3485 lines
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Entry
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- #167320 - INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1; IBMPFD1
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- OMIM
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<p>
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<span class="h4">#167320</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/167320"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS167320"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT 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><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10698&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1476/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8654" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=167320[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=52430" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0111385" 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>
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<div><a href="http://www.informatics.jax.org/disease/167320" 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>
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<div><a href="https://wormbase.org/resources/disease/DOID:0111385" 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 style="display: table-cell;">Cell Lines</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:167320" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</div>
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<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">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703544004<br />
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<strong>ORPHA:</strong> 52430<br />
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<strong>DO:</strong> 0111385<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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167320
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1; IBMPFD1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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MULTISYSTEM PROTEINOPATHY 1; MSP1<br />
|
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, WITH PAGET DISEASE OF BONE<br />
|
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PAGETOID AMYOTROPHIC LATERAL SCLEROSIS<br />
|
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PAGETOID NEUROSKELETAL SYNDROME<br />
|
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LOWER MOTOR NEURON DEGENERATION WITH PAGET-LIKE BONE DISEASE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<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/9/160?start=-3&limit=10&highlight=160">
|
|
9p13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/167320"> 167320 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
VCP
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601023"> 601023 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/167320" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS167320" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/167320" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/167320" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Facial weakness (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95666008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95666008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R29.810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R29.810</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.83</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/781.94" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.94</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427055&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427055</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007209</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CHEST </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ribs Sternum Clavicles & Scapulae </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Winged scapulae <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240953&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240953</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003691" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003691</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003691" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003691</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Paget disease (in 50% of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2089002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2089002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029401&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029401</a>, <a href="https://bioportal.bioontology.org/search?q=C1368019&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1368019</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034159" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034159</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Spine </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Back pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/161891005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">161891005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M54" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M54</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M54.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M54.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/724.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">724.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004604&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004604</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003418</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003418</a>]</span><br /> -
|
|
Lumbar lordosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/313471000119104" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">313471000119104</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1184923&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1184923</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002938</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002938</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Pelvis </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hip pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49218002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49218002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M25.559" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M25.559</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M25.55" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M25.55</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019559&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019559</a>, <a href="https://bioportal.bioontology.org/search?q=C1716793&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1716793</a>, <a href="https://bioportal.bioontology.org/search?q=C4551516&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551516</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003365</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030838" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030838</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030838" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030838</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Muscle weakness (in 90% of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26544005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26544005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151786&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151786</a>, <a href="https://bioportal.bioontology.org/search?q=C0030552&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030552</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span><br /> -
|
|
Proximal muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249939004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249939004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221629&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221629</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003701" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003701</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003701" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003701</a>]</span><br /> -
|
|
Shoulder weakness and atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833668&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833668</a>]</span><br /> -
|
|
Limb weakness and atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833669&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833669</a>]</span><br /> -
|
|
Pelvic girdle weakness and atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833670</a>]</span><br /> -
|
|
Distal muscle atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848736&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848736</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span><br /> -
|
|
Nonspecific myopathic changes seen on biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3549998&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3549998</a>]</span><br /> -
|
|
Rimmed vacuoles <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40236008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40236008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853932&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853932</a>, <a href="https://bioportal.bioontology.org/search?q=C0333773&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0333773</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003805" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003805</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003805" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003805</a>]</span><br /> -
|
|
Inclusion body myopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833672&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833672</a>]</span><br /> -
|
|
Difficulty walking up stairs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/282195009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">282195009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239067&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239067</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003551" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003551</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003551" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003551</a>]</span><br /> -
|
|
Primary myopathic changes seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3549999&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3549999</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> NEUROLOGIC </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Central Nervous System </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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- Gait abnormalities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /> -
|
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Frontotemporal dementia (in 30% of patients) <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 /> -
|
|
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
|
|
Expressive dysphasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/229665008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">229665008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0917814&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0917814</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 /> -
|
|
Dystrophic neurites <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674684&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674684</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025713</a>]</span><br /> -
|
|
Ubiquitin-positive intranuclear neuronal inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674685&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674685</a>]</span><br /> -
|
|
VCP-positive inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750320&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750320</a>]</span><br /> -
|
|
TDP43-positive inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750321&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750321</a>]</span><br /> -
|
|
MRI shows frontal and temporal cortical atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833665&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833665</a>]</span><br />
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|
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
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|
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<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased serum creatine kinase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span><br /> -
|
|
Increased serum bone-specific alkaline phosphatase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833667&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833667</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010639</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
|
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|
|
- Mean age at onset of muscle disease is 42 years (range 24-61)<br /> -
|
|
Mean age at onset of bone disease is 40 years (range 23-65)<br /> -
|
|
Mean age at onset of dementia is 57 years<br /> -
|
|
Many patients become wheelchair-bound<br /> -
|
|
Incomplete penetrance of the 3 main clinical signs, myopathy, dementia, and Paget disease<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> MOLECULAR BASIS </strong>
|
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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- Caused by mutation in the valosin-containing protein gene (VCP, <a href="/entry/601023#0001">601023.0001</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div class="text-right">
|
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
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</div>
|
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small">
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<div class="row">
|
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
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<h5>
|
|
Inclusion body myopathy/Paget disease/frontotemporal dementia
|
|
- <a href="/phenotypicSeries/PS167320">PS167320</a>
|
|
- 3 Entries
|
|
</h5>
|
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</div>
|
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<strong>Phenotype</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<a href="/geneMap/7/127?start=-3&limit=10&highlight=127"> 7p15.2 </a>
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<span class="mim-font">
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<a href="/entry/615422"> ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/615422"> 615422 </a>
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<a href="/entry/600124"> HNRNPA2B1 </a>
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<a href="/entry/167320"> Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/167320"> 167320 </a>
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<a href="/entry/601023"> VCP </a>
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<a href="/entry/601023"> 601023 </a>
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<span class="mim-font">
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<a href="/entry/615424"> ?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/615424"> 615424 </a>
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<a href="/entry/164017"> HNRNPA1 </a>
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<span class="mim-font">
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<a href="/entry/164017"> 164017 </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>A number sign (#) is used with this entry because of evidence that inclusion body myopathy with Paget disease and frontotemporal dementia-1 (IBMPFD1) is caused by heterozygous mutation in the VCP gene (<a href="/entry/601023">601023</a>) on chromosome 9p13.</p><p>Heterozygous mutation in the VCP gene can also cause frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; <a href="/entry/613954">613954</a>), which can show overlapping clinical features.</p>
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<p>IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by <a href="#21" class="mim-tip-reference" title="Weihl, C. C., Pestronk, A., Kimonis, V. E. <strong>Valosin-containing protein disease: Inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia.</strong> Neuromusc. Disord. 19: 308-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19380227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.01.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380227">Weihl et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of IBMPFD</em></strong></p><p>
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IBMPFD2 (<a href="/entry/615422">615422</a>) is caused by mutation in the HNRNPA2B1 gene (<a href="/entry/600124">600124</a>) on chromosome 7p15. IBMPFD3 (<a href="/entry/615424">615424</a>) is caused by mutation in the HNRNPA1 gene (<a href="/entry/164017">164017</a>) on chromosome 12q13.</p>
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<p>IBMPFD may also be referred to as FTLD-TDP (or TDP43), VCP-related, based on neuropathologic findings (<a href="#12" class="mim-tip-reference" title="Mackenzie, I. R. A., Neumann, M., Bigio, E. H., Cairns, N. J., Alafuzoff, I., Kril, J., Kovacs, G. G., Ghetti, B., Halliday, G., Holm, I. E., Ince, P. G., Kamphorst, W., and 9 others. <strong>Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update.</strong> Acta Neuropath. 119: 1-4, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19924424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19924424</a>] [<a href="https://doi.org/10.1007/s00401-009-0612-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19924424">MacKenzie et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19924424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bucelli, R. C., Arhzaouy, K., Pestronk, A., Pittman, S. K., Rojas, L., Sue, C. M., Evila, A., Hackman, P., Udd, B., Harms, M. B., Weihl, C. C. <strong>SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles.</strong> Neurology 85: 665-674, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26208961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26208961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26208961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26208961">Bucelli et al. (2015)</a> suggested use of the designation multisystem proteinopathy (MSP) for a group of genetic disorders clinically characterized by variable penetrance of FTD, ALS, Paget disease, and myopathy, which are unified by the pathologic accumulation of ubiquitin and TDP43; see <a href="/entry/617158">617158</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26208961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Tucker, W. S., Jr., Hubbard, W. H., Stryker, T. D., Morgan, S. W., Evans, O. B., Freemon, F. R., Theil, G. B. <strong>A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization.</strong> Trans. Assoc. Am. Phys. 95: 126-134, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7182974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7182974</a>]" pmid="7182974">Tucker et al. (1982)</a> studied a large kindred with a syndrome of lower motor neuron degeneration and polyostotic skeletal disorganization resembling Paget disease of bone (PDB; see <a href="/entry/167250">167250</a>). The disorder begins insidiously at about age 35 with weakness and atrophy of the leg and proximal arm muscles. Nerve conductions are normal; EMG shows muscle denervation, as does muscle biopsy. The disorder progresses to wheelchair confinement and later to bed confinement, quadriparesis, dementia, respiratory failure, and death before age 60 years. Even early in the neurologic illness, patients have coarse trabeculation, cortical thickening, and spotty sclerosis on bone x-rays; diffusely increased uptake of radionuclide and elevated heat-labile serum alkaline phosphatase. The disorder affected 6 females and 6 males in 5 sibships of 3 generations with no instance of male-to-male transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7182974" 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="#8" class="mim-tip-reference" title="Kimonis, V. E., Kovach, M. J., Waggoner, B., Leal, S., Salam, A., Rimer, L., Davis, K., Khardori, R., Gelber, D. <strong>Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone.</strong> Genet. Med. 2: 232-241, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11252708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11252708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11252708[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/00125817-200007000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11252708">Kimonis et al. (2000)</a> described a family in which autosomal dominant limb-girdle muscular dystrophy (LGMD) was associated with early-onset Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected individuals had both disorders. Onset of PDB occurred at a mean age of 35 years, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy was progressive with mildly elevated to normal CPK levels. Muscle biopsy in the oldest male revealed vacuolated fibers, but in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness and respiratory and cardiac failure in their forties to sixties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11252708" 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="Kovach, M. J., Waggoner, B., Leal, S. M., Gelber, D., Khardori, R., Levenstien, M. A., Shanks, C. A., Gregg, G., Al-Lozi, M. T., Miller, T., Rakowica, W., Lopate, G., Florence, J., Glosser, G., Simmons, Z., Morris, J. C., Whyte, M. P., Pestronk, A., Kimonis, V. E. <strong>Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.</strong> Molec. Genet. Metab. 74: 458-475, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11749051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11749051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11749051[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1006/mgme.2001.3256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11749051">Kovach et al. (2001)</a> described the clinical, biochemical, radiologic, and pathologic characteristics of 49 affected individuals from the family described by <a href="#8" class="mim-tip-reference" title="Kimonis, V. E., Kovach, M. J., Waggoner, B., Leal, S., Salam, A., Rimer, L., Davis, K., Khardori, R., Gelber, D. <strong>Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone.</strong> Genet. Med. 2: 232-241, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11252708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11252708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11252708[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/00125817-200007000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11252708">Kimonis et al. (2000)</a> and 3 other unrelated families with autosomal dominant inclusion body myopathy (IBM), PDB, and frontotemporal dementia. Ninety percent of the patients had myopathy, 43% had PDB, and 37% had premature frontotemporal dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11749051+11252708" 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="#19" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> reported 13 families with IBMPFD, 12 from the U.S. and 1 from Canada. Among those individuals, 82% of affected individuals had myopathy, 49% had PDB, and 30% had early-onset frontotemporal dementia. The mean age at presentation was 42 years for both IBM and PDB, whereas frontotemporal dementia typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathologic pathway. Family 11 in the report by <a href="#19" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> was originally reported by <a href="#16" class="mim-tip-reference" title="Tucker, W. S., Jr., Hubbard, W. H., Stryker, T. D., Morgan, S. W., Evans, O. B., Freemon, F. R., Theil, G. B. <strong>A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization.</strong> Trans. Assoc. Am. Phys. 95: 126-134, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7182974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7182974</a>]" pmid="7182974">Tucker et al. (1982)</a> (<a href="#10" class="mim-tip-reference" title="Kimonis, V. E. <strong>Personal Communication.</strong> Boston, Mass. 1/12/2005."None>Kimonis, 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7182974+15034582" 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="Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A. <strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong> Neurology 65: 1304-1305, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247064</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247064">Haubenberger et al. (2005)</a> reported an Austrian family in which 4 sibs had autosomal dominant inclusion body myopathy and Paget disease associated with a heterozygous mutation in the VCP gene (R159H; <a href="/entry/601023#0007">601023.0007</a>). None of the affected individuals developed frontotemporal dementia even though all were over 60 years of age. <a href="#6" class="mim-tip-reference" title="Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A. <strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong> Neurology 65: 1304-1305, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247064</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247064">Haubenberger et al. (2005)</a> noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, <a href="#17" class="mim-tip-reference" title="van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C. <strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong> Neurology 73: 626-632, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19704082">van der Zee et al. (2009)</a> noted that 1 patient had developed dementia at age 64. <a href="#17" class="mim-tip-reference" title="van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C. <strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong> Neurology 73: 626-632, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19704082">Van der Zee et al. (2009)</a> also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by <a href="#6" class="mim-tip-reference" title="Haubenberger, D., Bittner, R. E., Rauch-Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., Zimprich, A. <strong>Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.</strong> Neurology 65: 1304-1305, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16247064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16247064</a>] [<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16247064">Haubenberger et al. (2005)</a> were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; <a href="/entry/605078">605078</a>) protein. <a href="#17" class="mim-tip-reference" title="van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C. <strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong> Neurology 73: 626-632, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19704082">Van der Zee et al. (2009)</a> commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16247064+19704082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kimonis, V. E., Mehta, S. G., Fulchiero, E. C., Thomasova, D., Pasquali, M., Boycott, K., Nielan, E. G., Kartashov, A., Forman, M. S., Tucker, S., Kimonis, K., Mumm, S., Whyte, M. P., Smith, C. D., Watts, G. D. J. <strong>Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.</strong> Am. J. Med. Genet. 146A: 745-757, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18260132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18260132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18260132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.31862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18260132">Kimonis et al. (2008)</a> reported detailed clinical features of 49 patients from 9 families with IBMPFD confirmed by genetic analysis. One family had been previously reported by <a href="#16" class="mim-tip-reference" title="Tucker, W. S., Jr., Hubbard, W. H., Stryker, T. D., Morgan, S. W., Evans, O. B., Freemon, F. R., Theil, G. B. <strong>A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization.</strong> Trans. Assoc. Am. Phys. 95: 126-134, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7182974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7182974</a>]" pmid="7182974">Tucker et al. (1982)</a>. Forty-two (86%) patients had muscle disease, the majority of whom were initially misdiagnosed as having some other form of muscular dystrophy or spinal muscular atrophy. Weakness was distal and/or proximal, and many patients were confined to wheelchairs. Muscle biopsies showed inclusion bodies and/or rimmed vacuoles (39%) or nonspecific changes. Frontotemporal dementia was diagnosed in 13 (27%) of 49 individuals at a mean age of 57 years, of whom 3 had been originally diagnosed with Alzheimer disease (<a href="/entry/104300">104300</a>). Paget disease of bone was found in 28 (57%) of 49 patients at a mean age of 40 years and correlated with increased serum alkaline phosphatase. <a href="#9" class="mim-tip-reference" title="Kimonis, V. E., Mehta, S. G., Fulchiero, E. C., Thomasova, D., Pasquali, M., Boycott, K., Nielan, E. G., Kartashov, A., Forman, M. S., Tucker, S., Kimonis, K., Mumm, S., Whyte, M. P., Smith, C. D., Watts, G. D. J. <strong>Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.</strong> Am. J. Med. Genet. 146A: 745-757, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18260132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18260132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18260132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.31862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18260132">Kimonis et al. (2008)</a> postulated that IBMPFD is underdiagnosed among patients with myopathy and/or dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18260132+7182974" 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="Viassolo, V., Previtali, S. C., Schiatti, E., Magnani, G., Minetti, C., Zara, F., Grasso, M., Dagna-Bricarelli, F., Di Maria, E. <strong>Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling.</strong> Clin. Genet. 74: 54-60, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18341608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18341608</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00984.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18341608">Viassolo et al. (2008)</a> reported an Italian family in which 2 sibs and their mother had IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. Genetic analysis identified a heterozygous mutation in the VCP gene (R155H; <a href="/entry/601023#0001">601023.0001</a>). Several other family members were reportedly affected. <a href="#18" class="mim-tip-reference" title="Viassolo, V., Previtali, S. C., Schiatti, E., Magnani, G., Minetti, C., Zara, F., Grasso, M., Dagna-Bricarelli, F., Di Maria, E. <strong>Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling.</strong> Clin. Genet. 74: 54-60, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18341608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18341608</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00984.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18341608">Viassolo et al. (2008)</a> discussed the implications of the incomplete penetrance of some of the features for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18341608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Kim, E.-J., Park, Y.-E., Kim, D.-S., Ahn, B.-Y., Kim, H.-S., Chang, Y. H., Kim, S.-J,, Kim, H.-J., Lee, H.-W., Seeley, W. W., Kim, S. <strong>Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family.</strong> Arch. Neurol. 68: 787-796, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21320982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21320982</a>] [<a href="https://doi.org/10.1001/archneurol.2010.376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21320982">Kim et al. (2011)</a> reported 3 Korean sibs with IBMPFD confirmed by genetic analysis (<a href="/entry/601023#0002">601023.0002</a>). The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21320982" 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="Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau, P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C. <strong>Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.</strong> J. Med. Genet. 49: 41-46, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21984748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21984748</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21984748">Sacconi et al. (2012)</a> reported 2 unrelated men in their fifties who presented with a phenotype reminiscent of FSHD1 (<a href="/entry/158900">158900</a>) but were found to carry a heterozygous VCP mutation (R191Q; <a href="/entry/601023#0006">601023.0006</a>). One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. Both had a myopathic pattern on EMG. One was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21984748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Abrahao, A., Abath Neto, O., Kok, F., Zanoteli, E., Santos, B., de Rezende Pinto, W. B. V., Barsottini, O. G. P., Oliveira, A. S. B., Pedroso, J. L. <strong>One family, one gene and three phenotypes: a novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.</strong> J. Neurol. Sci. 368: 352-358, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27538664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27538664</a>] [<a href="https://doi.org/10.1016/j.jns.2016.07.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27538664">Abrahao et al. (2016)</a> reported a Brazilian family in which 2 brothers and their father had different clinical manifestations of VCP-related neurologic disease. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of IBMPFD1, but without Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant ALS without signs of Paget disease or frontotemporal dementia, and their father presented at age 66 with behavioral variant frontotemporal dementia without signs of myopathy, Paget disease, or ALS (see <a href="/entry/613954">613954</a>). The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27538664" 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>
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<a href="#15" class="mim-tip-reference" title="Schroder, R., Watts, G. D. J., Mehta, S. G., Evert, B. O., Broich, P., Fliessbach, K., Pauls, K., Hans, V. H., Kimonis, V., Thal, D. R. <strong>Mutant valosin-containing protein causes a novel type of frontotemporal dementia.</strong> Ann. Neurol. 57: 457-461, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732117</a>] [<a href="https://doi.org/10.1002/ana.20407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732117">Schroder et al. (2005)</a> reported a patient with frontotemporal dementia (FTD) and inclusion body myopathy caused by mutation in the VCP gene (<a href="/entry/601023#0002">601023.0002</a>). There was no evidence of Paget disease. Neuropathologic examination showed cortical atrophy and widespread neuronal loss; subcortical neuronal loss was less severe. The cerebral and cerebellar white matter had severe astrogliosis. Surviving cortical pyramidal neurons contained VCP- and ubiquitin (see <a href="/entry/191321">191321</a>)-positive intranuclear inclusions and displayed cytoplasmic autofluorescence consistent with lipofuscin. Nuclear inclusions were not seen in astrocytes, oligodendrocytes, or microglial cells. Western blot analysis showed a single 97-kD band corresponding to normal-sized VCP that was similar to control brains. <a href="#15" class="mim-tip-reference" title="Schroder, R., Watts, G. D. J., Mehta, S. G., Evert, B. O., Broich, P., Fliessbach, K., Pauls, K., Hans, V. H., Kimonis, V., Thal, D. R. <strong>Mutant valosin-containing protein causes a novel type of frontotemporal dementia.</strong> Ann. Neurol. 57: 457-461, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732117</a>] [<a href="https://doi.org/10.1002/ana.20407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732117">Schroder et al. (2005)</a> concluded that mutant VCP causes a novel form of frontotemporal dementia, distinct from tau (MAPT; <a href="/entry/157140">157140</a>)-associated FTD (see <a href="/entry/600274">600274</a>), characterized by neuronal nuclear inclusions containing ubiquitin and VCP. The authors suggested that mutant VCP interferes with ubiquitin-dependent pathways, leading to abnormal intracellular and intranuclear protein aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732117" 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 IBMPFD1 in the families reported by <a href="#9" class="mim-tip-reference" title="Kimonis, V. E., Mehta, S. G., Fulchiero, E. C., Thomasova, D., Pasquali, M., Boycott, K., Nielan, E. G., Kartashov, A., Forman, M. S., Tucker, S., Kimonis, K., Mumm, S., Whyte, M. P., Smith, C. D., Watts, G. D. J. <strong>Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.</strong> Am. J. Med. Genet. 146A: 745-757, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18260132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18260132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18260132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.31862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18260132">Kimonis et al. (2008)</a> was consistent with autosomal dominant inheritance with variable expressivity and incomplete penetrance of some features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18260132" 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 a family with autosomal dominant LGMD associated with early-onset PDB and cardiomyopathy, <a href="#8" class="mim-tip-reference" title="Kimonis, V. E., Kovach, M. J., Waggoner, B., Leal, S., Salam, A., Rimer, L., Davis, K., Khardori, R., Gelber, D. <strong>Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone.</strong> Genet. Med. 2: 232-241, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11252708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11252708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11252708[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/00125817-200007000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11252708">Kimonis et al. (2000)</a> excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci. They argued that their linkage analysis data indicated a unique locus in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11252708" 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="#11" class="mim-tip-reference" title="Kovach, M. J., Waggoner, B., Leal, S. M., Gelber, D., Khardori, R., Levenstien, M. A., Shanks, C. A., Gregg, G., Al-Lozi, M. T., Miller, T., Rakowica, W., Lopate, G., Florence, J., Glosser, G., Simmons, Z., Morris, J. C., Whyte, M. P., Pestronk, A., Kimonis, V. E. <strong>Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.</strong> Molec. Genet. Metab. 74: 458-475, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11749051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11749051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11749051[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1006/mgme.2001.3256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11749051">Kovach et al. (2001)</a> localized autosomal dominant IBM with PDB and frontotemporal dementia to a 1.08- to 6.46-cM critical interval on 9p13.3-p12. The maximum lod score generated from the combined genotype data was 9.29 for marker D91791. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11749051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#19" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> performed haplotype analysis of 13 families with IBMPFD and identified 2 ancestral disease-associated haplotypes, distinguishing families 1, 3, 7, and 16 (group A) from families 2 and 5 (group B). Both groups were of northern European ancestry. The predominant IBMPFD haplotype of group A includes a core haplotype flanked by D9S1118 and D9S234, probably transmitted from a shared ancestor. <a href="#19" class="mim-tip-reference" title="Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E. <strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong> Nature Genet. 