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<title>
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Entry
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- #151800 - LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH OR WITHOUT AXONAL PERIPHERAL NEUROPATHY; MSL
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- OMIM
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH WITHOUT AXONAL PERIPHERAL NEUROPATHY) OR (MFN2)" 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=878&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4266" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:14116" 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/151800" 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:14116" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</div>
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<div>
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 238902007<br />
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<strong>ORPHA:</strong> 2398<br />
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<strong>DO:</strong> 14116<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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151800
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
|
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<span class="mim-font">
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LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH OR WITHOUT AXONAL PERIPHERAL NEUROPATHY; MSL
|
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
LIPOMATOSIS, FAMILIAL BENIGN CERVICAL<br />
|
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LIPODYSTROPHY, CEPHALOTHORACIC
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
|
<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>
|
|
Location
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</th>
|
|
<th>
|
|
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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</th>
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</tr>
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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">
|
|
<a href="/geneMap/1/163?start=-3&limit=10&highlight=163">
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1p36.22
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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">
|
|
Lipomatosis, multiple symmetric, with or without peripheral neuropathy
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/151800"> 151800 </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 recessive">AR</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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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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MFN2
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</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608507"> 608507 </a>
|
|
</span>
|
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</td>
|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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|
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/151800" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/151800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/151800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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|
|
</div>
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Neck </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Neck lipomatosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829392</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Airway obstruction due to lipomatosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829391&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829391</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79688008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79688008</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006536" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006536</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hepatic steatosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/442191002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">442191002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197321007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197321007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2711227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2711227</a>, <a href="https://bioportal.bioontology.org/search?q=C0015695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015695</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001397" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001397</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001397" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001397</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Limbs </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Centromedullary cystic lesions of the long bones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829387&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829387</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Feet </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Foot deformities (in some patients) <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 />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Lipomatosis of the upper body <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829384&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829384</a>]</span><br /> -
|
|
Lipomatosis of the cervical and thoracic region <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829385</a>]</span><br /> -
|
|
Paucity of adipose tissue in the limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829386</a>]</span><br /> -
|
|
Distal muscle weakness due to peripheral neuropathy (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836731</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249942005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249942005</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span><br /> -
|
|
Distal muscle atrophy due to peripheral neuropathy (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844874</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Peripheral Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Axonal peripheral sensorimotor neuropathy (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3280978&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3280978</a>]</span><br /> -
|
|
Distal sensory loss (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 /> -
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Hyporeflexia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Insulin resistance <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48606007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48606007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/763325000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">763325000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021655&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021655</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000855" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000855</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000855" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000855</a>]</span><br /> -
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Hyperglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/444780001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">444780001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237598005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237598005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80394007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80394007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R73.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R73.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2919432&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2919432</a>, <a href="https://bioportal.bioontology.org/search?q=C0020456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020456</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003074</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003074</a>]</span><br /> -
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Low serum leptin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829388&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829388</a>]</span><br /> -
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Low adiponectin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829389&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829389</a>]</span><br /> -
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Increased lactate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7501002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7501002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392691&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392691</a>]</span><br /> -
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Increased triglycerides <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302870006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302870006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166848004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166848004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020557</a>, <a href="https://bioportal.bioontology.org/search?q=C0813230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0813230</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002155" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002155</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002155" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002155</a>]</span><br /> -
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Increased FGF21 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5829390&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5829390</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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- Onset of lipomatosis in the first or second decades<br /> -
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Variable onset of peripheral neuropathy (range childhood to adult)<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the mitofusin 2 gene (MFN2, <a href="/entry/608507#0013">608507.0013</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that multiple symmetric lipomatosis (MSL) with or without axonal peripheral neuropathy is caused by homozygous or compound heterozygous mutation in the MFN2 gene (<a href="/entry/608507">608507</a>) on chromosome 1p36.</p><p>Biallelic mutation in the MFN2 gene causes autosomal recessive axonal Charcot-Marie-Tooth disease type 2A2B (CMT2A2B; <a href="/entry/617087">617087</a>) without lipomatosis.</p>
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<strong>Description</strong>
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<p>Multiple symmetric lipomatosis (MSL) is an autosomal recessive metabolic disorder characterized by the growth of unencapsulated masses of adipose tissue with predilection for the cervical and thoracic regions. The lipoma growth is striking and disfiguring, and growth around the neck may cause difficulty swallowing or breathing. The age at onset ranges from childhood to young adulthood. Most, but not all, patients develop axonal peripheral neuropathy, which can appear at any age and varies in severity. