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Entry
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- #603689 - MYOPATHY, MYOFIBRILLAR, 9, WITH EARLY RESPIRATORY FAILURE; MFM9
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- OMIM
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<p>
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<span class="h4">#603689</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/603689"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS601419"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<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="#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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<li role="presentation">
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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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</h4>
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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 style="display: table-row">
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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</span>
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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=MYOPATHY, MYOFIBRILLAR, 9, WITH EARLY RESPIRATORY FAILURE" 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=18027&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/NBK185330/" 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/8524" 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://medlineplus.gov/genetics/condition/hereditary-myopathy-with-early-respiratory-failure" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603689[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=178464" 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="panel-title">
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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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</div>
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</a>
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</span>
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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:0111188" 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/603689" 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://omia.org/OMIA002330/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0111188" 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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<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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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 702373006<br />
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<strong>ORPHA:</strong> 178464<br />
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<strong>DO:</strong> 0111188<br />
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">ICD+</a>
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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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603689
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</span>
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</span>
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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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MYOPATHY, MYOFIBRILLAR, 9, WITH EARLY RESPIRATORY FAILURE; MFM9
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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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HEREDITARY MYOPATHY WITH EARLY RESPIRATORY FAILURE; HMERF<br />
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MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT; MPRM<br />
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EDSTROM MYOPATHY<br />
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MYOPATHY, DISTAL, WITH EARLY RESPIRATORY FAILURE, AUTOSOMAL DOMINANT
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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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<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">
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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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<td>
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<span class="mim-font">
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<a href="/geneMap/2/823?start=-3&limit=10&highlight=823">
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2q31.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Myopathy, myofibrillar, 9, with early respiratory failure
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603689"> 603689 </a>
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</span>
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</td>
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<td>
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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>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
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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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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
TTN
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188840"> 188840 </a>
|
|
</span>
|
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</td>
|
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</tr>
|
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</tbody>
|
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</table>
|
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</div>
|
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</div>
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<div>
|
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|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/603689" 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>
|
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|
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<div class="btn-group">
|
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|
|
<a href="/phenotypicSeries/PS601419" 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>
|
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<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/603689" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603689" 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>
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|
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<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
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|
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<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> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cardiac involvement (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194360&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194360</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Early respiratory failure <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807376&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807376</a>]</span><br /> -
|
|
Decreased vital capacity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/607007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">607007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520831&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520831</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002792" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002792</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002792" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002792</a>]</span><br /> -
|
|
Nocturnal hypoventilation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843643&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843643</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002877" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002877</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002877" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002877</a>]</span><br />
|
|
|
|
</span>
|
|
</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> Diaphragm </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Diaphragmatic weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95438009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95438009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0521532&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521532</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009113" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009113</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009113" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009113</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">
|
|
|
|
- Myofibrillar myopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/699269005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">699269005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2678065&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2678065</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003715" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003715</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003715" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003715</a>]</span><br /> -
|
|
Muscle weakness, proximal, distal, axial <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194358</a>]</span><br /> -
|
|
Distal lower limb anterior compartment weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807696&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807696</a>]</span><br /> -
|
|
