mutation carriers and healthy older adults. However, unlike the findings of <a href="#49" class="mim-tip-reference" title="Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., and 88 others. &lt;strong&gt;Common variants at 7p21 are associated with fronto-temporal lobar degeneration with TDP-43 inclusions.&lt;/strong&gt; Nature Genet. 42: 234-239, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20154673/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20154673&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20154673[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.536&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="20154673">Van Deerlin et al. (2010)</a>, <a href="#10" class="mim-tip-reference" title="Cruchaga, C., Graff, C., Chiang, H.-H., Wang, J., Hinrichs, A. L., Spiegel, N., Bertelsen, S., Mayo, K., Norton, J. B., Morris, J. C., Goate, A. &lt;strong&gt;Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels.&lt;/strong&gt; Arch. Neurol. 68: 581-586, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21220649/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21220649&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2010.350&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="21220649">Cruchaga et al. (2011)</a> found no association between the SNP and TMEM106B or GRN mRNA levels in frontal cortex from individuals without dementia, suggesting that the association of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a> with GRN plasma levels is not driven by changes in gene expression. The T185S variant was in perfect linkage disequilibrium with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21220649+20154673" 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="Gallagher, M. D., Posavi, M., Huang, P., Unger, T. L., Berlyand, Y., Gruenewald, A. L., Chesi, A., Manduchi, E., Wells, A. D., Grant, S. F. A., Blobel, G. A., Brown, C. D., Chen-Plotkin, A. S. &lt;strong&gt;A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression.&lt;/strong&gt; Am. J. Hum. Genet. 101: 643-663, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29056226/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29056226&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29056226[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.09.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29056226">Gallagher et al. (2017)</a> found an association between the A risk allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990622;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990622</a> and increased TMEM106B expression in several cells types, including lymphoblastoid cells lines, and in multiple brain regions of healthy human individuals. Increased expression of TMEM106B in HeLa cells and neurons resulted in enlarged lysosomes and increased cell death. A nearby noncoding variant, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1990620;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1990620</a>, was also identified, and was demonstrated to recruit the chromatin organizing protein CTCF (<a href="/entry/604167">604167</a>) to influence long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. The findings suggested that a variant at the locus on 7p21 may influence gene expression, including CTCF-mediated gene regulation of TMEM106B, with a putative role in neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29056226" 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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<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p><a href="#48" class="mim-tip-reference" title="Tsai, K.-J., Yang, C.-H., Fang, Y.-H., Cho, K.-H., Chien, W.-L., Wang, W.-T., Wu, T.-W., Lin, C.-P., Fu, W.-M., Shen, C.-K. J. &lt;strong&gt;Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.&lt;/strong&gt; J. Exp. Med. 207: 1661-1673, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20660618/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20660618&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20660618[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/10.1084/jem.20092164&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="20660618">Tsai et al. (2010)</a> generated an FTLDU mouse model by transgenically overexpressing Tdp43 in forebrain. Transgenic mice exhibited impaired learning and memory, progressive motor dysfunction, and hippocampal atrophy. The impairments were accompanied by reduced levels of phosphorylated Erk (see MAPK1; <a href="/entry/176948">176948</a>) and phosphorylated Creb (CREB1; <a href="/entry/123810">123810</a>) and increased levels of gliosis in brains of transgenic mice. Cells with Tdp43-positive, ubiquitin-positive neuronal cytoplasmic inclusions (NCIs) and Tdp43-deleted nuclei appeared in transgenic mouse brains in an age-dependent manner. <a href="#48" class="mim-tip-reference" title="Tsai, K.-J., Yang, C.-H., Fang, Y.-H., Cho, K.-H., Chien, W.-L., Wang, W.-T., Wu, T.-W., Lin, C.-P., Fu, W.-M., Shen, C.-K. J. &lt;strong&gt;Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.&lt;/strong&gt; J. Exp. Med. 207: 1661-1673, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20660618/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20660618&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20660618[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/10.1084/jem.20092164&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="20660618">Tsai et al. (2010)</a> concluded that increased levels of TDP43 protein in forebrain are sufficient to lead to formation TDP43-positive, ubiquitin-positive NCIs and neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660618" 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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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Almeida2014" class="mim-anchor"></a>
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Almeida, M. R., Baldeiras, I., Ribeiro, M. H., Santiago, B., Machado, C., Massano, J., Guimaraes, J., Resende Oliveira, C., Santana, I.
<strong>Progranulin peripheral levels as a screening tool for the identification of subjects with progranulin mutations in a Portuguese cohort.</strong>
Neurodegener. Dis. 13: 214-223, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24022032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24022032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24022032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000352022" target="_blank">Full Text</a>]
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<a id="Baker2006" class="mim-anchor"></a>
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Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others.
<strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong>
Nature 442: 916-919, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16862116" 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/nature05016" target="_blank">Full Text</a>]
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<a id="Basun1997" class="mim-anchor"></a>
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Basun, H., Almkvist, O., Axelman, K., Brun, A., Campbell, T. A., Collinge, J., Forsell, C., Froelich, S., Wahlund, L.-O., Wetterberg, L., Lannfelt, L.
<strong>Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.</strong>
Arch. Neurol. 54: 539-544, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9152110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9152110</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9152110" 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.1997.00550170021010" target="_blank">Full Text</a>]
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<a id="Behrens2007" class="mim-anchor"></a>
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Behrens, M. I., Mukherjee, O., Tu, P., Liscic, R. M., Grinberg, L. T., Carter, D., Paulsmeyer, K., Taylor-Reinwald, L., Gitcho, M., Norton, J. B., Chakraverty, S., Goate, A. M., Morris, J. C., Cairns, N. J.
<strong>Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.</strong>
Alzheimer Dis. Assoc. Disord. 21: 1-7, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334266</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/WAD.0b013e31803083f2" target="_blank">Full Text</a>]
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<a id="Benussi2009" class="mim-anchor"></a>
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Benussi, L., Ghidoni, R., Pegoiani, E., Moretti, D. V., Zanetti, O., Binetti, G.
<strong>Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.</strong>
Neurobiol. Dis 33: 379-385, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19101631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19101631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19101631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.nbd.2008.11.008" target="_blank">Full Text</a>]
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<a id="Borroni2008" class="mim-anchor"></a>
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Borroni, B., Archetti, S., Alberici, A., Agosti, C., Gennarelli, M., Bigni, B., Bonvicini, C., Ferrari, M., Bellelli, G., Galimberti, D., Scarpini, E., Di Lorenzo, D., Caimi, L., Caltagirone, C., Di Luca, M., Padovani, A.
<strong>Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series.</strong>
Neurogenetics 9: 197-205, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18392865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18392865</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18392865" 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/s10048-008-0127-3" target="_blank">Full Text</a>]
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<a id="Brouwers2007" class="mim-anchor"></a>
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Brouwers, N., Nuytemans, K., van der Zee, J., Gijselinck, I., Engelborghs, S., Theuns, J., Kumar-Singh, S., Pickut, B. A., Pals, P., Dermaut, B., Bogaerts, V., De Pooter, T., and 14 others.
<strong>Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family.</strong>
Arch. Neurol. 64: 1436-1446, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17923627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17923627</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17923627" 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.64.10.1436" target="_blank">Full Text</a>]
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<a id="Cairns2010" class="mim-anchor"></a>
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Cairns, N. J., Ghoshal, N.