36: 377-381, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>] [<a href="https://doi.org/10.1038/ng1332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034582">Watts et al. (2004)</a> identified 6 missense mutations in the valosin-containing protein (VCP; <a href="/entry/601023">601023</a>) in these families. Families 1, 3, 4, 7, 10, 15, and 16 shared the R155H mutation in exon 5 (<a href="/entry/601023#0001">601023.0001</a>); families 2 and 5 had an R155C mutation (<a href="/entry/601023#0002">601023.0002</a>); and family 11 had an R155P mutation (<a href="/entry/601023#0005">601023.0005</a>). Thus, 10 of the 13 families with IBMPFD had an amino acid change at codon 155 in VCP, which therefore seems to be a mutation hotspot. In addition, 1 family had a missense mutation at codon 232 (<a href="/entry/601023#0003">601023.0003</a>), another at codon 95 (<a href="/entry/601023#0004">601023.0004</a>), and another at codon 191 (<a href="/entry/601023#0006">601023.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, <a href="#1" class="mim-tip-reference" title="Abrahao, A., Abath Neto, O., Kok, F., Zanoteli, E., Santos, B., de Rezende Pinto, W. B. V., Barsottini, O. G. P., Oliveira, A. S. B., Pedroso, J. L. <strong>One family, one gene and three phenotypes: a novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.</strong> J. Neurol. Sci. 368: 352-358, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27538664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27538664</a>] [<a href="https://doi.org/10.1016/j.jns.2016.07.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27538664">Abrahao et al. (2016)</a> identified a heterozygous missense mutation in exon 3 of the VCP gene (N91Y; <a href="/entry/601023#0012">601023.0012</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband had features of IBMPFD1 without Paget disease or FTD, his brother had features of ALS without Paget disease or FTD, and their father had isolated behavioral variant FTD without features of myopathy, Paget disease, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27538664" 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="De Ridder, W., Azmi, A., Clemen, C. S., Eichinger, L., Hofmann, A., Schroder, R., Johnson, K., Topf, A., Straub, V., DeJonghe, P., Maudsley, S., De Bleecker, J. L., Baets, J. <strong>Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: a tale of the unexpected.</strong> Neurology 94: e785-e796, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31848255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31848255</a>] [<a href="https://doi.org/10.1212/WNL.0000000000008763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31848255">De Ridder et al. (2020)</a> reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene (<a href="/entry/601023#0007">601023.0007</a>). His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response. The findings indicated that homozygosity for this VCP mutation is viable and that the key features of the disorder are still present, although the overall phenotype may be more severe with earlier onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31848255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Mehta, S. G., Khare, M., Ramani, R., Watts, G. D. J., Simon, M., Osann, K. E., Donkervoort, S., Dec, E., Nalbandian, A., Platt, J., Pasquali, M., Wang, A., Mozaffar, T., Smith, C. D., Kimonis, V. E. <strong>Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.</strong> Clin. Genet. 83: 422-431, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22909335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22909335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22909335[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.12000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22909335">Mehta et al. (2013)</a> analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation. A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22909335" 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="Al-Obeidi, E., Al-Tahan, S., Surampalli, A., Goyal, N., Wang, A. K., Hermann, A., Omizo, M., Smith, C., Mozaffar, T., Kimonis, V. <strong>Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.</strong> Clin. Genet. 93: 119-125, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28692196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28692196</a>] [<a href="https://doi.org/10.1111/cge.13095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28692196">Al-Obeidi et al. (2018)</a> studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had the 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28692196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#20" class="mim-tip-reference" title="Weihl, C. C., Miller, S. E., Hanson, P. I., Pestronk, A. <strong>Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice.</strong> Hum. Molec. Genet. 16: 919-928, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17329348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17329348</a>] [<a href="https://doi.org/10.1093/hmg/ddm037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17329348">Weihl et al. (2007)</a> found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 (CAV3; <a href="/entry/601253">601253</a>) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17329348" 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="Custer, S. K., Neumann, M., Lu, H., Wright, A. C., Taylor, J. P. <strong>Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.</strong> Hum. Molec. Genet. 19: 1741-1755, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147319</a>] [<a href="https://doi.org/10.1093/hmg/ddq050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20147319">Custer et al. (2010)</a> developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (<a href="/entry/601023#0001">601023.0001</a>) or A232E (<a href="/entry/601023#0003">601023.0003</a>) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 pathology. The brain showed widespread TDP43 (<a href="/entry/605078">605078</a>) pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see <a href="/entry/164011">164011</a>) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1111/cge.13095" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000001864" target="_blank">Full Text</a>]
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Custer, S. K., Neumann, M., Lu, H., Wright, A. C., Taylor, J. P.
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<strong>Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.</strong>
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Hum. Molec. Genet. 19: 1741-1755, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20147319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20147319</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20147319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq050" target="_blank">Full Text</a>]
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De Ridder, W., Azmi, A., Clemen, C. S., Eichinger, L., Hofmann, A., Schroder, R., Johnson, K., Topf, A., Straub, V., DeJonghe, P., Maudsley, S., De Bleecker, J. L., Baets, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31848255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31848255</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31848255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000008763" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000180407.15369.92" target="_blank">Full Text</a>]
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Kim, E.-J., Park, Y.-E., Kim, D.-S., Ahn, B.-Y., Kim, H.-S., Chang, Y. H., Kim, S.-J,, Kim, H.-J., Lee, H.-W., Seeley, W. W., Kim, S.
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[<a href="https://doi.org/10.1001/archneurol.2010.376" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00125817-200007000-00006" target="_blank">Full Text</a>]
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<a id="Kimonis2008" class="mim-anchor"></a>
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Kimonis, V. E., Mehta, S. G., Fulchiero, E. C., Thomasova, D., Pasquali, M., Boycott, K., Nielan, E. G., Kartashov, A., Forman, M. S., Tucker, S., Kimonis, K., Mumm, S., Whyte, M. P., Smith, C. D., Watts, G. D. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18260132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18260132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18260132[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=18260132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31862" target="_blank">Full Text</a>]
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<a id="Kimonis2005" class="mim-anchor"></a>
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<div class="">
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Kimonis, V. E.
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<strong>Personal Communication.</strong>
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Boston, Mass. 1/12/2005.
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<a id="Kovach2001" class="mim-anchor"></a>
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Kovach, M. J., Waggoner, B., Leal, S. M., Gelber, D., Khardori, R., Levenstien, M. A., Shanks, C. A., Gregg, G., Al-Lozi, M. T., Miller, T., Rakowica, W., Lopate, G., Florence, J., Glosser, G., Simmons, Z., Morris, J. C., Whyte, M. P., Pestronk, A., Kimonis, V. E.
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<strong>Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.</strong>
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Molec. Genet. Metab. 74: 458-475, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11749051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11749051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11749051[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=11749051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/mgme.2001.3256" target="_blank">Full Text</a>]
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<a id="Mackenzie2010" class="mim-anchor"></a>
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Mackenzie, I. R. A., Neumann, M., Bigio, E. H., Cairns, N. J., Alafuzoff, I., Kril, J., Kovacs, G. G., Ghetti, B., Halliday, G., Holm, I. E., Ince, P. G., Kamphorst, W., and 9 others.