Foot drop, bilateral <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15638171000119103" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15638171000119103</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807697</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.37" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.37</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009027</a>]</span><br /> -
|
|
Lower limbs more affected than upper limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836052&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836052</a>]</span><br /> -
|
|
Frequent falls <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0850703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0850703</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002359" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002359</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002359" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002359</a>]</span><br /> -
|
|
Difficulty walking <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/719232003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">719232003</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/719.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">719.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0311394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0311394</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002355</a>]</span><br /> -
|
|
Quadriceps weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300948004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300948004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0577655&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0577655</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003731" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003731</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003731" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003731</a>]</span><br /> -
|
|
Pelvic girdle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249941003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249941003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427064&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427064</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003749" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003749</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003749" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003749</a>]</span><br /> -
|
|
Shoulder girdle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249940002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249940002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427063</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003547" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003547</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003547" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003547</a>]</span><br /> -
|
|
Neck flexion weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843637&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843637</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003722</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003722</a>]</span><br /> -
|
|
Calf hypertrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843057</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008981" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008981</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008981" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008981</a>]</span><br /> -
|
|
Myopathic changes seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3276190&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3276190</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/129565002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">129565002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G72.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G72.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M60-M63" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M60-M63</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/359.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">359.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003198</a>]</span><br /> -
|
|
Atrophy seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194359&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194359</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13331008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13331008</a>]</span><br /> -
|
|
Congophilic eosinophilic inclusions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807699</a>]</span><br /> -
|
|
Muscle fiber splitting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836057</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003555" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003555</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003555" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003555</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 /> -
|
|
Increased fat and fibrous tissue <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807701&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807701</a>]</span><br /> -
|
|
Increased fiber size variation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843700&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843700</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003557" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003557</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003557" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003557</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> LABORATORY ABNORMALITIES </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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|
|
- Increased creatine kinase, mild to moderate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843634&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843634</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432352001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432352001</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 />
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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> 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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|
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- Adult onset (range 20 to 70 years) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span><br /> -
|
|
Lower limb weakness is usually the presenting feature<br /> -
|
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Slowly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854494</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span><br /> -
|
|
Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
|
|
Clinical heterogeneity, even within families<br />
|
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|
|
</span>
|
|
</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> 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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|
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<div>
|
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<span class="mim-font">
|
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|
|
- Caused by mutation in the titin gene (TTN, <a href="/entry/188840#0011">188840.0011</a>)<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 class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
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<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Myopathy, myofibrillar
|
|
- <a href="/phenotypicSeries/PS601419">PS601419</a>
|
|
- 14 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/823?start=-3&limit=10&highlight=823"> 2q31.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603689"> Myopathy, myofibrillar, 9, with early respiratory failure </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603689"> 603689 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188840"> TTN </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/188840"> 188840 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/1040?start=-3&limit=10&highlight=1040"> 2q35 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601419"> Myopathy, myofibrillar, 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601419"> 601419 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/125660"> DES </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/125660"> 125660 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/702?start=-3&limit=10&highlight=702"> 3q22.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617114"> Myopathy, myofibrillar, 7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617114"> 617114 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605739"> KY </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605739"> 605739 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/497?start=-3&limit=10&highlight=497"> 5q31.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609200"> Myopathy, myofibrillar, 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609200"> 609200 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604103"> MYOT </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604103"> 604103 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
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<a href="/geneMap/7/659?start=-3&limit=10&highlight=659"> 7q32.1 </a>
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<a href="/entry/609524"> Myopathy, myofibrillar, 5 </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/609524"> 609524 </a>
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<a href="/entry/102565"> FLNC </a>
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<a href="/entry/102565"> 102565 </a>
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<a href="/geneMap/10/129?start=-3&limit=10&highlight=129"> 10p11.23 </a>
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<span class="mim-font">
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<a href="/entry/619040"> Myofibrillar myopathy 10 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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/619040"> 619040 </a>