<strong>FUS: a new actor on the frontotemporal lobar degeneration stage.</strong>
Neurology 74: 354-356, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20124200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20124200</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20124200" 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.0b013e3181ce5dd6" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Chen-Plotkin2011" class="mim-anchor"></a>
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Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M., Bing, S., Grossman, M., Schellenberg, G. D., Hatanpaa, K. J., Weiner, M. F., White, C. L., III, and 43 others.
<strong>Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.</strong>
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[<a href="https://doi.org/10.1001/archneurol.2011.53" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.350" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature05017" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000267701.58488.69" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awn352" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31820a0e3b" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20873" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2017.09.004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20785" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.64.10.1449" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410410205" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awaa456" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.113" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.54.4.818" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/104.1.61" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00002093-200304000-00009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddz280" target="_blank">Full Text</a>]
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Le Ber, I., van der Zee, J., Hannequin, D., Gijselinck, I., Campion, D., Puel, M., Laquerriere, A., De Pooter, T., Camuzat, A., Van den Broeck, M., Dubois, B., Sellal, F., and 13 others.
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[<a href="https://doi.org/10.1002/humu.20520" target="_blank">Full Text</a>]
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Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M.
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[<a href="https://doi.org/10.1212/wnl.50.6.1546" target="_blank">Full Text</a>]
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Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M.
<strong>A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.</strong>
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[<a href="https://doi.org/10.1093/brain/awh724" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.64.1.43" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410160407" target="_blank">Full Text</a>]
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Mukherjee, O., Pastor, P., Cairns, N. J., Chakraverty, S., Kauwe, J. S. K., Shears, S., Behrens, M. I., Budde, J., Hinrichs, A. L., Norton, J., Levitch, D., Taylor-Reinwald, L., Gitcho, M., Tu, P.-H., Grinberg, L. T., Liscic, R. M., Armendariz, J., Morris, J. C., Goate, A. M.
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[<a href="https://doi.org/10.1002/ana.20963" target="_blank">Full Text</a>]
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Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y.
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Rademakers, R., Eriksen, J. L., Baker, M., Robinson, T., Ahmed, Z., Lincoln, S. J., Finch, N., Rutherford, N. J., Crook, R. J., Josephs, K. A., Boeve, B. F., Knopman, D. S., and 10 others.
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Rohrer, J. D., Guerreiro, R., Vandrovcova, J., Uphill, J., Reiman, D., Beck, J., Isaacs, A. M., Authier, A., Ferrari, R., Fox, N. C., Mackenzie, I. R. A., Warren, J. D., de Silva, R., Holton, J., Revesz, T., Hardy, J., Mead, S., Rossor, M. N.
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Rohrer, J. D., Warren, J. D., Omar, R., Mead, S., Beck, J., Revesz, T., Holton, J., Stevens, J. M., Al-Sarraj, S., Pickering-Brown, S. M., Hardy, J., Cox, N. C., Collinge, J., Warrington, E. K., Rossor, M. N.
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Rosso, S. M., Kamphorst, W., de Graaf, B., Willemsen, R., Ravid, R., Niermeijer, M. F., Spillantini, M. G., Heutink, P., van Swieten, J. C.
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<strong>Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.</strong>
J. Exp. Med. 207: 1661-1673, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20660618[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=20660618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1084/jem.20092164" target="_blank">Full Text</a>]
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<a id="49" class="mim-anchor"></a>
<a id="Van Deerlin2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., and 88 others.
<strong>Common variants at 7p21 are associated with fronto-temporal lobar degeneration with TDP-43 inclusions.</strong>
Nature Genet. 42: 234-239, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20154673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20154673</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20154673[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=20154673" 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/ng.536" target="_blank">Full Text</a>]
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<a id="Van Deerlin2007" class="mim-anchor"></a>
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Van Deerlin, V. M., Wood, E. M., Moore, P., Yuan, W., Forman, M. S., Clark, C. M., Neumann, M., Kwong, L. K., Trojanowski, J. Q., Lee, V. M.-Y., Grossman, M.
<strong>Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations.</strong>
Arch. Neurol. 64: 1148-1153, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698705" 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.64.8.1148" target="_blank">Full Text</a>]
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<a id="51" class="mim-anchor"></a>
<a id="van der Zee2006" class="mim-anchor"></a>
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van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lubke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., Dermaut, B.
<strong>A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.</strong>
Brain 129: 841-852, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16495329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16495329</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16495329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/awl029" target="_blank">Full Text</a>]
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<a id="Yang2021" class="mim-anchor"></a>
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Yang, W., Deng, B., Huang, Y., Liu, J., Huang, Z., Chang, Z., Zhu, S., Chan, L.-L., Chaudhuri, K. R., Tan, E.-K., Wang, Q.
<strong>Two heterozygous progranulin mutations in progressive supranuclear palsy.</strong>
Brain 144: e27, 2021.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33844830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33844830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33844830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/awaa428" target="_blank">Full Text</a>]
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<a id="Yu2010" class="mim-anchor"></a>
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Yu, C.-E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., Galloway, N. M., Feldman, H., Woltjer, R., Miller, C. A., Wood, E. M., Grossman, M., and 13 others.
<strong>The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.</strong>
Arch. Neurol. 67: 161-170, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20142524[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=20142524" 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/archneurol.2009.328" target="_blank">Full Text</a>]
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<a id="54" class="mim-anchor"></a>
<a id="Zhukareva2001" class="mim-anchor"></a>
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<p class="mim-text-font">
Zhukareva, V., Vogelsberg-Ragaglia, V., Van Deerlin, V. M. D., Bruce, J., Shuck, T., Grossman, M., Clark, C. M., Arnold, S. E., Masliah, E., Galasko, D., Trojanowski, J. Q., Lee, V. M.-Y.