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<strong>Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update.</strong>
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Acta Neuropath. 119: 1-4, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19924424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19924424</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19924424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00401-009-0612-2" target="_blank">Full Text</a>]
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<a id="Mehta2013" class="mim-anchor"></a>
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Mehta, S. G., Khare, M., Ramani, R., Watts, G. D. J., Simon, M., Osann, K. E., Donkervoort, S., Dec, E., Nalbandian, A., Platt, J., Pasquali, M., Wang, A., Mozaffar, T., Smith, C. D., Kimonis, V. E.
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<strong>Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.</strong>
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Clin. Genet. 83: 422-431, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22909335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22909335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22909335[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=22909335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.12000" target="_blank">Full Text</a>]
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</p>
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<a id="14" class="mim-anchor"></a>
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<a id="Sacconi2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau, P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C.
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<strong>Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.</strong>
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J. Med. Genet. 49: 41-46, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21984748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21984748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21984748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100101" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Schroder2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schroder, R., Watts, G. D. J., Mehta, S. G., Evert, B. O., Broich, P., Fliessbach, K., Pauls, K., Hans, V. H., Kimonis, V., Thal, D. R.
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<strong>Mutant valosin-containing protein causes a novel type of frontotemporal dementia.</strong>
|
|
Ann. Neurol. 57: 457-461, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732117</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20407" target="_blank">Full Text</a>]
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Tucker1982" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tucker, W. S., Jr., Hubbard, W. H., Stryker, T. D., Morgan, S. W., Evans, O. B., Freemon, F. R., Theil, G. B.
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<strong>A new familial disorder of combined lower motor neuron degeneration and skeletal disorganization.</strong>
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Trans. Assoc. Am. Phys. 95: 126-134, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7182974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7182974</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7182974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<a id="17" class="mim-anchor"></a>
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<a id="van der Zee2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Zee, J., Pirici, D., Van Langenhove, T., Engelborghs, S., Vandenberghe, R., Hoffmann, M., Pusswald, G., Van den Broeck, M., Peeters, K., Mattheijssens, M., Martin, J.-J., De Deyn, P. P., Cruts, M., Haubenberger, D., Kumar-Singh, S., Zimprich, A., Van Broeckhoven, C.
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<strong>Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.</strong>
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Neurology 73: 626-632, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19704082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19704082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19704082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181b389d9" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Viassolo2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Viassolo, V., Previtali, S. C., Schiatti, E., Magnani, G., Minetti, C., Zara, F., Grasso, M., Dagna-Bricarelli, F., Di Maria, E.
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<strong>Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling.</strong>
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Clin. Genet. 74: 54-60, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18341608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18341608</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18341608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2008.00984.x" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Watts2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., Kimonis, V. E.
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<strong>Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.</strong>
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Nature Genet. 36: 377-381, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034582</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1332" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Weihl2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weihl, C. C., Miller, S. E., Hanson, P. I., Pestronk, A.
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<strong>Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice.</strong>
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Hum. Molec. Genet. 16: 919-928, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17329348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17329348</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17329348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm037" target="_blank">Full Text</a>]
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Weihl2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weihl, C. C., Pestronk, A., Kimonis, V. E.
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<strong>Valosin-containing protein disease: Inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia.</strong>
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Neuromusc. Disord. 19: 308-315, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19380227[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=19380227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2009.01.009" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/17/2020
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/17/2013<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 12/8/2011<br>George E. Tiller - updated : 12/1/2011<br>Cassandra L. Kniffin - updated : 3/8/2011<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Cassandra L. Kniffin - updated : 10/29/2009<br>Cassandra L. Kniffin - updated : 4/23/2009<br>Cassandra L. Kniffin - updated : 3/24/2008<br>Cassandra L. Kniffin - updated : 2/5/2007<br>Cassandra L. Kniffin - updated : 5/18/2005
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/09/2022
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/23/2020<br>carol : 12/22/2020<br>ckniffin : 12/17/2020<br>carol : 10/20/2017<br>alopez : 11/15/2016<br>ckniffin : 10/25/2016<br>carol : 08/23/2016<br>carol : 06/30/2015<br>carol : 2/2/2015<br>carol : 6/25/2014<br>carol : 12/19/2013<br>mcolton : 12/18/2013<br>ckniffin : 12/17/2013<br>alopez : 10/18/2013<br>alopez : 9/25/2013<br>alopez : 9/24/2013<br>alopez : 9/24/2013<br>carol : 4/26/2012<br>ckniffin : 4/25/2012<br>carol : 12/16/2011<br>ckniffin : 12/8/2011<br>alopez : 12/5/2011<br>terry : 12/1/2011<br>carol : 9/16/2011<br>carol : 6/1/2011<br>wwang : 5/18/2011<br>ckniffin : 5/5/2011<br>wwang : 3/11/2011<br>ckniffin : 3/8/2011<br>wwang : 1/14/2010<br>ckniffin : 12/21/2009<br>ckniffin : 12/21/2009<br>terry : 12/1/2009<br>wwang : 11/5/2009<br>ckniffin : 10/29/2009<br>wwang : 5/13/2009<br>ckniffin : 4/23/2009<br>wwang : 4/3/2008<br>ckniffin : 3/24/2008<br>terry : 1/4/2008<br>carol : 5/10/2007<br>wwang : 2/9/2007<br>ckniffin : 2/5/2007<br>wwang : 5/27/2005<br>ckniffin : 5/18/2005<br>carol : 1/13/2005<br>mimadm : 1/14/1995<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>reenie : 6/2/1986
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 167320
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1; IBMPFD1
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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MULTISYSTEM PROTEINOPATHY 1; MSP1<br />
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, WITH PAGET DISEASE OF BONE<br />
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PAGETOID AMYOTROPHIC LATERAL SCLEROSIS<br />
