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Entry
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- #619112 - NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13; HMND13
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- OMIM
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<p>
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<span class="h4">#619112</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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<li role="presentation">
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<a href="/clinicalSynopsis/619112"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS182960"> <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="#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><a href="https://clinicaltrials.gov/search?cond=(NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT) OR (BSCL2)" class="mim-tip-hint" title="Clinical Trials" 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=16916&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://medlineplus.gov/genetics/condition/distal-hereditary-motor-neuropathy-type-v" 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=619112[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=139536" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0081401" 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/619112" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0081401" 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 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 href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 139536<br />
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<strong>DO:</strong> 0081401<br />
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">ICD+</a>
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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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619112
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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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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13; HMND13
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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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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</p>
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<div>
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<h4>
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<span class="mim-font">
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VC; HMN5C<br />
|
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NEUROPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VC; DHMN5C<br />
|
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DHMN VC<br />
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SPINAL MUSCULAR ATROPHY, DISTAL, HARDING TYPE VC; DSMAVC
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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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<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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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/11/489?start=-3&limit=10&highlight=489">
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11q12.3
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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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Neuronopathy, distal hereditary motor, autosomal dominant 13
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<td>
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<span class="mim-font">
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<a href="/entry/619112"> 619112 </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 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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BSCL2
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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/606158"> 606158 </a>
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</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 class="btn-group ">
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<a href="/clinicalSynopsis/619112" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS182960" class="btn btn-info" role="button"> Phenotypic Series </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/619112" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/619112" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </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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- 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 />
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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> SKELETAL </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Feet </em>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Foot deformities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/229844004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">229844004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016506&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016506</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001760" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001760</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001760" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001760</a>]</span><br /> -
|
|
Pes cavus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205091006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205091006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36755004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36755004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86900005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86900005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/736.73" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">736.73</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/754.71" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.71</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0728829&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0728829</a>, <a href="https://bioportal.bioontology.org/search?q=C0039273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039273</a>, <a href="https://bioportal.bioontology.org/search?q=C2239098&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2239098</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001761" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001761</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001761" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001761</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ad12e53b20f47e5685234fa29da6610" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Pes_Cavus-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ad12e53b20f47e5685234fa29da6610" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
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</span>
|