<strong>Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia.</strong>
Ann. Neurol. 49: 165-175, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11220736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11220736</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11220736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1531-8249(20010201)49:2&lt;165::aid-ana36&gt;3.0.co;2-3" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 08/21/2024
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Hilary J. Vernon - updated : 02/12/2021<br>Cassandra L. Kniffin - updated : 12/28/2017<br>Cassandra L. Kniffin - updated : 4/19/2012<br>Cassandra L. Kniffin - updated : 10/17/2011<br>Cassandra L. Kniffin - updated : 3/8/2011<br>Paul J. Converse - updated : 2/8/2011<br>Cassandra L. Kniffin - updated : 9/15/2010<br>Cassandra L. Kniffin - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 5/19/2010<br>Cassandra L. Kniffin - updated : 5/6/2010<br>Cassandra L. Kniffin - updated : 3/18/2010<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/18/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 1/5/2009<br>Cassandra L. Kniffin - updated : 10/31/2008<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Cassandra L. Kniffin - updated : 4/16/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 10/17/2007<br>Cassandra L. Kniffin - updated : 9/20/2007<br>Ada Hamosh - updated : 10/25/2006<br>Ada Hamosh - updated : 9/8/2006<br>Cassandra L. Kniffin - updated : 6/9/2004
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Creation Date:
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Victor A. McKusick : 1/16/2003
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alopez : 09/11/2024
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joanna : 09/10/2024<br>alopez : 08/22/2024<br>ckniffin : 08/21/2024<br>carol : 02/15/2021<br>carol : 02/12/2021<br>carol : 09/24/2019<br>carol : 01/03/2018<br>ckniffin : 12/28/2017<br>carol : 10/19/2016<br>joanna : 06/29/2016<br>carol : 1/27/2016<br>carol : 9/17/2013<br>carol : 11/28/2012<br>carol : 4/26/2012<br>ckniffin : 4/19/2012<br>carol : 10/24/2011<br>carol : 10/21/2011<br>terry : 10/21/2011<br>terry : 10/21/2011<br>ckniffin : 10/17/2011<br>ckniffin : 10/17/2011<br>carol : 10/4/2011<br>ckniffin : 10/3/2011<br>terry : 3/14/2011<br>wwang : 3/11/2011<br>ckniffin : 3/8/2011<br>mgross : 2/8/2011<br>ckniffin : 1/14/2011<br>ckniffin : 10/6/2010<br>wwang : 9/16/2010<br>ckniffin : 9/15/2010<br>wwang : 7/7/2010<br>ckniffin : 6/25/2010<br>wwang : 5/24/2010<br>ckniffin : 5/19/2010<br>ckniffin : 5/19/2010<br>wwang : 5/10/2010<br>ckniffin : 5/6/2010<br>wwang : 3/22/2010<br>ckniffin : 3/18/2010<br>wwang : 6/25/2009<br>carol : 5/1/2009<br>wwang : 4/10/2009<br>ckniffin : 3/27/2009<br>carol : 2/20/2009<br>ckniffin : 2/18/2009<br>wwang : 1/22/2009<br>ckniffin : 1/14/2009<br>wwang : 1/14/2009<br>ckniffin : 1/5/2009<br>wwang : 11/10/2008<br>ckniffin : 10/31/2008<br>wwang : 7/29/2008<br>ckniffin : 7/22/2008<br>wwang : 4/17/2008<br>ckniffin : 4/16/2008<br>wwang : 12/5/2007<br>ckniffin : 11/29/2007<br>wwang : 10/25/2007<br>ckniffin : 10/17/2007<br>wwang : 10/2/2007<br>ckniffin : 9/20/2007<br>ckniffin : 9/20/2007<br>alopez : 11/2/2006<br>terry : 10/25/2006<br>alopez : 9/20/2006<br>terry : 9/8/2006<br>terry : 3/3/2005<br>carol : 6/11/2004<br>ckniffin : 6/9/2004<br>carol : 1/17/2003<br>carol : 1/17/2003<br>ckniffin : 1/16/2003
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<strong>#</strong> 607485
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FRONTOTEMPORAL DEMENTIA 2; FTD2
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<em>Alternative titles; symbols</em>
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FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED<br />
FTLD-TDP, GRN-RELATED<br />
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, GRN-RELATED<br />
FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS; FTLDU<br />
FRONTOTEMPORAL DEMENTIA, UBIQUITIN-POSITIVE; FTDU<br />
DEMENTIA, HEREDITARY DYSPHASIC DISINHIBITION; HDDD<br />
APHASIA, PRIMARY PROGRESSIVE; PPA
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<strong>ICD10CM:</strong> G31.01; &nbsp;
<strong>ORPHA:</strong> 100070, 282; &nbsp;
<strong>DO:</strong> 0060672; &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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17q21.31
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Aphasia, primary progressive
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607485
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Autosomal dominant; Autosomal recessive
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3
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GRN
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138945
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17q21.31
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Frontotemporal dementia 2
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607485
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Autosomal dominant; Autosomal recessive
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3
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GRN
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138945
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that frontotemporal dementia-2 (FTD2) is caused by mutation in the GRN gene (138945) on chromosome 17q21. Most affected individuals have heterozygous loss-of-function mutations, although rare patients may have biallelic presumably hypomorphic mutations.</p><p>Biallelic mutations in the GRN gene cause CLN11 (614706).</p>
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<strong>Description</strong>
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<p>Frontotemporal dementia-2 (FTD2) is a neurodegenerative disorder characterized by adult onset of progressive cognitive decline which shows variable phenotypic expression but most commonly presents as behavioral changes with executive dysfunction (bvFTD) and/or language deterioration. The age at onset for individuals with heterozygous GRN mutations ranges from 40 to 85 years. Gestural apraxia, parkinsonism, visual loss, and visual hallucinations are present in 25 to 40% of patients. Other variations of the phenotype have been referred to as 'dysphasic disinhibition dementia,' 'primary progressive aphasia' (PPA), or 'corticobasal degeneration.' Some patients may present with a clinical diagnosis of Alzheimer disease (AD; 104300) or Parkinson disease (PD; 168600), features of which are part of the phenotypic spectrum of this disorder. Most GRN mutations are null and lead to haploinsufficiency. Rare individuals with biallelic, likely hypomorphic mutations have been reported (Brouwers et al., 2007; Huey et al., 2006; Mukherjee et al., 2006; Mesulam et al., 2007; Huin et al., 2020). </p><p>See also FTD1 (600274), caused by mutation in the MAPT gene (157140), which is also on chromosome 17q21.</p><p><strong><em>Genetic Heterogeneity of FTLD-TDP</em></strong></p><p>
The specific presence of TDP43 (TARDBP; 605078)-positive inclusions on neuropathologic examination defines a genetically heterogeneous group of dementias known collectively as 'FTLD-TDP.' FTLD-TDP is a neuropathologic diagnosis; only about 20% of patients with this neuropathologic diagnosis have GRN mutations (review by Van Deerlin et al., 2010). </p><p>TDP43-positive inclusions also occur in ALS10 (612069), caused by mutation in the TARDBP gene (605078); IBMPFD (167320), caused by mutation in the VCP gene (601023); and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260).</p><p>Mackenzie and Rademakers (2007) provided a detailed review of the molecular genetics of FTLD, with special emphasis on FTLDU. Cairns and Ghoshal (2010) reviewed the molecular pathology and genetic heterogeneity of FTLD, including FTLD-TDP, and also noted that FTLDU is now referred to as FTLD-TDP. </p>
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<strong>Clinical Features</strong>