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PAGETOID NEUROSKELETAL SYNDROME<br />
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LOWER MOTOR NEURON DEGENERATION WITH PAGET-LIKE BONE DISEASE
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 703544004;
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<strong>ORPHA:</strong> 52430;
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<strong>DO:</strong> 0111385;
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</tr>
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</thead>
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<tbody>
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<td>
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<span class="mim-font">
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9p13.3
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</td>
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<td>
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<span class="mim-font">
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Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1
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167320
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Autosomal dominant
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3
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VCP
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601023
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that inclusion body myopathy with Paget disease and frontotemporal dementia-1 (IBMPFD1) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13.</p><p>Heterozygous mutation in the VCP gene can also cause frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954), which can show overlapping clinical features.</p>
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<strong>Description</strong>
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<p>IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009). </p><p><strong><em>Genetic Heterogeneity of IBMPFD</em></strong></p><p>
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IBMPFD2 (615422) is caused by mutation in the HNRNPA2B1 gene (600124) on chromosome 7p15. IBMPFD3 (615424) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13.</p>
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<strong>Nomenclature</strong>
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<p>IBMPFD may also be referred to as FTLD-TDP (or TDP43), VCP-related, based on neuropathologic findings (MacKenzie et al., 2010). </p><p>Bucelli et al. (2015) suggested use of the designation multisystem proteinopathy (MSP) for a group of genetic disorders clinically characterized by variable penetrance of FTD, ALS, Paget disease, and myopathy, which are unified by the pathologic accumulation of ubiquitin and TDP43; see 617158. </p>
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<strong>Clinical Features</strong>
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<p>Tucker et al. (1982) studied a large kindred with a syndrome of lower motor neuron degeneration and polyostotic skeletal disorganization resembling Paget disease of bone (PDB; see 167250). The disorder begins insidiously at about age 35 with weakness and atrophy of the leg and proximal arm muscles. Nerve conductions are normal; EMG shows muscle denervation, as does muscle biopsy. The disorder progresses to wheelchair confinement and later to bed confinement, quadriparesis, dementia, respiratory failure, and death before age 60 years. Even early in the neurologic illness, patients have coarse trabeculation, cortical thickening, and spotty sclerosis on bone x-rays; diffusely increased uptake of radionuclide and elevated heat-labile serum alkaline phosphatase. The disorder affected 6 females and 6 males in 5 sibships of 3 generations with no instance of male-to-male transmission. </p><p>Kimonis et al. (2000) described a family in which autosomal dominant limb-girdle muscular dystrophy (LGMD) was associated with early-onset Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected individuals had both disorders. Onset of PDB occurred at a mean age of 35 years, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy was progressive with mildly elevated to normal CPK levels. Muscle biopsy in the oldest male revealed vacuolated fibers, but in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness and respiratory and cardiac failure in their forties to sixties. </p><p>Kovach et al. (2001) described the clinical, biochemical, radiologic, and pathologic characteristics of 49 affected individuals from the family described by Kimonis et al. (2000) and 3 other unrelated families with autosomal dominant inclusion body myopathy (IBM), PDB, and frontotemporal dementia. Ninety percent of the patients had myopathy, 43% had PDB, and 37% had premature frontotemporal dementia. </p><p>Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S. and 1 from Canada. Among those individuals, 82% of affected individuals had myopathy, 49% had PDB, and 30% had early-onset frontotemporal dementia. The mean age at presentation was 42 years for both IBM and PDB, whereas frontotemporal dementia typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathologic pathway. Family 11 in the report by Watts et al. (2004) was originally reported by Tucker et al. (1982) (Kimonis, 2005). </p><p>Haubenberger et al. (2005) reported an Austrian family in which 4 sibs had autosomal dominant inclusion body myopathy and Paget disease associated with a heterozygous mutation in the VCP gene (R159H; 601023.0007). None of the affected individuals developed frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation. </p><p>Kimonis et al. (2008) reported detailed clinical features of 49 patients from 9 families with IBMPFD confirmed by genetic analysis. One family had been previously reported by Tucker et al. (1982). Forty-two (86%) patients had muscle disease, the majority of whom were initially misdiagnosed as having some other form of muscular dystrophy or spinal muscular atrophy. Weakness was distal and/or proximal, and many patients were confined to wheelchairs. Muscle biopsies showed inclusion bodies and/or rimmed vacuoles (39%) or nonspecific changes. Frontotemporal dementia was diagnosed in 13 (27%) of 49 individuals at a mean age of 57 years, of whom 3 had been originally diagnosed with Alzheimer disease (104300). Paget disease of bone was found in 28 (57%) of 49 patients at a mean age of 40 years and correlated with increased serum alkaline phosphatase. Kimonis et al. (2008) postulated that IBMPFD is underdiagnosed among patients with myopathy and/or dementia. </p><p>Viassolo et al. (2008) reported an Italian family in which 2 sibs and their mother had IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. Genetic analysis identified a heterozygous mutation in the VCP gene (R155H; 601023.0001). Several other family members were reportedly affected. Viassolo et al. (2008) discussed the implications of the incomplete penetrance of some of the features for genetic counseling. </p><p>Kim et al. (2011) reported 3 Korean sibs with IBMPFD confirmed by genetic analysis (601023.0002). The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia. </p><p>Sacconi et al. (2012) reported 2 unrelated men in their fifties who presented with a phenotype reminiscent of FSHD1 (158900) but were found to carry a heterozygous VCP mutation (R191Q; 601023.0006). One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. Both had a myopathic pattern on EMG. One was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Abrahao et al. (2016) reported a Brazilian family in which 2 brothers and their father had different clinical manifestations of VCP-related neurologic disease. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of IBMPFD1, but without Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant ALS without signs of Paget disease or frontotemporal dementia, and their father presented at age 66 with behavioral variant frontotemporal dementia without signs of myopathy, Paget disease, or ALS (see 613954). The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. </p><p><strong><em>Neuropathologic Findings</em></strong></p><p>
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Schroder et al. (2005) reported a patient with frontotemporal dementia (FTD) and inclusion body myopathy caused by mutation in the VCP gene (601023.0002). There was no evidence of Paget disease. Neuropathologic examination showed cortical atrophy and widespread neuronal loss; subcortical neuronal loss was less severe. The cerebral and cerebellar white matter had severe astrogliosis. Surviving cortical pyramidal neurons contained VCP- and ubiquitin (see 191321)-positive intranuclear inclusions and displayed cytoplasmic autofluorescence consistent with lipofuscin. Nuclear inclusions were not seen in astrocytes, oligodendrocytes, or microglial cells. Western blot analysis showed a single 97-kD band corresponding to normal-sized VCP that was similar to control brains. Schroder et al. (2005) concluded that mutant VCP causes a novel form of frontotemporal dementia, distinct from tau (MAPT; 157140)-associated FTD (see 600274), characterized by neuronal nuclear inclusions containing ubiquitin and VCP. The authors suggested that mutant VCP interferes with ubiquitin-dependent pathways, leading to abnormal intracellular and intranuclear protein aggregation. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of IBMPFD1 in the families reported by Kimonis et al. (2008) was consistent with autosomal dominant inheritance with variable expressivity and incomplete penetrance of some features. </p>