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</div>
|
|
</div>
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</div>
|
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</div>
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Neurogenic distal muscle weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4748288&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4748288</a>]</span><br /> -
|
|
Neurogenic distal muscle atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4748289&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4748289</a>]</span><br /> -
|
|
Atrophy of the intrinsic hand muscles <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864716&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864716</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008954</a>]</span><br /> -
|
|
Neurogenic process seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5436816&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5436816</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Gait impairment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808195&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808195</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 /> -
|
|
Hyperreflexia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
|
|
Pyramidal signs (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14648003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14648003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234132&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234132</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span><br /> -
|
|
Spasticity (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br />
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|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Peripheral Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Motor neuronopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5436839&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5436839</a>]</span><br /> -
|
|
Distal sensory impairment (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847584</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002936</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002936</a>]</span><br /> -
|
|
Axonal peripheral neuropathy (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128208007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128208007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1263857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1263857</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003477" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003477</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003477" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003477</a>]</span><br /> -
|
|
Mild decrease in myelin density and regeneration seen on sural nerve biopsy (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5436840&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5436840</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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<div>
|
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<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<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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|
|
- Onset usually in the first decades<br /> -
|
|
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 /> -
|
|
Upper limb involvement is prominent<br /> -
|
|
Lower limb involvement may occur at the same time or later <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5394330&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5394330</a>]</span><br /> -
|
|
Highly variable phenotype even within families<br /> -
|
|
Incomplete penetrance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</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> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the BSCL2 gene (BSCL2, <a href="/entry/606158#0013">606158.0013</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small">
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<div class="row">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<h5>
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Neuronopathy, distal hereditary motor, autosomal dominant
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- <a href="/phenotypicSeries/PS182960">PS182960</a>
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- 15 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
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|
<thead>
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<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</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>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
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|
<a href="/geneMap/2/118?start=-3&limit=10&highlight=118"> 2p23.3 </a>
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620080"> Neuronopathy, distal hereditary motor, autosomal dominant 10 </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/620080"> 620080 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/130660"> EMILIN1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/130660"> 130660 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/377?start=-3&limit=10&highlight=377"> 2p13.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607641"> Neuronopathy, distal hereditary motor, autosomal dominant 14 </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/607641"> 607641 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601143"> DCTN1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601143"> 601143 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/441?start=-3&limit=10&highlight=441"> 2p11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614751"> ?Neuronopathy, distal hereditary motor, autosomal dominant 12 </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/614751"> 614751 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609139"> REEP1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609139"> 609139 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/542?start=-3&limit=10&highlight=542"> 2q12.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/158580"> Neuronopathy, distal hereditary motor, autosomal dominant 7 </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/158580"> 158580 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608761"> SLC5A7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608761"> 608761 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/160?start=-3&limit=10&highlight=160"> 5q11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613376"> ?Neuronopathy, distal hereditary motor, autosomal dominant 4 </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/613376"> 613376 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604624"> HSPB3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604624"> 604624 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/643?start=-3&limit=10&highlight=643"> 5q32 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615575"> Neuronopathy, distal hereditary motor, autosomal dominant 6 </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/615575"> 615575 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608533"> FBXO38 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608533"> 608533 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/165?start=-3&limit=10&highlight=165"> 7p14.