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<p>In an Ohio family of Bavarian origin, Morris et al. (1984) described a distinct disease entity, which they termed 'hereditary dysphasic dementia,' in 10 of 16 members who lived past the age of 60. Over 3 generations, the disease was inherited as an autosomal dominant trait; male-to-male transmission was observed. The clinical characteristics included progressive cognitive deficits with memory loss and personality changes, severe dysphasic disturbances leading to mutism, and hyperphagia. Morris et al. (1984) suggested that the kindred reported by Kim et al. (1981) had the same disorder. This was a family of Italian extraction in which 4 of 10 members of a single generation developed dementia, dysphasia, and, in some cases, parkinsonian signs and bulimia. </p><p>Froelich et al. (1997) and Basun et al. (1997) reported a large Swedish family with rapidly progressive FTD inherited in an autosomal dominant pattern. The mean age at onset was 51 years, and mean disease duration was 3 years. Four patients were described in detail. Two patients presented with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia with akinesia and muscular rigidity, and 1 patient developed reckless driving and personality changes. All developed loss of spontaneous speech, and 3 had emotional bluntness. Cerebral perfusion was decreased in the frontal areas in all patients. Postmortem examination showed frontal lobe degeneration with spongy changes and gliosis. Skoglund et al. (2009) reported follow-up of the Swedish family reported by Froelich et al. (1997) and Basun et al. (1997) and added 6 additional affected individuals. These additional patients presented with personality and behavioral changes (2), language impairment (2), and memory impairment (2). Although there was a large variation of the initial symptoms in this family, the common pattern of clinical features included rapid disease progression and ultimately nonfluent aphasia with loss of spontaneous speech patients. Limb ataxia and parkinsonism were uncommon symptoms, and there was no motor neuron disease, although dysphagia was seen in 3 patients. Neuropathologic examination revealed frontotemporal neurodegeneration with ubiquitin and TDP43 immunoreactive intraneuronal inclusions. Molecular analysis identified a frameshift mutation in the GRN gene (138945.0016) that resulted in functional haploinsufficiency. </p><p>Lendon et al. (1998) studied a kindred with the same manifestations as those in the kindred reported by Morris et al. (1984) and renamed the disorder hereditary dysphasic disinhibition dementia (HDDD). For both kindreds, the mean age of disease onset was approximately 60 years. The range of duration of disease was 5 to 11 years in the kindred reported by Lendon et al. (1998) and 4 to 22 years in the kindred reported by Morris et al. (1984). Early manifestations included gradual onset with progressive memory loss and other cognitive deficits. There were more abnormalities of language earlier in the course of disease, frequently as the initial symptom, than are typically seen in the dementia of Alzheimer disease (AD; 104300). These included hesitancy of speech, reduction in spontaneous output, diminished fluency, and dysnomia progressing to auditory and reading-comprehension deficits, and eventual mutism. Behavioral and personality changes were occasional in the kindred reported by Morris et al. (1984) and more notable in the kindred reported by Lendon et al. (1998), sometimes occurring as the initial symptoms. Disinhibition, hypersexuality, bulimia, inappropriate behavior, and unaccustomed excessive alcohol consumption was present in some patients in both kindreds. Also in both families, parkinsonian features frequently developed, usually at a later stage of the disease. </p><p>Kertesz et al. (2000) reported a family with a highly penetrant form of autosomal dominant frontotemporal dementia, or 'clinical Pick disease.' Age at onset ranged from 38 to 44 years, with a rapid progression. Affected members had similar clinical features characterized by social withdrawal, lack of motivation, inappropriate behavior, disinhibition, and perseveration. Strikingly similar features were hyperorality and stealing. Kertesz et al. (2000) noted the similarities to Kluver-Bucy syndrome. Neuropsychologic examination indicated inattention, word-finding difficulties, and disorganization of memories. </p><p>Rosso et al. (2001) reported a large Dutch family, previously reported by Heutink et al. (1997) with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 17q21-q22 (lod score of 3.46), but without mutations in the tau gene (MAPT; 157140). Mean age at onset was 61 years, with loss of initiative and decreased spontaneous speech as the most predominant presenting symptoms. Other features included agitation and restlessness, language difficulties, and hyperorality. </p><p>Krefft et al. (2003) reported 3 sibs with classic primary progressive aphasia, defined as an isolated progressive language dysfunction. Onset of word-finding and naming difficulties occurred at ages 60, 61, and 65 years, respectively. All showed left frontotemporal atrophy. The eldest sib had mild right motor impairment, including hemiparesis and mild tremor, and died mute and bedridden 12 years after onset. A younger brother had behavioral changes, and a younger sister had significant parkinsonism, cortical release signs, and dementia. She died 4 years after onset, and postmortem neuropathologic examination showed marked cortical thinning with neuronal loss, gliosis, spongiosis, and ubiquitin-positive inclusions within cortical neurons. Other features included hippocampal sclerosis and Lewy bodies in the substantia nigra, which may have represented a concurrent pathologic process. Genetic analysis excluded common mutations in the MAPT gene. </p><p>Mesulam et al. (2007) reported 2 sisters with a typical presentation of primary progressive aphasia. The phenotype was an isolated aphasia beginning at ages 65 and 62 years, respectively, without other features. There was rapid progression of aphasia to complete mutism within 2 to 3 years. One sister developed a right-sided tremor, clumsiness, rigidity, and impaired motor function. Genetic analysis identified a heterozygous mutation in the GRN gene (R493X; 138945.0009) in both sisters. Gliebus et al. (2010) reported neuropathologic findings of 1 of the sisters with PPA reported by Mesulam et al. (2007). She died at the age of 67 years, 5 years after onset. She had significantly more neuronal intranuclear and cytoplasmic TDP43-positive inclusions and dystrophic neurites in the left inferior parietal lobule and superior temporal gyrus compared to the right, consistent with involvement of language areas of the brain. The findings illustrated a concordance between the aphasic phenotype in this patient and pathologic involvement of the language-related regions of the brain rather than memory-related regions. </p><p>In a retrospective study, Van Deerlin et al. (2007) compared the clinical features of 9 patients with FTLDU and GRN mutations to 19 patients with the same pathologic diagnosis of FTLDU but without GRN mutations. Family history was significantly more common in those with mutations. Although both patient groups had social and personality deficits, neuropsychologic testing showed that those with a GRN mutation had a significant recognition memory deficit, whereas those without a GRN mutation had a significant language deficit. Van Deerlin et al. (2007) concluded that patients with a GRN mutation differ clinically from those with the same pathologic diagnosis but no GRN mutation. </p><p>Rogalski et al. (2008) observed a significantly higher frequency of self-reported learning disabilities among 108 PPA probands (14.8%) and their first-degree relatives (29.6%) compared to 84 individuals with the behavioral variant of FTD (7.1%) and their relatives (14.3%), 154 individuals with AD (4.5%) and their relatives (10.4%), and 353 controls (1.4%) and their relatives (6.8%). PPA patients and PPA family members reported deficits specifically in the area of language, suggesting that individuals who develop PPA may have an antecedent selective vulnerability in the anatomic brain regions that underlie language. </p><p>Rohrer et al. (2008) reported a large British kindred with FTLDU associated with a mutation in the GRN gene (138945.0005). The average age at disease onset was 57.8 years. All patients had clinical and radiographic features of frontotemporal lobar degeneration with behavioral changes and language deficits. Nonfluent aphasia was present in 2 patients, and 3 became mute several years into the illness. Most also had features suggestive of parietal lobe involvement, including dyscalculia, visuoperceptual/visuospatial dysfunction, and limb apraxia. Brain imaging