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<strong>Mapping</strong>
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<p>In a family with autosomal dominant LGMD associated with early-onset PDB and cardiomyopathy, Kimonis et al. (2000) excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci. They argued that their linkage analysis data indicated a unique locus in this family. </p><p>By linkage analysis, Kovach et al. (2001) localized autosomal dominant IBM with PDB and frontotemporal dementia to a 1.08- to 6.46-cM critical interval on 9p13.3-p12. The maximum lod score generated from the combined genotype data was 9.29 for marker D91791. </p>
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<strong>Molecular Genetics</strong>
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<p>Watts et al. (2004) performed haplotype analysis of 13 families with IBMPFD and identified 2 ancestral disease-associated haplotypes, distinguishing families 1, 3, 7, and 16 (group A) from families 2 and 5 (group B). Both groups were of northern European ancestry. The predominant IBMPFD haplotype of group A includes a core haplotype flanked by D9S1118 and D9S234, probably transmitted from a shared ancestor. Watts et al. (2004) identified 6 missense mutations in the valosin-containing protein (VCP; 601023) in these families. Families 1, 3, 4, 7, 10, 15, and 16 shared the R155H mutation in exon 5 (601023.0001); families 2 and 5 had an R155C mutation (601023.0002); and family 11 had an R155P mutation (601023.0005). Thus, 10 of the 13 families with IBMPFD had an amino acid change at codon 155 in VCP, which therefore seems to be a mutation hotspot. In addition, 1 family had a missense mutation at codon 232 (601023.0003), another at codon 95 (601023.0004), and another at codon 191 (601023.0006). </p><p>In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous missense mutation in exon 3 of the VCP gene (N91Y; 601023.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband had features of IBMPFD1 without Paget disease or FTD, his brother had features of ALS without Paget disease or FTD, and their father had isolated behavioral variant FTD without features of myopathy, Paget disease, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. </p><p>De Ridder et al. (2020) reported a 36-year-old Belgian man with onset of IBMPFD1 at age 29 years who carried a homozygous R159H mutation in the VCP gene (601023.0007). His 63-year-old father, who carried the mutation in heterozygous state, had a similar myopathic phenotype with later onset at age 58. His 60-year-old mother, who was also heterozygous for the mutation, was clinically unaffected. The proband presented with progressive proximal muscle weakness with possible neurogenic features and high serum creatine kinase; an asymptomatic Paget bone lesion was later identified. Neither patient had dementia. Functional studies of the variant were not performed, but proteomic analysis of skeletal muscle from the proband and his father, as well as from 3 additional patients with VCP-related myopathy, showed changes in upstream regulators involved in myogenesis, muscle regeneration, oxidative stress, endoplasmic reticulum stress, stress granules, and the unfolded protein response. The findings indicated that homozygosity for this VCP mutation is viable and that the key features of the disorder are still present, although the overall phenotype may be more severe with earlier onset. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Mehta et al. (2013) analyzed clinical and biochemical markers from a database of 190 individuals from 27 families harboring 10 missense mutations in the VCP gene. Among these, 145 mutation carriers were symptomatic and 45 were presymptomatic. The most common clinical feature (in 91% of patients) was onset of myopathic weakness at a mean age of 43 years. Paget disease of the bone was found in 52% of patients at a mean age of 41 years. Frontotemporal dementia occurred in 30% of patients at a mean age of 55 years. Significant genotype-phenotype correlations were difficult to establish because of small numbers. However, patients with the R155C mutation had a more severe phenotype with an earlier onset of myopathy and Paget disease, as well as decreased survival, compared to those with the R155H mutation. A diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27 families, including 10 patients with the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson disease. </p><p>Al-Obeidi et al. (2018) studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had the 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families. </p>
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<p>Weihl et al. (2007) found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation. </p><p>Custer et al. (2010) developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (601023.0001) or A232E (601023.0003) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 pathology. The brain showed widespread TDP43 (605078) pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see 164011) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain. </p>
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<strong>REFERENCES</strong>
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Abrahao, A., Abath Neto, O., Kok, F., Zanoteli, E., Santos, B., de Rezende Pinto, W. B. V., Barsottini, O. G. P., Oliveira, A. S. B., Pedroso, J. L.
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<strong>One family, one gene and three phenotypes: a novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.</strong>
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J. Neurol. Sci. 368: 352-358, 2016.
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[PubMed: 27538664]
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[Full Text: https://doi.org/10.1016/j.jns.2016.07.048]
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Al-Obeidi, E., Al-Tahan, S., Surampalli, A., Goyal, N., Wang, A. K., Hermann, A., Omizo, M., Smith, C., Mozaffar, T., Kimonis, V.
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<strong>Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.</strong>
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Clin. Genet. 93: 119-125, 2018.
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[PubMed: 28692196]
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[Full Text: https://doi.org/10.1111/cge.13095]
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Bucelli, R. C., Arhzaouy, K., Pestronk, A., Pittman, S. K., Rojas, L., Sue, C. M., Evila, A., Hackman, P., Udd, B., Harms, M. B., Weihl, C. C.
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<strong>SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles.</strong>
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Neurology 85: 665-674, 2015.
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[PubMed: 26208961]
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[Full Text: https://doi.org/10.1212/WNL.0000000000001864]
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Custer, S. K., Neumann, M., Lu, H., Wright, A. C., Taylor, J. P.
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<strong>Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone.</strong>
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Hum. Molec. Genet. 19: 1741-1755, 2010.
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[PubMed: 20147319]
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[Full Text: https://doi.org/10.1093/hmg/ddq050]
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De Ridder, W., Azmi, A., Clemen, C. S., Eichinger, L., Hofmann, A., Schroder, R., Johnson, K., Topf, A., Straub, V., DeJonghe, P., Maudsley, S., De Bleecker, J. L., Baets, J.
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<strong>Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation: a tale of the unexpected.</strong>
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Neurology 94: e785-e796, 2020. Note: Electronic Article.
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[PubMed: 31848255]
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[Full Text: https://doi.org/10.1212/WNL.0000000000008763]
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