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600794"> Neuronopathy, distal hereditary motor, autosomal dominant 5 </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/600794"> 600794 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600287"> GARS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600287"> 600287 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/355?start=-3&limit=10&highlight=355"> 7q11.23 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608634"> Neuronopathy, distal hereditary motor, autosomal dominant 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/608634"> 608634 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602195"> HSPB1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602195"> 602195 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/722?start=-3&limit=10&highlight=722"> 7q34-q36 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/182960"> Neuronopathy, distal hereditary motor, autosomal dominant 1 </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="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/182960"> 182960 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/182960"> HMND1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/182960"> 182960 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/9/548?start=-3&limit=10&highlight=548"> 9q34.11 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620528"> Neuronopathy, distal hereditary motor, autosomal dominant 11 </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/620528"> 620528 </a>
|
|
</span>
|
|
</td>
|
|
<td>
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<a href="/entry/621094"> ?Neuronopathy, distal hereditary motor, autosomal dominant 15 </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>A number sign (#) is used with this entry because of evidence that autosomal dominant distal hereditary motor neuronopathy-13 (HMND13) is caused by heterozygous mutation in the BSCL2 gene (<a href="/entry/606158">606158</a>) on chromosome 11q12.</p><p>Heterozygous mutation in the BSCL2 gene can also cause Silver syndrome (SPG17; <a href="/entry/270685">270685</a>), a similar disorder with more prominent spasticity.</p>
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<p>Autosomal dominant distal hereditary motor neuronopathy-13 (HMND13) is a neurologic disorder characterized by distal muscle weakness and atrophy affecting both the upper and lower limbs, resulting in difficulty walking and poor fine hand motor skills. Some patients show spasticity and hyperreflexia, mainly of the lower limbs: these features overlap with those observed in Silver syndrome, an allelic disorder. In addition, some patients with BSCL2 mutations show features of Charcot-Marie-Tooth type 2 (CMT2) with distal sensory impairment. HMND13, Silver syndrome (SPG17), and features of axonal sensorimotor peripheral neuropathy (CMT2) thus represent a phenotypic spectrum associated with heterozygous mutations in the BSCL2 gene. Individuals with the same mutation may manifest features consistent with any of those disorders; variability is even observed within the same family (summary by <a href="#8" class="mim-tip-reference" title="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">Van de Warrenburg et al., 2006</a>; <a href="#7" class="mim-tip-reference" title="Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M. <strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong> Muscle Nerve 42: 448-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>] [<a href="https://doi.org/10.1002/mus.21734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20806400">Luigetti et al., 2010</a>; <a href="#4" class="mim-tip-reference" title="Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K. <strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong> Neurogenetics 14: 35-42, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>] [<a href="https://doi.org/10.1007/s10048-012-0346-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23142943">Choi et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16427281+20806400+23142943" 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 general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMND1 (<a href="/entry/182960">182960</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P. <strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong> Brain 123: 1612-1623, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908191</a>] [<a href="https://doi.org/10.1093/brain/123.8.1612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10908191">Auer-Grumbach et al. (2000)</a> reported a large 4-generation Austrian family in which 21 members were affected with DSMAV in an autosomal dominant pattern of inheritance. The phenotype was highly variable. Most affected members had onset before age 20 years of a progressive asymmetric wasting of the thenar and the first dorsal interosseus muscles. Twenty patients had foot deformity, ranging from mild to severe, and about half had peroneal muscular atrophy. A subset of patients also had brisk tendon reflexes, suggesting spasticity. Sensory abnormalities were virtually absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10908191" 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="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> reported the phenotypic findings in 90 patients from 1 large Austrian family (previously reported by them) and 2 unrelated German families with HMN5C. There was considerable phenotypic variability, including asymptomatic nonpenetrance (4.4%), subclinical involvement (20%), distal spinal muscular atrophy characterized by prominent hand muscle involvement (31.1%), Silver syndrome (14.5%) with hand muscle involvement and spasticity, a Charcot-Marie-Tooth-like phenotype with distal muscle weakness and wasting of the lower limbs and sensory abnormalities (20%), and spastic paraparesis without hand involvement (10%). <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> concluded that the N88S mutation causes a motor neuron disease affecting the upper motor neurons, lower motor neurons, or both. Hand muscle involvement was a frequent, although not regular, feature, and sensory involvement was usually not present. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732094" 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="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">Van de Warrenburg et al. (2006)</a> reported 2 unrelated Dutch families with a neurologic phenotype consistent with both HMN5C and Silver syndrome. The first family contained 5 affected individuals spanning 3 generations. All presented with pes cavus and foot or leg muscle weakness and atrophy between 11 and 26 years of age. There was slow progression, with gradually evolving lower limb hypertonia and hyperreflexia with extensor plantar responses without prominent spasticity. Two patients also developed weakness and atrophy of the first dorsal interosseus and abductor pollicis brevis muscles without involvement of the hypothenar muscles. In the second family, there were multiple affected individuals spanning 3 generations. Age at onset was before age 20 years. About half of the patients presented with foot or leg muscle weakness and atrophy, whereas the other half presented with hand muscle weakness and atrophy. Most developed hyperreflexia with extensor plantar responses; spasticity was observed in older patients. <a href="#8" class="mim-tip-reference" title="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">Van de Warrenburg et al. (2006)</a> emphasized the phenotypic variability and incomplete penetrance of some symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5C. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperreflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396477" 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="Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M. <strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong> Muscle Nerve 42: 448-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>] [<a href="https://doi.org/10.1002/mus.21734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20806400">Luigetti et al. (2010)</a> reported an Italian family in which a mother and her 2 daughters presented with features of distal motor neuropathy and spasticity. The 67-year-old mother presented in her late forties with progressive gait difficulties since 35 years of age. She had atrophy and weakness of distal muscles in both the upper and lower limbs. She also had mild distal sensory impairment. EMG indicated a neurogenic pattern, and electrophysiologic studies were consistent with an axonal sensorimotor neuropathy; sural nerve biopsy showed mild loss of myelinated fibers and some regenerating clusters. Her 2 daughters presented with gait abnormalities and foot deformities in the first decade. They had distal muscle weakness and atrophy of the upper and lower limbs and brisk tendon reflexes, but no sensory impairment. The phenotype was consistent with peroneal muscular atrophy with pyramidal signs. The report expanded the clinical spectrum associated with BSCL2 mutations to include subclinical sensory involvement. <a href="#7" class="mim-tip-reference" title="Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M. <strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong> Muscle Nerve 42: 448-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>] [<a href="https://doi.org/10.1002/mus.21734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20806400">Luigetti et al. (2010)</a> emphasized the clinical variability within the family, noting that motor function is predominantly affected, but that patients may rarely develop sensory symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20806400" 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="Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K. <strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong> Neurogenetics 14: 35-42, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>] [<a href="https://doi.org/10.1007/s10048-012-0346-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23142943">Choi et al. (2013)</a> reported a large multigenerational Korean family diagnosed clinically with axonal Charcot-Marie-Tooth disease type 2 (CMT2). Clinical features of 11 patients were reported. The age at onset of symptoms was usually in the second or third decade, although 1 patient had onset at 5 years of age. Presenting features included distal muscle weakness and atrophy mainly affecting the upper limbs and hands, although many also had involvement of the lower limbs. Most patients also had distal sensory impairment to pin prick and vibration. Additional features included spastic gait, hyperreflexia, plantar response, and pes cavus; none had a steppage gait. Electrophysiologic studies were consistent with an axonal sensorimotor neuropathy. Sural nerve biopsy of 2 patients showed a mild increase in the density of myelinated fibers, although large fibers were decreased and there were regenerative axonal clusters, suggesting axonal atrophy and an axonal neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23142943" 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 HMND13 in the family reported by <a href="#1" class="mim-tip-reference" title="Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P. <strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong> Brain 123: 1612-1623, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908191</a>] [<a href="https://doi.org/10.1093/brain/123.8.1612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10908191">Auer-Grumbach et al. (2000)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10908191" 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="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">Van de Warrenburg et al. (2006)</a> observed autosomal dominant inheritance and incomplete penetrance of some symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427281" 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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In a large 4-generation Austrian family with autosomal dominant DSMAV, <a href="#1" class="mim-tip-reference" title="Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P. <strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong> Brain 123: 1612-1623, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908191</a>] [<a href="https://doi.org/10.1093/brain/123.8.1612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10908191">Auer-Grumbach et al. (2000)</a> excluded linkage to the DSMAV locus on 7p, indicating genetic heterogeneity of the disorder. Linkage was also excluded from the adult spinal muscular atrophy locus on chromosome 12q (<a href="/entry/158590">158590</a>) and the juvenile ALS locus on 9q (ALS4; <a href="/entry/602433">602433</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10908191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Loci</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> and <a href="#8" class="mim-tip-reference" title="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">van de Warrenburg et al. (2006)</a>, who also carried the N88S mutation, and suggested the presence of other genetic or environmental factors. In their family, <a href="#3" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. <a href="#3" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> postulated that a locus on chromosome 16p may contain a disease modifier in their family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19396477+15732094+16427281" 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 affected members of 1 Italian, 1 English, and 8 Austrian families with HMND13, including the one reported by <a href="#1" class="mim-tip-reference" title="Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P. <strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong> Brain 