showed extension of the atrophy to the parietal lobe. </p><p>Moreno et al. (2009) reported the clinical features of 21 patients of Basque origin with FTD caused by the same heterozygous mutation in the GRN gene (138945.0019). The mean age at onset was 59.2 years (range, 42 to 71 years), and 4 of 21 patients died after a mean duration of 4.75 years. Overall, 14 (66.7%) had a diagnosis of behavioral variant FTD, 10 (47.6%) had a diagnosis of corticobasal degeneration, and 7 (33.3%) had a diagnosis of progressive nonfluent aphasia. None developed signs of motor neuron disease/ALS, but 8 with corticobasal degeneration had motor signs, including limb rigidity or apraxia and myoclonus. The most prominent behavioral symptoms were apathy, impulsivity, disinhibition, and bulimia, suggesting involvement of the medial frontal and orbitofrontal cortex. Dysgraphia, dyscalculia, apraxia, and hemineglect suggested parietal dysfunction. </p><p>Kelley et al. (2010) reported a large family with autosomal dominant inheritance of FTLD associated with a heterozygous mutation in the GRN gene (154delA; 138945.0017). Of 10 affected individuals, 6 presented with early amnestic symptoms resulting in initial clinical diagnoses of Alzheimer disease or amnestic mild cognitive impairment, and 3 with frontotemporal dementia; 1 had nonspecific dementia. Neuropathologic examination of 6 individuals showed FTLD with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions, even in those with an AD diagnosis. The mean age at onset was younger in the third generation (60.7 years) than in the second generation (75.8 years). Kelley et al. (2010) noted that the presentation in some individuals with GRN-related FTLD may include Alzheimer disease-like clinical features, particularly anterograde amnesia. </p><p>In an international collaborative study comparing clinical features of 97 unrelated patients with FTLD due to GRN mutations and 453 patients with FTLD who did not have GRN mutations, Chen-Plotkin et al. (2011) found clinical differences between the 2 groups. Those with GRN mutations had a younger age at disease onset (median age 58.0 vs 61.0 years), younger age at death (median age 65.5 vs 69.0 years), and less motor neuron disease (5.4% vs 26.3%). Clinical diagnoses of Parkinson disease, corticobasal syndrome, and progressive supranuclear palsy were more common in GRN mutation carriers (5.3% vs 1.3%), and more patients with GRN mutations presented with aphasia. Fifty different mutations were identified, with the most common being R493X (138945.0009), found in 18.6% of GRN cases. The A9D mutation (138945.0008) was found in 6.2% of cases and associated with an even younger age at onset (51.0 years) and more parkinsonian features compared to those with other GRN mutations. </p><p><strong><em>Biallelic GRN Mutations</em></strong></p><p>
Huin et al. (2020) reported 4 patients from 2 unrelated French families with FTD2 associated with homozygous mutations in the GRN gene. A 56-year-old woman (family FTD-1042) presented with visual hallucinations, followed by progressive language and behavioral abnormalities, including compulsive shopping, stereotyped behaviors, aggression, and hyperphagia, consistent with executive dysfunction. She rapidly became mute and was diagnosed with behavioral variant FTD (bvFTD). Physical examination showed an akinetic-rigid syndrome, pyramidal spasticity of all limbs, and right extensor plantar responses. Brain imaging showed cortico/subcortical atrophy with right temporal lobe involvement. Plasma progranulin was decreased to about half of normal values. Parental information was not available. Her 2 asymptomatic children, who were heterozygous for the mutation, had low plasma progranulin levels, but not as low as their affected mother. In a second family (family FTDP-N12/1611), 3 French brothers had a progressive neurodegenerative disorder characterized by visual impairment and retinitis pigmentosa resulting in blindness, cognitive deterioration with behavioral disorders, including disinhibition, impulsivity, emotional lability, and apathy, consistent with executive dysfunction, and loss of autonomy. Two had visual hallucinations. One brother (P1) also had atypical parkinsonism, including upper limb tremor, postural instability, impaired gait, hypophonia, dysarthria, and freezing. The 2 other brothers did not have movement disorders. Brain imaging showed cortical atrophy with normal cerebellum. Plasma progranulin, measured in 2, was undetectable. Two died in their sixties. Family history revealed that their father had dementia and died at age 66, the mother had Parkinson disease and died at age 83, and 2 maternal aunts had dementia at age 65. Consanguinity was possible. None of the patients had epilepsy or cerebellar ataxia. Genetic studies identified homozygous mutations in the GRN gene in each family: a splice site mutation (138945.0023) and a frameshift (138945.0024). Aside from the 2 sibs in 1 family, additional family segregation studies could not be performed. Huin et al. (2020) noted that both mutations had been detected in the heterozygous state in patients with autosomal dominant FTD2, suggesting the presence of additional modifying factors. </p><p><strong><em>Neuropathologic Findings</em></strong></p><p>
Morris et al. (1984) reported that complete neuropathologic examination of 4 of their patients showed asymmetric focal cerebral atrophy (characteristic of Pick disease), neuritic plaques (characteristic of Alzheimer disease), and depletion of neurons in the pigmented nuclei of the brainstem (characteristic of paralysis agitans). There was also cortical neuronal loss, nonspecific spongiform degeneration of the external layers of cerebral cortex, and reactive gliosis. Pick cells and Pick bodies were absent, and in 1 patient, Lewy bodies were present in nigral neurons. Transmissibility studies were negative. Morris et al. (1984) concluded that this is a distinct entity but 'may be best considered as part of a Pick-Alzheimer spectrum of cortical neuronal degenerations.' </p><p>Behrens et al. (2007) provided neuropathologic analysis of another member of the family reported by Morris et al. (1984). She had a disease course similar to that of other family members, with onset at age 62 years of personality changes and disinhibition, followed by nonfluent dysphasia and memory loss that progressed to mutism and total dependence, with death at age 84. There was severe generalized brain atrophy. Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in the frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and neurofibrillary tangles in the parietal and occipital cortices. The case met neuropathologic criteria for both FTLD-U and Alzheimer disease. No Pick bodies were present. </p><p>Neuropathologic examination of affected members of a family by Kertesz et al. (2000) showed severe hippocampal atrophy, frontal lobe atrophy, loss of pigmented neurons in the substantia nigra, and ubiquitin-positive inclusions that were not immunoreactive to tau or alpha-synuclein (SNCA; 163890). The authors referred to these inclusions as ITSNU. No mutations in the MAPT gene were detected. Neuropathologic examination of affected members of a family by Rosso et al. (2001) also showed ubiquitin-positive inclusions that were not immunoreactive to tau or alpha-synuclein. There were no abnormalities in tau isoform distribution. </p><p>Four affected members of the large Canadian family reported by Mackenzie et al. (2006) had undergone postmortem examination. In all cases cerebral atrophy was moderate to severe and was largely restricted to the frontal lobe. There was often mild atrophy at the head of the caudate nucleus and some loss of pigmentation of the substantia nigra. Microscopic examination of the neocortex showed nonspecific chronic degenerative changes including neuronal loss and gliosis with an anterior-to-posterior anatomic gradient of severity. Apart from a small number of neurofibrillary tangles identified in 1 family member, no other pathology was identified with silver stains, or immunohistochemistry for tau, alpha-synuclein, or nonphosphorylated or phosphorylated neurofilament; specifically, there were no senile plaques, Pick bodies, Lewy bodies, glial inclusions, or achromatic neurons. In contrast, ubiquitin-immunoreactive neurites and neuronal cytoplasmic inclusions were present in the superficial laminae of the frontal and temporal neocortex in all cases. Discrete dense ubiquitin-immunoreactive neuronal intranuclear inclusions were identified in all 4 cases and had a similar anatomic distribution to the dense neuronal cytoplasmic inclusions, being most numerous in the frontal neocortex and striatum and less common in the dentate granule cells, globus pallidus, and thalamus. The number of neuronal intranuclear inclusions varied between the anatomic regions, and they were always much less numerous than the neuronal cytoplasmic inclusions. All neuronal intranuclear inclusions were reactive to SUMO1 in addition to ubiquitin, and a proportion was positive for PML, suggesting to Mackenzie et al. (2006) that these inclusions form in the nuclear body and providing a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21. </p><p>Neumann et al. (2006) identified TDP43 (605078) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration and amyotrophic lateral sclerosis (see 105400). Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. Neumann et al. (2006) concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders. </p><p>Mukherjee et al. (2006) described additional neuropathologic findings of 8 affected individuals from the family reported by Lendon et al. (1998). Atrophy varied from moderate to severe and was most pronounced in the frontal lobe, with lesser degrees of atrophy in the temporal and parietal lobes. All cases had severe cortical neuronal loss, status spongiosus, and reactive astrocytosis. The hippocampus was less atrophied and showed less neuronal loss than is usually seen in Alzheimer disease. Immunohistochemical analysis showed ubiquitin-positive, tau-negative, neuronal cytoplasmic inclusions; dystrophic neurites; and neuronal intranuclear inclusions in 7 of 8 cases. Further studies showed that progranulin was not a component of any of the pathologic inclusions. </p><p>Forman et al. (2006) performed a clinicopathologic assessment of 124 patients with either a clinical or pathologic diagnosis of frontotemporal dementia. Neuropathologic examination showed that 46% had a tauopathy, 29% had FTLD with ubiquitin inclusions, and 17% had findings consistent with Alzheimer disease. Patients with FTLD with ubiquitin inclusions were more likely to present with social and language dysfunction; tauopathies were more commonly associated with an extrapyramidal disorder; and AD was associated with greater deficits in memory and executive function. </p><p>Davion et al. (2007) found that 4 of 9 patients with a pathologic diagnosis of FTLDU had mutations in the GRN gene (138945.0009; 138945.0012; 138945.0013). Two presented with frontotemporal dementia and 2 with primary progressive aphasia. Neuropathologic examination of all 9 cases showed that those with the GRN mutations had more frequent ubiquitinated neuronal cytoplasmic and intranuclear inclusions in the frontal lobe, temporal lobe, and striatum than those without GRN mutations, who had more neurocytoplasmic inclusions in the dentate gyrus. </p><p>Grossman et al. (2007) noted that several subtypes of FTLDU had been characterized based on neuropathologic localization of TDP43-positive ubiquitin inclusions. In a retrospective review of 23 patients, the authors found notable clinical differences between the subtypes. Only 4 of the 23 patients had mutations in the GRN gene; this was a pathologic study. Patients with numerous TDP43-positive neuronal intracytoplasmic inclusions had shorter survival; patients with numerous TDP43-positive neurites had difficulty with object naming; and patients with TDP43-positive neuronal intranuclear inclusions had substantial executive deficits. Different anatomical distributions of ubiquitin pathologic features in FTLDU subgroups were consistent with their cognitive deficits. </p>
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<strong>Diagnosis</strong>
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<p>Finch et al. (2009) used ELISA analysis to measure plasma GRN levels in a consecutive series of 207 patients with FTLD, 70 control individuals, 72 early-onset probable Alzheimer disease patients, and 9 symptomatic and 18 asymptomatic relatives of GRN mutation carriers. All 8 FTLD patients with GRN loss-of-function mutations showed significantly reduced plasma GRN levels of about one-third of the levels found in non-GRN carriers and controls individuals (p less than 0.001). There was no overlap in the distribution of plasma GRN levels between the 8 GRN mutation carriers (range, 53-94 ng/ml) and 191 non-GRN mutation carriers (range, 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. ELISA analysis also identified 1 (1.4%) probable AD patient who carried a GRN mutation. The ELISA technique only identified full-length GRN, but not GRN fragments. The study demonstrated that ELISA analysis of plasma GRN can detect asymptomatic carriers of pathogenic GRN mutations. </p><p>In a cohort of 244 Portuguese individuals with neurodegenerative dementias, including FTLD-related disorders and Alzheimer disease, Almeida et al. (2014) found that serum/plasma levels of progranulin accurately detected all 7 individuals with heterozygous loss-of-function mutations in the GRN gene. In these 7 individuals, serum/plasma progranulin levels were reduced by about one-third compared to controls, which corresponded well with heterozygous null GRN mutations leading to haploinsufficiency. There was no relationship between serum progranulin levels and age of symptom onset. Both their novel ELISA assay and a kit from Adipogen measuring serum/plasma progranulin levels yielded a sensitivity and specificity of 100% for identification of individuals with null GRN mutations. </p>
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<strong>Clinical Management</strong>
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<p>To evaluate whether aminoglycosides could facilitate the readthrough of nonsense mutations in the GRN gene, Kuang et al. (2020) transfected N2A cells with plasmids with wildtype GRN or one of 3 mutations associated with FTD (R493X, 138945.0009; Q125X 138945.0002; or Y229X), and tested the readthrough effects of 11 aminoglycosides and a clinically approved readthrough small molecule, PTC124. Both G418 and gentamicin induced the readthrough of GRN with the R493X mutation, but not the other GRN mutants, in a time- and dose-dependent manner. G418 had a stronger effect on readthrough than gentamicin. The readthrough product of the R493X GRN mutant had similar subcellular localization as wildtype GRN. Based on these findings, Kuang et al. (2020) suggested that readthrough-promoting therapies could provide a potential avenue of treatment in individuals with FTD due to a nonsense mutation. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of FTD2 in the family reported by Cruts et al. (2006) and van der Zee et al. (2006) was consistent with autosomal dominant inheritance. </p><p>The transmission pattern of FTD2 in family FTPD-N12/16 reported by Huin et al. (2020) was consistent with autosomal recessive inheritance. </p>
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<strong>Mapping</strong>
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<p>Froelich et al. (1997) mapped FTD in a large Swedish family to chromosome 17. Probable linkage to chromosome 17q12-q21 was found, with a maximum 2-point lod score of 2.76 at theta = 0.0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Sequencing analysis excluded mutations in the MAPT gene. </p><p>By linkage analysis, Lendon et al. (1998) demonstrated linkage of the disorder in their kindred to chromosome 17q21-q22, with a maximum lod score of 3.68 at 0.0 recombination. </p><p>Rademakers et al. (2002) reported the results of a genomewide search in a 4-generation pedigree with autosomal dominant early-onset dementia (mean age of onset 64.9 years, range 53 to 79 years). In this family they excluded mutations in Alzheimer disease genes, mutations in the prion protein gene (PRNP; 176640), and exons 9 through 13 of the MAPT gene. Rademakers et al. (2002) obtained conclusive linkage with chromosome 17q21 markers with a maximum multipoint lod score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Clinical and neuropathologic follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia characterized by dense ubiquitin-positive neuronal inclusions that were tau-negative. Extensive mutation analysis of MAPT identified 38 sequence variants in exons, introns, untranslated regions, and the 5-prime regulatory sequence; however, none occurred within the disease haplotype. </p><p>Mackenzie et al. (2006) reported a large Canadian family with autosomal dominant FTD linked to chromosome 17q21 with a maximum multipoint lod score of 3.911 containing MAPT. They could not identify point mutations in MAPT by direct sequencing or any gross MAPT gene alterations using fluorescence in situ hybridization. </p>