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<a href="/entry/604126"> SVIL </a>
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<span class="mim-font">
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<a href="/entry/604126"> 604126 </a>
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<a href="/geneMap/10/355?start=-3&limit=10&highlight=355"> 10q23.2 </a>
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<span class="mim-font">
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<a href="/entry/609452"> Myopathy, myofibrillar, 4 </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/609452"> 609452 </a>
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<a href="/entry/605906"> LDB3 </a>
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<span class="mim-font">
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<a href="/entry/605906"> 605906 </a>
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<a href="/geneMap/10/613?start=-3&limit=10&highlight=613"> 10q26.11 </a>
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<span class="mim-font">
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<a href="/entry/612954"> Myopathy, myofibrillar, 6 </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/612954"> 612954 </a>
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<a href="/entry/603883"> BAG3 </a>
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<a href="/entry/603883"> 603883 </a>
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<a href="/geneMap/11/925?start=-3&limit=10&highlight=925"> 11q23.1 </a>
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<span class="mim-font">
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<a href="/entry/613869"> Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/613869"> 613869 </a>
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<a href="/entry/123590"> CRYAB </a>
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<span class="mim-font">
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<a href="/entry/123590"> 123590 </a>
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<a href="/geneMap/11/925?start=-3&limit=10&highlight=925"> 11q23.1 </a>
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<a href="/entry/608810"> Myopathy, myofibrillar, 2 </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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<a href="/entry/123590"> CRYAB </a>
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<a href="/entry/123590"> 123590 </a>
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<a href="/entry/617258"> Myopathy, myofibrillar, 8 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<a href="/entry/617220"> PYROXD1 </a>
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<a href="/entry/617220"> 617220 </a>
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<span class="mim-font">
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<a href="/entry/619424"> Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<a href="/entry/619424"> 619424 </a>
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<a href="/entry/160781"> MYL2 </a>
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<a href="/entry/160781"> 160781 </a>
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<a href="/geneMap/12/858?start=-3&limit=10&highlight=858"> 12q24.23 </a>
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<a href="/entry/621078"> Myopathy, myofibrillar, 13, with rimmed vacuoles </a>
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<a href="/entry/621078"> 621078 </a>
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<a href="/entry/608014"> HSPB8 </a>
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<a href="/entry/608014"> 608014 </a>
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<a href="/entry/619178"> Myofibrillar myopathy 11 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/619178"> 619178 </a>
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<a href="/entry/611220"> 611220 </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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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that myofibrillar myopathy-9 with early respiratory failure (MFM9) is caused by heterozygous mutation in the protein kinase domain of titin (TTN; <a href="/entry/188840">188840</a>) on chromosome 2q31.</p>
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<p>Myofibrillar myopathy-9 with early respiratory failure (MFM9) is an autosomal dominant muscle disorder characterized by adult onset of slowly progressive muscle weakness with diaphragmatic involvement causing respiratory insufficiency. Patients present between 20 and 70 years of age with distal or proximal muscle weakness, mainly affecting the lower limbs with foot drop or difficulty walking. The age at onset is highly variable, even within families. Nearly all patients eventually develop significant proximal and distal weakness, as well as respiratory insufficiency requiring nocturnal ventilation. Additional, more variable features may include axial weakness, neck muscle weakness, and rarely, cardiac involvement. Muscle biopsy shows myopathic or dystrophic changes with fiber splitting, eosinophilic cytoplasmic inclusions consistent with myofibrillar myopathy, rimmed vacuoles, and increased connective or fatty tissue (summary by <a href="#6" class="mim-tip-reference" title="Pfeffer, G., Barresi, R., Wilson, I. J., Hardy, S. A., Griffin, H., Hudson, J., Elliott, H. R., Ramesh, A. V., Radunovic, A., Winer, J. B., Vaidya, S., Raman, A., and 11 others. <strong>Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.</strong> J. Neurol. Neurosurg. Psychiat. 85: 331-338, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23486992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23486992</a>] [<a href="https://doi.org/10.1136/jnnp-2012-304728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23486992">Pfeffer et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23486992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (<a href="/entry/601419">601419</a>).</p>
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<strong>Clinical Features</strong>
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<p><a href="#3" class="mim-tip-reference" title="Edstrom, L., Thornell, L. E., Albo, J., Landin, S., Samuelsson, M. <strong>Myopathy with respiratory failure and typical myofibrillar lesions.</strong> J. Neurol. Sci. 96: 211-228, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2376753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2376753</a>] [<a href="https://doi.org/10.1016/0022-510x(90)90134-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2376753">Edstrom et al. (1990)</a> described 16 individuals from 7 Swedish families who had autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. All patients showed proximal weakness of the upper and lower extremities. In many patients, the respiratory muscles, especially the diaphragm, were involved. Neck flexors were typically affected, and foot extensor weakness was also present in some patients. The age at onset of significant symptoms varied from the second to the fifth decade, with an average age of approximately 35 years. The creatine kinase (CK) levels were normal or slightly elevated in all cases. Typical muscle biopsy samples showed, at the light microscopic level, cytoplasmic bodies that were highly positive for rhodamine-conjugated phalloidin. Rhodamine-conjugated phalloidin selectively binds to F-actin. Ultrastructural analysis showed abnormal Z discs and actin aggregates with dissolving Z disc, I band, and M band structures, as well as focal myofibrillar breakdown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2376753" 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="Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D. <strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong> Ann. Neurol. 49: 443-452, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310621</a>]" pmid="11310621">Chinnery et al. (2001)</a> reported a kindred in which 11 individuals over 2 generations had an adult-onset myopathy characterized by distal anterior compartment weakness in the lower limbs and early respiratory failure. Mean age of onset was 50.2 years (range, 32-75 years) and the most common presenting feature was insidiously progressive symmetric lower limb anterior compartment weakness leading to bilateral foot drop. One individual presented with hip flexion weakness. Other variable features appearing later in the disease course included shoulder girdle weakness, neck flexion weakness, and quadriceps weakness. Facial weakness, external ophthalmoplegia, and dysphagia were not seen. There was global respiratory muscle weakness with reduced respiratory vital capacity, and 5 patients had symptoms suggestive of nocturnal hypoventilation. EMG showed myopathic changes and muscle biopsy showed generalized atrophy, congophilic eosinophilic inclusions, fiber splitting, rimmed vacuoles, and increased fat and fibrous tissue. Linkage analysis excluded linkage to phenotypically similar disorders, including Welander myopathy (<a href="/entry/604454">604454</a>), myopathy with proximal weakness and early respiratory failure (<a href="/entry/603689">603689</a>), tibial muscular dystrophy (<a href="/entry/600334">600334</a>), vocal cord and pharyngeal dysfunction with distal myopathy (<a href="/entry/606070">606070</a>), Laing distal myopathy (<a href="/entry/160500">160500</a>), and inclusion body myopathy-3 (see <a href="/entry/605637">605637</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310621" 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="#1" class="mim-tip-reference" title="Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F. <strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong> Neuromusc. Disord. 