123: 1612-1623, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908191</a>] [<a href="https://doi.org/10.1093/brain/123.8.1612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10908191">Auer-Grumbach et al. (2000)</a>, <a href="#9" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> identified a heterozygous missense mutation in the BSCL2 gene (N88S; <a href="/entry/606158#0013">606158.0013</a>). In the same study, <a href="#9" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> also identified mutations in the BSCL2 gene in patients with Silver syndrome, indicating that the 2 disorders are extreme phenotypes with the same genetic etiology. The large affected Austrian kindred comprised 4 family branches with Silver syndrome and 8 family branches with DSMAVC; all affected Austrian patients had the N88S mutation in the BSCL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14981520+10908191" 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="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> reported the phenotypic findings in 90 patients from 1 large Austrian family (previously reported by them) and 2 unrelated German families with HMN5C associated with a heterozygous N88S mutation in the BSCL2 gene. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732094" 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="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">Van de Warrenburg et al. (2006)</a> reported 2 unrelated Dutch families with a neurologic phenotype consistent with both HMN5C and Silver syndrome. Affected individuals carried the same heterozygous missense mutation in the BSCL2 gene (N88S). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5C who carried a heterozygous N88S mutation in the BSCL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro functional expression analysis, <a href="#5" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong> Ann. Neurol. 61: 237-250, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387721</a>] [<a href="https://doi.org/10.1002/ana.21070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387721">Ito and Suzuki (2007)</a> demonstrated that the N88S and S90L (<a href="/entry/606158#0014">606158.0014</a>) mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum (ER) retention. Mutant proteins activated the unfolded protein response (UPR), resulting in apoptotic cell death through ER stress. <a href="#5" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong> Ann. Neurol. 61: 237-250, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387721</a>] [<a href="https://doi.org/10.1002/ana.21070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387721">Ito and Suzuki (2007)</a> concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the UPR, cell death, and neurodegeneration. <a href="#6" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Seipinopathy: a novel endoplasmic reticulum stress-associated disease.</strong> Brain 132: 8-15, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18790819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18790819</a>] [<a href="https://doi.org/10.1093/brain/awn216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18790819">Ito and Suzuki (2009)</a> provided a review. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17387721+18790819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Italian mother and her 2 affected daughters with variable manifestations of HMN5C, <a href="#7" class="mim-tip-reference" title="Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M. <strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong> Muscle Nerve 42: 448-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>] [<a href="https://doi.org/10.1002/mus.21734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20806400">Luigetti et al. (2010)</a> identified a heterozygous S90L mutation in the BSCL2 gene. The mutation was found by sequence analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20806400" 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 a Korean family with HMN5C and features of CMT2, <a href="#4" class="mim-tip-reference" title="Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K. <strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong> Neurogenetics 14: 35-42, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>] [<a href="https://doi.org/10.1007/s10048-012-0346-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23142943">Choi et al. (2013)</a> identified a heterozygous S90W mutation in the BSCL2 gene (<a href="/entry/606158#0020">606158.0020</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the affected residue is the same as the previously identified S90L mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23142943" 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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Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P.
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<strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong>
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Brain 123: 1612-1623, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908191</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10908191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group.
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<strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong>
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Ann. Neurol. 57: 415-424, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20410" target="_blank">Full Text</a>]
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Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M.
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<strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong>
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Neurogenetics 10: 289-297, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K.
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<strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong>
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Neurogenetics 14: 35-42, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23142943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ito, D., Suzuki, N.
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<strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong>
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Ann. Neurol. 61: 237-250, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17387721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.21070" target="_blank">Full Text</a>]
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Ito, D., Suzuki, N.
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<strong>Seipinopathy: a novel endoplasmic reticulum stress-associated disease.</strong>
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Brain 132: 8-15, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18790819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18790819</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18790819" 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/awn216" target="_blank">Full Text</a>]