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<strong>Molecular Genetics</strong>
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<p>Zhukareva et al. (2001) stated that no tau gene mutation had been detected in the family reported by Lendon et al. (1998) in which linkage to 17q21-q22 had been established. However, they identified a loss of tau protein by Western blot analysis of protein extracts from brain regions both with and without neuronal degeneration, and concluded that, functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene. </p><p>In a series of 98 genealogically unrelated Belgian patients with frontotemporal lobar degeneration (FTLD), van der Zee et al. (2006) identified an ancestral 8-cM MAPT-containing haplotype in 2 patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 (maximum summed lod score of 5.28 at D17S931). Interestingly, the same DR2/DR8 ancestral haplotype was observed in 5 additional familial FTLD patients, indicating a founder effect. In the FTLD series, the DR2/DR8 ancestral haplotype explained 7% (7 of 98) of FTLD and 17% (7 of 42) of familial FTLD and was 7 times more frequent than MAPT mutations (1 of 98, or 1%). Clinically, DR2/DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in 1 carrier the neuropathologic diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, van der Zee et al. (2006) concluded that their results strongly suggested that the DR2/DR8 founder haplotype in 17q21 harbors a tau-negative FTLD-causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations. </p><p>Baker et al. (2006) identified a frameshift mutation in exon 1 of the progranulin gene (138945.0005) in family UBC17 reported by Mackenzie et al. (2006). Baker et al. (2006) then sequenced GRN in affected individuals from an additional 41 families with clinical and pathologic features consistent with tau-negative FTD. This analysis identified an additional 7 GRN mutations in 8 families, each predicted to cause premature termination of the coding sequence. The mutations included 4 nonsense mutations, 2 frameshift mutations, and a mutation at the 5-prime site of exon 8. </p><p>Cruts et al. (2006) independently found mutation in progranulin in a Belgian founder family reported by van der Zee et al. (2006): a mutation in the splice donor site of intron 0, indicating loss of mutant transcript by nuclear degradation (138945.0001). Cruts et al. (2006) also found a mutation of the initiating methionine and found that GRN haploinsufficiency leads to neurodegeneration because of reduced GRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, GRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of GRN in FTD pathogenesis. </p><p>Both Baker et al. (2006) and Cruts et al. (2006) found a premature termination mutation in the Dutch family reported by Rademakers et al. (2002) (138945.0002). </p><p>In affected members of the family with HDDD originally reported by Lendon et al. (1998), Mukherjee et al. (2006) identified a heterozygous mutation in the GRN gene (A9D; 138945.0008). </p><p>Huey et al. (2006) identified a nonsense mutation in the GRN gene (R493X; 138945.0009) in 3 unrelated patients with rapidly progressive frontotemporal dementia. All had predominantly behavioral symptoms, and 2 families showed mild parkinsonism. Brain imaging of 2 patients showed frontotemporal atrophy and hypometabolism with a right-sided predominance. In the patients with primary progressive aphasia reported by Krefft et al. (2003), Mesulam et al. (2007) identified a heterozygous R493X mutation in the GRN gene. </p><p>Le Ber et al. (2007) identified 9 novel null mutations in the GRN gene in 10 (4.8%) of 210 unrelated patients with frontotemporal dementia. The frequency was 12.8% (5 of 39) in familial cases and 3.2% (5 of 158) in sporadic cases. The phenotype was heterogeneous with age at onset ranging from 45 to 74 years and frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%). No GRN mutations were identified in 43 patients with a dementia and motor neuron disease. Le Ber et al. (2007) stated that 31 GRN mutations had been identified in patients worldwide. </p><p>In affected members of the family originally reported by Morris et al. (1984), Mukherjee et al. (2008) identified a heterozygous mutation in the GRN gene (138945.0014). Affected members of another family with the disorder were found to carry the same mutation, and haplotype analysis indicated a founder effect. Western blot analysis showed a 50% reduction in GRN protein compared to controls, suggesting haploinsufficiency. </p><p>Borroni et al. (2008) identified a pathogenic mutation in the GRN gene (138945.0015) in 4 (1.64%) of 243 unrelated Italian patients with a clinical diagnosis of FTLD. Two female patients were diagnosed with the behavioral variant of frontotemporal dementia, and 2 males with progressive nonfluent aphasia. The estimated age at onset ranged from 53 to 64 years, and all showed evidence of hypoperfusion of the frontotemporal brain regions. Three of the 4 had a family history of the disorder. Considering all patients in the study with a well-known family history for dementia, the frequency of this mutation was 6% (4 of 84). Haplotype analysis indicated a founder effect. </p><p>Gijselinck et al. (2008) provided a detailed review of granulin mutations associated with frontotemporal lobar degeneration. They noted that 63 heterozygous loss-of-function mutations had been identified in 163 families worldwide, representing about 5 to 10% of FTLD. </p><p>Seelaar et al. (2008) found a family history consistent with autosomal dominant inheritance in 98 (27%) of 364 probands with frontotemporal dementia. Among the familial cases, mutations in the GRN and MAPT gene were identified in 6% and 11%, respectively. Those with GRN mutations had a higher mean age at onset (61.8 years) compared to those with MAPT mutations (52.4). Neuropathologic findings, when available, were consistent with genetic analysis. </p><p>In a population-based study of 59 patients with pathologically confirmed FTLDU and 433 controls, Rademakers et al. (2008) identified a C-to-T SNP (rs5848; 138945.0018) in the 3-prime untranslated region of the GRN gene that conferred increased risk for the development of FTLDU when present in the homozygous state. Functional studies showed that the minor T allele increased binding of MIR659, a translation suppressor, providing a novel mechanism for loss of GRN function. </p><p>Among 225 patients with a diagnosis of FTLD, Rohrer et al. (2009) found that 41.8% had some family history of the disorder, although only 10.2% had a clear autosomal dominant history. Those with the behavioral variant of the disorder were more likely to have a positive family history than those with the language syndromes. Mutations in the MAPT and GRN genes were found in 8.9% and 8.4% of the cohort, respectively. </p><p>Benussi et al. (2009) found the heterozygous c.813delCACT mutation in the GRN gene (Thr272SerfsTer10; 138945.0015) in 22 (15%) of 151 Italian patients with a clinical diagnosis of neurodegenerative frontotemporal dementia-related disorders, indicating that it is one of the most common GRN mutations. GRN mutation carriers had variable clinical diagnoses, including corticobasal degeneration syndrome, FTD with motorneuron disease, behavioral variant FTD, primary progressive aphasia, and Lewy body dementia. </p><p>Yu et al. (2010) reported the results of a large collaborative study of GRN mutations involving 8 academic centers. Twenty-four pathogenic GRN mutations, including 8 novel mutations, were found among 434 patients with various forms of cognitive neurodegenerative diseases. Approximately 55% of the patients with FTD for whom information was available had a family history of the disorder. Overall, the frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases. The frequency was 21.4% (9 of 42) in those with a pathologically confirmed diagnosis of FTLD-U; 16.0% (28 of 