15: 595-600, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16084088">Birchall et al. (2005)</a> performed muscle MRI studies on 5 patients from the family originally reported by <a href="#2" class="mim-tip-reference" title="Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D. <strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong> Ann. Neurol. 49: 443-452, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310621</a>]" pmid="11310621">Chinnery et al. (2001)</a> (family A) and 3 individuals from a second unrelated family (family B) with a similar disorder. There was a consistent specific pattern of fatty replacement in the lower limbs, mostly affecting the semitendinosus, iliopsoas, obturator externus, extensor hallucis longus, extensor digitorum longus, peroneus longus, and tibialis anterior, with variable involvement of the vastus and gluteal muscles. The semimembranosus, gastrocnemius, and soleus muscles were spared. There was also selective involvement of certain shoulder muscles, such as the supraspinatus, subscapularis, and trapezius. Some of the muscles affected on imaging did not show clinical involvement, suggesting a presymptomatic state. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11310621+16084088" 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="Pfeffer, G., Elliott, H. R., Griffin, H., Barresi, R., Miller, J., Marsh, J., Evila, A., Vihola, A., Hackman, P., Straub, V., Dick, D. J., Horvath, R., Santibanez-Koref, M., Udd, B., Chinnery, P. F. <strong>Titin mutation segregates with hereditary myopathy with early respiratory failure.</strong> Brain 135: 1695-1713, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22577215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22577215</a>] [<a href="https://doi.org/10.1093/brain/aws102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22577215">Pfeffer et al. (2012)</a> reported 3 unrelated English families with MFM9. Two of the families (families A and B) had previously been reported by <a href="#2" class="mim-tip-reference" title="Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D. <strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong> Ann. Neurol. 49: 443-452, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310621</a>]" pmid="11310621">Chinnery et al. (2001)</a> and <a href="#1" class="mim-tip-reference" title="Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F. <strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong> Neuromusc. Disord. 15: 595-600, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16084088">Birchall et al. (2005)</a>. Family A had 21 affected individuals with an age at onset ranging from 33 to 71 years. The most common presenting symptoms was distal weakness, although some presented with dyspnea or proximal muscle weakness. The myopathy was proximal, distal, or both, and weakness predominantly affected the lower limbs, resulting in the need for walking aids or a wheelchair. Patients also had neck weakness and respiratory insufficiency requiring nocturnal ventilation. Family B had 9 affected members and the age at onset ranged from 22 to 55 years. The phenotype was heterogeneous: 5 presented with distal muscle weakness and foot drop, 3 had proximal muscle weakness, and 3 had respiratory symptoms. Additional features noted by <a href="#1" class="mim-tip-reference" title="Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F. <strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong> Neuromusc. Disord. 15: 595-600, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16084088">Birchall et al. (2005)</a> included reduced exercise tolerance, weakness of the upper limbs, diaphragmatic weakness, and calf hypertrophy. Muscle biopsy showed increased fiber size variation, rimmed vacuoles, and eosinophilic inclusions. Elevated serum creatine kinase was observed in 6, and 5 showed myopathy with spontaneous activity on neurophysiology studies. The third family (family C) contained the proband and his deceased brother and mother, who were reportedly affected. The proband presented with foot drop at age 45 and was found on examination to have proximal and distal muscle weakness, calf hypertrophy, and mild weakness of the proximal and distal upper extremities. About 10 years later, he became wheelchair-bound and required nocturnal positive airway pressure ventilation. In all families, the disorder was slowly progressive and patients had a gradual decline in pulmonary function tests. None of the patients had cardiac involvement. Postmortem examination in 1 patient from family A showed fiber size variation, internal nuclei, fibrosis, and fat replacement in all muscles analyzed, but these features were more marked in the diaphragm. Additional features included muscle fiber fragmentation and eosinophilic inclusions, as well as myofibrillar inclusions. There was reduced or even absent immunostaining for calpain-3 (CAPN3; <a href="/entry/114240">114240</a>), particularly in the diaphragm and gastrocnemius, but Western blot analysis of titin was normal. Heart muscle histology was normal. MRI of muscles were consistent with the report by <a href="#1" class="mim-tip-reference" title="Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F. <strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong> Neuromusc. Disord. 15: 595-600, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16084088">Birchall et al. (2005)</a> with the addition of axial muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11310621+16084088+22577215" 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="Pfeffer, G., Barresi, R., Wilson, I. J., Hardy, S. A., Griffin, H., Hudson, J., Elliott, H. R., Ramesh, A. V., Radunovic, A., Winer, J. B., Vaidya, S., Raman, A., and 11 others. <strong>Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.</strong> J. Neurol. Neurosurg. Psychiat. 85: 331-338, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23486992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23486992</a>] [<a href="https://doi.org/10.1136/jnnp-2012-304728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23486992">Pfeffer et al. (2014)</a> reported 5 families of British descent with MFM9. Onset was typically in the twenties or thirties, and symptoms included tripping or falling, myalgia, and walking difficulties. The disorder was slowly progressive with eventual involvement of the proximal, distal, and axial muscles. Most patients had abnormal pulmonary function tests, and many required nocturnal ventilatory assistance many years (up to 20 or 30 years) after disease onset. Two individuals had mildly impaired cardiac function, and some patients had spinal rigidity or scapular winging. Muscle biopsy showed dystrophic changes, with variation in fiber size, central nuclei, fiber splitting, increased connective tissue, rimmed vacuoles, eosinophilic inclusions, and cytoplasmic inclusions consistent with a myofibrillar myopathy. Immunostaining showed variable cytoplasmic accumulation of desmin (<a href="/entry/125660">125660</a>), myotilin (<a href="/entry/604103">604103</a>), and P62 (SQSTM1; <a href="/entry/601530">601530</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23486992" 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 MFM9 in the family reported by <a href="#2" class="mim-tip-reference" title="Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D. <strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong> Ann. Neurol. 49: 443-452, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310621</a>]" pmid="11310621">Chinnery et al. (2001)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 Swedish families with this disorder, <a href="#5" class="mim-tip-reference" title="Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z. <strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong> Am. J. Hum. Genet. 64: 788-792, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053013</a>] [<a href="https://doi.org/10.1086/302281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10053013">Nicolao et al. (1999)</a> established linkage of the phenotype to the chromosomal region 2q24-q31. A maximum combined 2-point lod score of 4.87 at a recombination fraction of 0.0 was obtained with marker D2S1245. Haplotype analysis indicated that the gene responsible for the disease is likely to be located in the 17-cM region between markers D2S2384 and D2S364. The affected individuals from these 2 families shared an identical haplotype, which suggested a common origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10053013" 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="Xiang, F., Nicolao, P., Chapon, F., Edstrom, L., Anvret, M., Zhang, Z. <strong>A second locus for autosomal dominant myopathy with proximal muscle weakness and early respiratory muscle involvement: a likely chromosomal locus on 2q21.</strong> Neuromusc. Disord. 9: 308-312, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10407851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10407851</a>] [<a href="https://doi.org/10.1016/s0960-8966(99)00030-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10407851">Xiang et al. (1999)</a> performed linkage analysis in a French family with similar clinical phenotype and findings on muscle biopsy to those in the Swedish families reported by <a href="#5" class="mim-tip-reference" title="Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z. <strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong> Am. J. Hum. Genet. 64: 788-792, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053013</a>] [<a href="https://doi.org/10.1086/302281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10053013">Nicolao et al. (1999)</a>, and excluded linkage to the 2q24-q33 region. They conducted a genomewide scan in the French family using polymorphic microsatellite markers and obtained a maximum 2-point lod score of 2.11 (the highest lod score that could be achieved in this family) for markers in the 2q21 region. They suggested that there may be a second locus for this disorder in that region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10053013+10407851" 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="#5" class="mim-tip-reference" title="Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z. <strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong> Am. J. Hum. Genet. 64: 788-792, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053013</a>] [<a href="https://doi.org/10.1086/302281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10053013">Nicolao et al. (1999)</a> considered the titin gene to be a strong candidate for this disorder. Titin, or connectin, is the largest polypeptide known and forms filaments that span from the Z discs to the M lines. The entire coding region of the gene (approximately 300 kb) maps within the candidate region demonstrated by <a href="#5" class="mim-tip-reference" title="Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z. <strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong> Am. J. Hum. Genet. 64: 788-792, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053013</a>] [<a href="https://doi.org/10.1086/302281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10053013">Nicolao et al. (1999)</a> for Edstrom myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10053013" 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 the 2 Swedish families described by <a href="#5" class="mim-tip-reference" title="Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z. <strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong> Am. J. Hum. Genet. 64: 788-792, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053013</a>] [<a href="https://doi.org/10.1086/302281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10053013">Nicolao et al. (1999)</a> as well as in 1 additional Swedish patient with an identical phenotype, <a href="#4" class="mim-tip-reference" title="Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edstrom, L., Ehler, E., Udd, B., Gautel, M. <strong>The kinase domain of titin controls muscle gene expression and protein turnover.</strong> Science 308: 1599-1603, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15802564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15802564</a>] [<a href="https://doi.org/10.1126/science.1110463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15802564">Lange et al. (2005)</a> identified a C-to-T transition resulting in an arginine-to-tryptophan substitution at codon 279 of the titin gene (R279W; <a href="/entry/188840#0011">188840.0011</a>), which lies within alpha helix R1 (alpha-R1) of the protein kinase domain. The single patient had no known genealogic relationship to any of the 2 original families but had the same mutation on the same haplotype, indicating a common ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10053013+15802564" 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="Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edstrom, L., Ehler, E., Udd, B., Gautel, M. <strong>The kinase domain of titin controls muscle gene expression and protein turnover.</strong> Science 308: 1599-1603, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15802564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15802564</a>] [<a href="https://doi.org/10.1126/science.1110463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15802564">Lange et al. (2005)</a> found no difference in calmodulin (<a href="/entry/114180">114180</a>)-stimulated catalytic activity between recombinant R279W mutant titin kinase domain (TK) and wildtype. Because the R279W mutation in alpha-R1 results in a drastic change of a surface-exposed basic to a nonpolar, bulky amino acid in the NBR1 (<a href="/entry/166945">166945</a>) binding site, <a href="#4" class="mim-tip-reference" title="Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edstrom, L., Ehler, E., Udd, B., Gautel, M. <strong>The kinase domain of titin controls muscle gene expression and protein turnover.</strong> Science 308: 1599-1603, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15802564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15802564</a>] [<a href="https://doi.org/10.1126/science.1110463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15802564">Lange et al. (2005)</a> tested the interaction of TK with NBR1, which was dramatically reduced in the mutant protein kinase domain. In patient biopsies, NBR1 was localized abnormally diffusely in diseased muscle instead of being M band- and Z disc-associated, although in HMERF 50% of TK was expected to be wildtype. P62 (<a href="/entry/601530">601530</a>) accumulated in many diseased muscle fibers of HMERF patients. MURF2 (<a href="/entry/606469">606469</a>) showed unusual nuclear localization in centralized nuclei of patient muscle fibers not observed in peripheral nuclei of normal muscle or in 3 other myopathies with centralized nuclei (DMD, <a href="/entry/310200">310200</a>; tibial muscular dystrophy, <a href="/entry/600334">600334</a>; and myotubular myopathy, <a href="/entry/310400">310400</a>). Furthermore, MURF1 (<a href="/entry/606131">606131</a>), a close homolog of MURF2, did not show nuclear localization in HMERF patients or in the other myopathies tested with centralized nuclei. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15802564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 3 unrelated English families with MFM9, <a href="#7" class="mim-tip-reference" title="Pfeffer, G., Elliott, H. R., Griffin, H., Barresi, R., Miller, J., Marsh, J., Evila, A., Vihola, A., Hackman, P., Straub, V., Dick, D. J., Horvath, R., Santibanez-Koref, M., Udd, B., Chinnery, P. F. <strong>Titin mutation segregates with hereditary myopathy with early respiratory failure.</strong> Brain 135: 1695-1713, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22577215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22577215</a>] [<a href="https://doi.org/10.1093/brain/aws102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22577215">Pfeffer et al. (2012)</a> identified a heterozygous missense mutation in the TTN gene (C30071R; <a href="/entry/188840#0016">188840.0016</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed, but the size and abundance of the titin protein was normal in affected muscle. However, affected muscle showed decreased levels of the titin binding partner calpain-3 (CAPN3; <a href="/entry/114240">114240</a>). Family A had previously been reported by <a href="#2" class="mim-tip-reference" title="Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D. <strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong> Ann. Neurol. 49: 443-452, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310621</a>]" pmid="11310621">Chinnery et al. (2001)</a> and <a href="#1" class="mim-tip-reference" title="Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F. <strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong> Neuromusc. Disord. 15: 595-600, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16084088">Birchall et al. (2005)</a>, and family B had previously been reported by <a href="#1" class="mim-tip-reference" title="Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F. <strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong> Neuromusc. Disord. 15: 595-600, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16084088">Birchall et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11310621+16084088+22577215" 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="Pfeffer, G., Barresi, R., Wilson, I. J., Hardy, S. A., Griffin, H., Hudson, J., Elliott, H. R., Ramesh, A. V., Radunovic, A., Winer, J. B., Vaidya, S., Raman, A., and 11 others. <strong>Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.</strong> J. Neurol. Neurosurg. Psychiat. 85: 331-338, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23486992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23486992</a>] [<a href="https://doi.org/10.1136/jnnp-2012-304728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23486992">Pfeffer et al. (2014)</a> identified the C30071R mutation in affected members of 5 additional families with HMERF. The patients were ascertained from 127 probands with a clinical presentation compatible with myofibrillar myopathy, thus accounting for 3.9% of the cohort. The families with the mutation were of English descent, and haplotype analysis indicated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23486992" 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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Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F.
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<strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong>
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Neuromusc. Disord. 15: 595-600, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16084088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16084088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16084088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D.
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<strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong>
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Ann. Neurol. 49: 443-452, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Edstrom, L., Thornell, L. E., Albo, J., Landin, S., Samuelsson, M.
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<strong>Myopathy with respiratory failure and typical myofibrillar lesions.</strong>
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J. Neurol. Sci. 96: 211-228, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2376753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2376753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2376753" 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/10.1016/0022-510x(90)90134-9" target="_blank">Full Text</a>]
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Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edstrom, L., Ehler, E., Udd, B., Gautel, M.