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Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M.
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<strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong>
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Muscle Nerve 42: 448-451, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20806400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/mus.21734" target="_blank">Full Text</a>]
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Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M.
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<strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong>
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Neuromusc. Disord. 16: 122-125, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank">Full Text</a>]
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Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K.
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<strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong>
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Nature Genet. 36: 271-276, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14981520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1313" target="_blank">Full Text</a>]
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Cassandra L. Kniffin : 11/30/2020
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alopez : 10/18/2023
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alopez : 10/16/2023<br>ckniffin : 10/11/2023<br>alopez : 08/30/2022<br>alopez : 02/08/2021<br>alopez : 12/17/2020<br>ckniffin : 12/01/2020
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13; HMND13
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VC; HMN5C<br />
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NEUROPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VC; DHMN5C<br />
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DHMN VC<br />
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SPINAL MUSCULAR ATROPHY, DISTAL, HARDING TYPE VC; DSMAVC
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<strong>ORPHA:</strong> 139536;
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<strong>DO:</strong> 0081401;
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11q12.3
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Neuronopathy, distal hereditary motor, autosomal dominant 13
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619112
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Autosomal dominant
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BSCL2
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606158
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<p>A number sign (#) is used with this entry because of evidence that autosomal dominant distal hereditary motor neuronopathy-13 (HMND13) is caused by heterozygous mutation in the BSCL2 gene (606158) on chromosome 11q12.</p><p>Heterozygous mutation in the BSCL2 gene can also cause Silver syndrome (SPG17; 270685), a similar disorder with more prominent spasticity.</p>
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<p>Autosomal dominant distal hereditary motor neuronopathy-13 (HMND13) is a neurologic disorder characterized by distal muscle weakness and atrophy affecting both the upper and lower limbs, resulting in difficulty walking and poor fine hand motor skills. Some patients show spasticity and hyperreflexia, mainly of the lower limbs: these features overlap with those observed in Silver syndrome, an allelic disorder. In addition, some patients with BSCL2 mutations show features of Charcot-Marie-Tooth type 2 (CMT2) with distal sensory impairment. HMND13, Silver syndrome (SPG17), and features of axonal sensorimotor peripheral neuropathy (CMT2) thus represent a phenotypic spectrum associated with heterozygous mutations in the BSCL2 gene. Individuals with the same mutation may manifest features consistent with any of those disorders; variability is even observed within the same family (summary by Van de Warrenburg et al., 2006; Luigetti et al., 2010; Choi et al., 2013). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMND1 (182960).</p>
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<p>Auer-Grumbach et al. (2000) reported a large 4-generation Austrian family in which 21 members were affected with DSMAV in an autosomal dominant pattern of inheritance. The phenotype was highly variable. Most affected members had onset before age 20 years of a progressive asymmetric wasting of the thenar and the first dorsal interosseus muscles. Twenty patients had foot deformity, ranging from mild to severe, and about half had peroneal muscular atrophy. A subset of patients also had brisk tendon reflexes, suggesting spasticity. Sensory abnormalities were virtually absent. </p><p>Auer-Grumbach et al. (2005) reported the phenotypic findings in 90 patients from 1 large Austrian family (previously reported by them) and 2 unrelated German families with HMN5C. There was considerable phenotypic variability, including asymptomatic nonpenetrance (4.4%), subclinical involvement (20%), distal spinal muscular atrophy characterized by prominent hand muscle involvement (31.1%), Silver syndrome (14.5%) with hand muscle involvement and spasticity, a Charcot-Marie-Tooth-like phenotype with distal muscle weakness and wasting of the lower limbs and sensory abnormalities (20%), and spastic paraparesis without hand involvement (10%). Auer-Grumbach et al. (2005) concluded that the N88S mutation causes a motor neuron disease affecting the upper motor neurons, lower motor neurons, or both. Hand muscle involvement was a frequent, although not regular, feature, and sensory involvement was usually not present. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. </p><p>Van de Warrenburg et al. (2006) reported 2 unrelated Dutch families with a neurologic phenotype consistent with both HMN5C and Silver syndrome. The first family contained 5 affected individuals spanning 3 generations. All presented with pes cavus and foot or leg muscle weakness and atrophy between 11 and 26 years of age. There was slow progression, with gradually evolving lower limb hypertonia and hyperreflexia with extensor plantar responses without prominent spasticity. Two patients also developed weakness and atrophy of the first dorsal interosseus and abductor pollicis brevis muscles without involvement of the hypothenar muscles. In the second family, there were multiple affected individuals spanning 3 generations. Age at onset was before age 20 years. About half of the patients presented with foot or leg muscle weakness and atrophy, whereas the other half presented with hand muscle weakness and atrophy. Most developed hyperreflexia with extensor plantar responses; spasticity was observed in older patients. Van de Warrenburg et al. (2006) emphasized the phenotypic variability and incomplete penetrance of some symptoms. </p><p>Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5C. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperreflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. </p><p>Luigetti et al. (2010) reported an Italian family in which a mother and her 2 daughters presented with features of distal motor neuropathy and spasticity. The 67-year-old mother presented in her late forties with progressive gait difficulties since 35 years of age. She had atrophy and weakness of distal muscles in both the upper and lower limbs. She also had mild distal sensory impairment. EMG indicated a neurogenic pattern, and electrophysiologic studies were consistent with an axonal sensorimotor neuropathy; sural nerve biopsy showed mild loss of myelinated fibers and some regenerating clusters. Her 2 daughters presented with gait abnormalities and foot deformities in the first decade. They had distal muscle weakness and atrophy of the upper and lower limbs and brisk tendon reflexes, but no sensory impairment. The phenotype was consistent with peroneal muscular atrophy with pyramidal signs. The report expanded the clinical spectrum associated with BSCL2 mutations to include subclinical sensory involvement. Luigetti et al. (2010) emphasized the clinical variability within the family, noting that motor function is predominantly affected, but that patients may rarely develop sensory symptoms. </p><p>Choi et al. (2013) reported a large multigenerational Korean family diagnosed clinically with axonal Charcot-Marie-Tooth disease type 2 (CMT2). Clinical features of 11 patients were reported. The age at onset of symptoms was usually in the second or third decade, although 1 patient had onset at 5 years of age. Presenting features included distal muscle weakness and atrophy mainly affecting the upper limbs and hands, although many also had involvement of the lower limbs. Most patients also had distal sensory impairment to pin prick and vibration. Additional features included spastic gait, hyperreflexia, plantar response, and pes cavus; none had a steppage gait. Electrophysiologic studies were consistent with an axonal sensorimotor neuropathy. Sural nerve biopsy of 2 patients showed a mild increase in the density of myelinated fibers, although large fibers were decreased and there were regenerative axonal clusters, suggesting axonal atrophy and an axonal neuropathy. </p>
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<p>The transmission pattern of HMND13 in the family reported by Auer-Grumbach et al. (2000) was consistent with autosomal dominant inheritance. </p><p>Van de Warrenburg et al. (2006) observed autosomal dominant inheritance and incomplete penetrance of some symptoms. </p>
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<p><strong><em>Exclusion Studies</em></strong></p><p>
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In a large 4-generation Austrian family with autosomal dominant DSMAV, Auer-Grumbach et al. (2000) excluded linkage to the DSMAV locus on 7p, indicating genetic heterogeneity of the disorder. Linkage was also excluded from the adult spinal muscular atrophy locus on chromosome 12q (158590) and the juvenile ALS locus on 9q (ALS4; 602433). </p><p><strong><em>Modifier Loci</em></strong></p><p>
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Brusse et al. (2009) noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by Auer-Grumbach et al. (2005) and van de Warrenburg et al. (2006), who also carried the N88S mutation, and suggested the presence of other genetic or environmental factors. In their family, Brusse et al. (2009) used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. Brusse et al. (2009) postulated that a locus on chromosome 16p may contain a disease modifier in their family. </p>
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<p>In affected members of 1 Italian, 1 English, and 8 Austrian families with HMND13, including the one reported by Auer-Grumbach et al. (2000), Windpassinger et al. (2004) identified a heterozygous missense mutation in the BSCL2 gene (N88S; 606158.0013). In the same study, Windpassinger et al. (2004) also identified mutations in the BSCL2 gene in patients with Silver syndrome, indicating that the 2 disorders are extreme phenotypes with the same genetic etiology. The large affected Austrian kindred comprised 4 family branches with Silver syndrome and 8 family branches with DSMAVC; all affected Austrian patients had the N88S mutation in the BSCL2 gene. </p><p>Auer-Grumbach et al. (2005) reported the phenotypic findings in 90 patients from 1 large Austrian family (previously reported by them) and 2 unrelated German families with HMN5C associated with a heterozygous N88S mutation in the BSCL2 gene. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. </p><p>Van de Warrenburg et al. (2006) reported 2 unrelated Dutch families with a neurologic phenotype consistent with both HMN5C and Silver syndrome. Affected individuals carried the same heterozygous missense mutation in the BSCL2 gene (N88S). </p><p>Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5C who carried a heterozygous N88S mutation in the BSCL2 gene. </p><p>By in vitro functional expression analysis, Ito and Suzuki (2007) demonstrated that the N88S and S90L (606158.0014) mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum (ER) retention. Mutant proteins activated the unfolded protein response (UPR), resulting in apoptotic cell death through ER stress. Ito and Suzuki (2007) concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the UPR, cell death, and neurodegeneration. Ito and Suzuki (2009) provided a review. </p><p>In an Italian mother and her 2 affected daughters with variable manifestations of HMN5C, Luigetti et al. (2010) identified a heterozygous S90L mutation in the BSCL2 gene. The mutation was found by sequence analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed. </p><p>In affected members of a Korean family with HMN5C and features of CMT2, Choi et al. (2013) identified a heterozygous S90W mutation in the BSCL2 gene (606158.0020). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the affected residue is the same as the previously identified S90L mutation. </p>
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Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P.
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<strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong>
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Brain 123: 1612-1623, 2000.
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[PubMed: 10908191]
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[Full Text: https://doi.org/10.1093/brain/123.8.1612]
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Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group.
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<strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong>
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Ann. Neurol. 57: 415-424, 2005.
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[PubMed: 15732094]
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[Full Text: https://doi.org/10.1002/ana.20410]
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