175) of FTD-spectrum cases with a family history; and 56.2% (9 of 16) of FTLD-U with a family history. The authors noted that GRN mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases, such as Pick disease (172700) or progressive supranuclear palsy (PSNP1; 601104). In addition, GRN mutations were not found in patients with ALS (105400) or multiple system atrophy (MSA; 146500) in whom TDP43 deposits were a neuropathologic feature. Yu et al. (2010) concluded that haploinsufficiency of GRN is the predominant mechanism leading to FTD. </p><p>Yang et al. (2021) reported a 65-year-old Chinese man who presented with bradykinesia, rigidity, and postural instability, which was later complicated by supranuclear gaze palsy, dysarthria, and dysphagia. Brain MRI showed mild generalized cortical atrophy, midbrain atrophy and the 'hummingbird' sign. He was diagnosed clinically with progressive supranuclear palsy (PSP). Genetic studies showed 2 heterozygous missense variants in the GRN gene (Q249E and T268P), which were on the same chromosome, presumably in cis, although the paper stated they were in trans. Expression of the variants in HEK293 cells resulted in decreased stability of the mutant protein and decreased secretion of progranulin by about 50% compared to controls. He had no family history of a neurologic disorder and family members were not available for study. Huin et al. (2021) cast doubt on the pathogenicity of the variants reported by Yang et al. (2021) in a patient who presented with PSP. Huin et al. (2021) noted that family members were not assessed, plasma progranulin levels were not measured in the patient, and there was not convincing evidence that the mutations occurred in trans. Huin et al. (2021) suggested that the Q294E and T268P changes should be classified as 'variants of uncertain significance' (VUS). </p><p><strong><em>Genetic Modifiers</em></strong></p><p>
Van Deerlin et al. (2010) performed a genomewide association study of 515 individuals with FTLD-TDP and 2,509 controls from 45 clinical centers representing 11 countries. Eighty-nine (17.7%) of the patients had mutations in the GRN gene, and 23% had accompanying motor neuron disease. A significant association was found between FTLD-TDP and 12 SNPs in strong linkage disequilibrium (LD) within a 68-kb interval spanning the TMEM106B gene (613413) on chromosome 7p21.3. The most significant association was with a T-to-C transition (rs1990622) located 6.9-kb downstream of TMEM106B (odds ratio of 0.61; p = 1.08 x 10(-11)). The findings were replicated in a cohort of 89 patients, including 10 (13.5%) with GRN mutations. When stratified by GRN mutation status, rs1990622 still showed a significant association with FTLD-TDP, both in those with and without GRN mutations (p = 1.34 x 10(-9) and 6.90 x 10(-7), respectively). Further studies showed the T risk allele of rs1990622 was significantly correlated with increased TMEM106B protein and mRNA expression in lymphoblastoid cell lines. Brain tissue from 18 patients with FTLD-TDP showed increased TMEM106B expression compared to controls, and this expression correlated with presence of the T risk allele; these results were found in both GRN-positive and GRN-negative individuals. The results were compatible with a model in which mutations in GRN may act upstream of TMEM106B expression in increasing the risk for FTLD-TDP. Van Deerlin et al. (2010) concluded that a locus on chromosome 7p21.3, most likely reflecting variants affecting expression of the TMEM106B gene, represents a genetic risk factor for the development of FTLD-TDP, both in patients with and without GRN mutations. </p><p>Finch et al. (2011) found a significant association between SNPs in the TMEM106B gene and disease penetrance in patients with FTLD due to GRN mutations. In a group of 78 GRN mutation-positive patients, there was a highly significant decrease in the frequency of homozygous carriers of the minor alleles of 3 SNPs, with the strongest results for rs1990622 (CC genotype frequency of 2.6% in patients vs 19.1% in controls, p = 0.009). Only 2 patients were homozygous for these SNPs, and both showed later disease onset compared to other patients. There was also a significant association between the minor alleles of these SNPs and increased plasma GRN protein levels in controls and increased GRN mRNA levels in patients and controls. There was an inverse correlation between TMEM106B levels and GRN levels. Sequencing of the TMEM106B gene identified a coding variant (thr185-to-ser, T185S, rs3173615) that was in linkage disequilibrium with 2 of the other SNPs. Finch et al. (2011) noted that haploinsufficiency for GRN is associated with disease development, and postulated that variation in TMEM106B may alter GRN levels, thus influencing disease penetrance in mutation carriers. </p><p>In a study of 50 GRN mutation carriers from 4 families with FTLD, Cruchaga et al. (2011) found a significant association between the A risk allele of rs1990622 and earlier age at onset: those homozygous for the risk A allele had a median onset 13 years earlier than those heterozygous and homozygous for the minor G allele (p = 9.9 x 10(-7)). There was also an association between the risk allele and decreased GRN plasma levels in both mutation carriers and healthy older adults. However, unlike the findings of Van Deerlin et al. (2010), Cruchaga et al. (2011) found no association between the SNP and TMEM106B or GRN mRNA levels in frontal cortex from individuals without dementia, suggesting that the association of rs1990622 with GRN plasma levels is not driven by changes in gene expression. The T185S variant was in perfect linkage disequilibrium with rs1990622. </p><p>Gallagher et al. (2017) found an association between the A risk allele of rs1990622 and increased TMEM106B expression in several cells types, including lymphoblastoid cells lines, and in multiple brain regions of healthy human individuals. Increased expression of TMEM106B in HeLa cells and neurons resulted in enlarged lysosomes and increased cell death. A nearby noncoding variant, rs1990620, was also identified, and was demonstrated to recruit the chromatin organizing protein CTCF (604167) to influence long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. The findings suggested that a variant at the locus on 7p21 may influence gene expression, including CTCF-mediated gene regulation of TMEM106B, with a putative role in neurodegeneration. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Tsai et al. (2010) generated an FTLDU mouse model by transgenically overexpressing Tdp43 in forebrain. Transgenic mice exhibited impaired learning and memory, progressive motor dysfunction, and hippocampal atrophy. The impairments were accompanied by reduced levels of phosphorylated Erk (see MAPK1; 176948) and phosphorylated Creb (CREB1; 123810) and increased levels of gliosis in brains of transgenic mice. Cells with Tdp43-positive, ubiquitin-positive neuronal cytoplasmic inclusions (NCIs) and Tdp43-deleted nuclei appeared in transgenic mouse brains in an age-dependent manner. Tsai et al. (2010) concluded that increased levels of TDP43 protein in forebrain are sufficient to lead to formation TDP43-positive, ubiquitin-positive NCIs and neurodegeneration. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
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Cassandra L. Kniffin - updated : 08/21/2024<br>Hilary J. Vernon - updated : 02/12/2021<br>Cassandra L. Kniffin - updated : 12/28/2017<br>Cassandra L. Kniffin - updated : 4/19/2012<br>Cassandra L. Kniffin - updated : 10/17/2011<br>Cassandra L. Kniffin - updated : 3/8/2011<br>Paul J. Converse - updated : 2/8/2011<br>Cassandra L. Kniffin - updated : 9/15/2010<br>Cassandra L. Kniffin - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 5/19/2010<br>Cassandra L. Kniffin - updated : 5/6/2010<br>Cassandra L. Kniffin - updated : 3/18/2010<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/18/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 1/5/2009<br>Cassandra L. Kniffin - updated : 10/31/2008<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Cassandra L. Kniffin - updated : 4/16/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 10/17/2007<br>Cassandra L. Kniffin - updated : 9/20/2007<br>Ada Hamosh - updated : 10/25/2006<br>Ada Hamosh - updated : 9/8/2006<br>Cassandra L. Kniffin - updated : 6/9/2004
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