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<strong>The kinase domain of titin controls muscle gene expression and protein turnover.</strong>
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Science 308: 1599-1603, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15802564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15802564</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15802564" 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/10.1126/science.1110463" target="_blank">Full Text</a>]
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Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z.
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<strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong>
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Am. J. Hum. Genet. 64: 788-792, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053013</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10053013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Pfeffer, G., Barresi, R., Wilson, I. J., Hardy, S. A., Griffin, H., Hudson, J., Elliott, H. R., Ramesh, A. V., Radunovic, A., Winer, J. B., Vaidya, S., Raman, A., and 11 others.
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<strong>Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.</strong>
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J. Neurol. Neurosurg. Psychiat. 85: 331-338, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23486992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23486992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23486992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Pfeffer, G., Elliott, H. R., Griffin, H., Barresi, R., Miller, J., Marsh, J., Evila, A., Vihola, A., Hackman, P., Straub, V., Dick, D. J., Horvath, R., Santibanez-Koref, M., Udd, B., Chinnery, P. F.
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<strong>Titin mutation segregates with hereditary myopathy with early respiratory failure.</strong>
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Brain 135: 1695-1713, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22577215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22577215</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22577215" 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/brain/aws102" target="_blank">Full Text</a>]
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Xiang, F., Nicolao, P., Chapon, F., Edstrom, L., Anvret, M., Zhang, Z.
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<strong>A second locus for autosomal dominant myopathy with proximal muscle weakness and early respiratory muscle involvement: a likely chromosomal locus on 2q21.</strong>
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Neuromusc. Disord. 9: 308-312, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10407851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10407851</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10407851" 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/s0960-8966(99)00030-9" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 04/04/2019
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Ada Hamosh - updated : 2/3/2006<br>Victor A. McKusick - updated : 10/25/1999
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Victor A. McKusick : 3/31/1999
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carol : 08/16/2019
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alopez : 04/08/2019<br>ckniffin : 04/04/2019<br>carol : 06/20/2016<br>terry : 10/12/2010<br>terry : 7/3/2008<br>alopez : 2/6/2006<br>terry : 2/3/2006<br>mgross : 3/18/2004<br>carol : 10/25/1999<br>carol : 3/31/1999
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<strong>#</strong> 603689
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MYOPATHY, MYOFIBRILLAR, 9, WITH EARLY RESPIRATORY FAILURE; MFM9
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HEREDITARY MYOPATHY WITH EARLY RESPIRATORY FAILURE; HMERF<br />
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MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT; MPRM<br />
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EDSTROM MYOPATHY<br />
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MYOPATHY, DISTAL, WITH EARLY RESPIRATORY FAILURE, AUTOSOMAL DOMINANT
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<strong>SNOMEDCT:</strong> 702373006;
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<strong>ORPHA:</strong> 178464;
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<strong>DO:</strong> 0111188;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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2q31.2
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Myopathy, myofibrillar, 9, with early respiratory failure
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603689
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Autosomal dominant
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3
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TTN
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188840
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<p>A number sign (#) is used with this entry because of evidence that myofibrillar myopathy-9 with early respiratory failure (MFM9) is caused by heterozygous mutation in the protein kinase domain of titin (TTN; 188840) on chromosome 2q31.</p>
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<strong>Description</strong>
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<p>Myofibrillar myopathy-9 with early respiratory failure (MFM9) is an autosomal dominant muscle disorder characterized by adult onset of slowly progressive muscle weakness with diaphragmatic involvement causing respiratory insufficiency. Patients present between 20 and 70 years of age with distal or proximal muscle weakness, mainly affecting the lower limbs with foot drop or difficulty walking. The age at onset is highly variable, even within families. Nearly all patients eventually develop significant proximal and distal weakness, as well as respiratory insufficiency requiring nocturnal ventilation. Additional, more variable features may include axial weakness, neck muscle weakness, and rarely, cardiac involvement. Muscle biopsy shows myopathic or dystrophic changes with fiber splitting, eosinophilic cytoplasmic inclusions consistent with myofibrillar myopathy, rimmed vacuoles, and increased connective or fatty tissue (summary by Pfeffer et al., 2014). </p><p>For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).</p>
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<strong>Clinical Features</strong>
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<p>Edstrom et al. (1990) described 16 individuals from 7 Swedish families who had autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. All patients showed proximal weakness of the upper and lower extremities. In many patients, the respiratory muscles, especially the diaphragm, were involved. Neck flexors were typically affected, and foot extensor weakness was also present in some patients. The age at onset of significant symptoms varied from the second to the fifth decade, with an average age of approximately 35 years. The creatine kinase (CK) levels were normal or slightly elevated in all cases. Typical muscle biopsy samples showed, at the light microscopic level, cytoplasmic bodies that were highly positive for rhodamine-conjugated phalloidin. Rhodamine-conjugated phalloidin selectively binds to F-actin. Ultrastructural analysis showed abnormal Z discs and actin aggregates with dissolving Z disc, I band, and M band structures, as well as focal myofibrillar breakdown. </p><p>Chinnery et al. (2001) reported a kindred in which 11 individuals over 2 generations had an adult-onset myopathy characterized by distal anterior compartment weakness in the lower limbs and early respiratory failure. Mean age of onset was 50.2 years (range, 32-75 years) and the most common presenting feature was insidiously progressive symmetric lower limb anterior compartment weakness leading to bilateral foot drop. One individual presented with hip flexion weakness. Other variable features appearing later in the disease course included shoulder girdle weakness, neck flexion weakness, and quadriceps weakness. Facial weakness, external ophthalmoplegia, and dysphagia were not seen. There was global respiratory muscle weakness with reduced respiratory vital capacity, and 5 patients had symptoms suggestive of nocturnal hypoventilation. EMG showed myopathic changes and muscle biopsy showed generalized atrophy, congophilic eosinophilic inclusions, fiber splitting, rimmed vacuoles, and increased fat and fibrous tissue. Linkage analysis excluded linkage to phenotypically similar disorders, including Welander myopathy (604454), myopathy with proximal weakness and early respiratory failure (603689), tibial muscular dystrophy (600334), vocal cord and pharyngeal dysfunction with distal myopathy (606070), Laing distal myopathy (160500), and inclusion body myopathy-3 (see 605637). </p><p>Birchall et al. (2005) performed muscle MRI studies on 5 patients from the family originally reported by Chinnery et al. (2001) (family A) and 3 individuals from a second unrelated family (family B) with a similar disorder. There was a consistent specific pattern of fatty replacement in the lower limbs, mostly affecting the semitendinosus, iliopsoas, obturator externus, extensor hallucis longus, extensor digitorum longus, peroneus longus, and tibialis anterior, with variable involvement of the vastus and gluteal muscles. The semimembranosus, gastrocnemius, and soleus muscles were spared. There was also selective involvement of certain shoulder muscles, such as the supraspinatus, subscapularis, and trapezius. Some of the muscles affected on imaging did not show clinical involvement, suggesting a presymptomatic state. </p><p>Pfeffer et al. (2012) reported 3 unrelated English families with MFM9. Two of the families (families A and B) had previously been reported by Chinnery et al. (2001) and Birchall et al. (2005). Family A had 21 affected individuals with an age at onset ranging from 33 to 71 years. The most common presenting symptoms was distal weakness, although some presented with dyspnea or proximal muscle weakness. The myopathy was proximal, distal, or both, and weakness predominantly affected the lower limbs, resulting in the need for walking aids or a wheelchair. Patients also had neck weakness and respiratory insufficiency requiring nocturnal ventilation. Family B had 9 affected members and the age at onset ranged from 22 to 55 years. The phenotype was heterogeneous: 5 presented with distal muscle weakness and foot drop, 3 had proximal muscle weakness, and 3 had respiratory symptoms. Additional features noted by Birchall et al. (2005) included reduced exercise tolerance, weakness of the upper limbs, diaphragmatic weakness, and calf hypertrophy. Muscle biopsy showed increased fiber size variation, rimmed vacuoles, and eosinophilic inclusions. Elevated serum creatine kinase was observed in 6, and 5 showed myopathy with spontaneous activity on neurophysiology studies. The third family (family C) contained the proband and his deceased brother and mother, who were reportedly affected. The proband presented with foot drop at age 45 and was found on examination to have proximal and distal muscle weakness, calf hypertrophy, and mild weakness of the proximal and distal upper extremities. About 10 years later, he became wheelchair-bound and required nocturnal positive airway pressure ventilation. In all families, the disorder was slowly progressive and patients had a gradual decline in pulmonary function tests. None of the patients had cardiac involvement. Postmortem examination in 1 patient from family A showed fiber size variation, internal nuclei, fibrosis, and fat replacement in all muscles analyzed, but these features were more marked in the diaphragm. Additional features included muscle fiber fragmentation and eosinophilic inclusions, as well as myofibrillar inclusions. There was reduced or even absent immunostaining for calpain-3 (CAPN3; 114240), particularly in the diaphragm and gastrocnemius, but Western blot analysis of titin was normal. Heart muscle histology was normal. MRI of muscles were consistent with the report by Birchall et al. (2005) with the addition of axial muscles. </p><p>Pfeffer et al. (2014) reported 5 families of British descent with MFM9. Onset was typically in the twenties or thirties, and symptoms included tripping or falling, myalgia, and walking difficulties. The disorder was slowly progressive with eventual involvement of the proximal, distal, and axial muscles. Most patients had abnormal pulmonary function tests, and many required nocturnal ventilatory assistance many years (up to 20 or 30 years) after disease onset. Two individuals had mildly impaired cardiac function, and some patients had spinal rigidity or scapular winging. Muscle biopsy showed dystrophic changes, with variation in fiber size, central nuclei, fiber splitting, increased connective tissue, rimmed vacuoles, eosinophilic inclusions, and cytoplasmic inclusions consistent with a myofibrillar myopathy. Immunostaining showed variable cytoplasmic accumulation of desmin (125660), myotilin (604103), and P62 (SQSTM1; 601530). </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of MFM9 in the family reported by Chinnery et al. (2001) was consistent with autosomal dominant inheritance. </p>
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<strong>Mapping</strong>
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<p>In 2 Swedish families with this disorder, Nicolao et al. (1999) established linkage of the phenotype to the chromosomal region 2q24-q31. A maximum combined 2-point lod score of 4.87 at a recombination fraction of 0.0 was obtained with marker D2S1245. Haplotype analysis indicated that the gene responsible for the disease is likely to be located in the 17-cM region between markers D2S2384 and D2S364. The affected individuals from these 2 families shared an identical haplotype, which suggested a common origin. </p><p>Xiang et al. (1999) performed linkage analysis in a French family with similar clinical phenotype and findings on muscle biopsy to those in the Swedish families reported by Nicolao et al. (1999), and excluded linkage to the 2q24-q33 region. They conducted a genomewide scan in the French family using polymorphic microsatellite markers and obtained a maximum 2-point lod score of 2.11 (the highest lod score that could be achieved in this family) for markers in the 2q21 region. They suggested that there may be a second locus for this disorder in that region. </p>
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<p>Nicolao et al. (1999) considered the titin gene to be a strong candidate for this disorder. Titin, or connectin, is the largest polypeptide known and forms filaments that span from the Z discs to the M lines. The entire coding region of the gene (approximately 300 kb) maps within the candidate region demonstrated by Nicolao et al. (1999) for Edstrom myopathy. </p><p>In the 2 Swedish families described by Nicolao et al. (1999) as well as in 1 additional Swedish patient with an identical phenotype, Lange et al. (2005) identified a C-to-T transition resulting in an arginine-to-tryptophan substitution at codon 279 of the titin gene (R279W; 188840.0011), which lies within alpha helix R1 (alpha-R1) of the protein kinase domain. The single patient had no known genealogic relationship to any of the 2 original families but had the same mutation on the same haplotype, indicating a common ancestry. </p><p>Lange et al. (2005) found no difference in calmodulin (114180)-stimulated catalytic activity between recombinant R279W mutant titin kinase domain (TK) and wildtype. Because the R279W mutation in alpha-R1 results in a drastic change of a surface-exposed basic to a nonpolar, bulky amino acid in the NBR1 (166945) binding site, Lange et al. (2005) tested the interaction of TK with NBR1, which was dramatically reduced in the mutant protein kinase domain. In patient biopsies, NBR1 was localized abnormally diffusely in diseased muscle instead of being M band- and Z disc-associated, although in HMERF 50% of TK was expected to be wildtype. P62 (601530) accumulated in many diseased muscle fibers of HMERF patients. MURF2 (606469) showed unusual nuclear localization in centralized nuclei of patient muscle fibers not observed in peripheral nuclei of normal muscle or in 3 other myopathies with centralized nuclei (DMD, 310200; tibial muscular dystrophy, 600334; and myotubular myopathy, 310400). Furthermore, MURF1 (606131), a close homolog of MURF2, did not show nuclear localization in HMERF patients or in the other myopathies tested with centralized nuclei. </p><p>In affected members of 3 unrelated English families with MFM9, Pfeffer et al. (2012) identified a heterozygous missense mutation in the TTN gene (C30071R; 188840.0016). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed, but the size and abundance of the titin protein was normal in affected muscle. However, affected muscle showed decreased levels of the titin binding partner calpain-3 (CAPN3; 114240). Family A had previously been reported by Chinnery et al. (2001) and Birchall et al. (2005), and family B had previously been reported by Birchall et al. (2005). </p><p>Pfeffer et al. (2014) identified the C30071R mutation in affected members of 5 additional families with HMERF. The patients were ascertained from 127 probands with a clinical presentation compatible with myofibrillar myopathy, thus accounting for 3.9% of the cohort. The families with the mutation were of English descent, and haplotype analysis indicated a founder effect. </p>
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<strong>REFERENCES</strong>
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Birchall, D., von der Hagen, M., Bates, D., Bushby, K. M. D., Chinnery, P. F.
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<strong>Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure.</strong>
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Neuromusc. Disord. 15: 595-600, 2005.
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[PubMed: 16084088]
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[Full Text: https://doi.org/10.1016/j.nmd.2005.05.002]
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Chinnery, P. F., Johnson, M. A., Walls, T. J., Gibson, G. J., Fawcett, P. R. W., Jamieson, S., Fulthorpe, J. J., Cullen, M., Hudgson, P., Bushby, K. M. D.
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<strong>A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci.</strong>
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Ann. Neurol. 49: 443-452, 2001.
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[PubMed: 11310621]
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Edstrom, L., Thornell, L. E., Albo, J., Landin, S., Samuelsson, M.
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</p>
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Lange, S., Xiang, F., Yakovenko, A., Vihola, A., Hackman, P., Rostkova, E., Kristensen, J., Brandmeier, B., Franzen, G., Hedberg, B., Gunnarsson, L. G., Hughes, S. M., Marchand, S., Sejersen, T., Richard, I., Edstrom, L., Ehler, E., Udd, B., Gautel, M.
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<strong>The kinase domain of titin controls muscle gene expression and protein turnover.</strong>
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Science 308: 1599-1603, 2005.
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[PubMed: 15802564]
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[Full Text: https://doi.org/10.1126/science.1110463]
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Nicolao, P., Xiang, F., Gunnarsson, L.-G., Giometto, B., Edstrom, L., Anvret, M., Zhang, Z.
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<strong>Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.</strong>
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Pfeffer, G., Barresi, R., Wilson, I. J., Hardy, S. A., Griffin, H., Hudson, J., Elliott, H. R., Ramesh, A. V., Radunovic, A., Winer, J. B., Vaidya, S., Raman, A., and 11 others.
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<strong>Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.</strong>
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Pfeffer, G., Elliott, H. R., Griffin, H., Barresi, R., Miller, J., Marsh, J., Evila, A., Vihola, A., Hackman, P., Straub, V., Dick, D. J., Horvath, R., Santibanez-Koref, M., Udd, B., Chinnery, P. F.
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<strong>Titin mutation segregates with hereditary myopathy with early respiratory failure.</strong>
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Brain 135: 1695-1713, 2012.
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Xiang, F., Nicolao, P., Chapon, F., Edstrom, L., Anvret, M., Zhang, Z.
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Cassandra L. Kniffin - updated : 04/04/2019<br>Ada Hamosh - updated : 2/3/2006<br>Victor A. McKusick - updated : 10/25/1999
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Victor A. McKusick : 3/31/1999
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carol : 08/16/2019<br>alopez : 04/08/2019<br>ckniffin : 04/04/2019<br>carol : 06/20/2016<br>terry : 10/12/2010<br>terry : 7/3/2008<br>alopez : 2/6/2006<br>terry : 2/3/2006<br>mgross : 3/18/2004<br>carol : 10/25/1999<br>carol : 3/31/1999
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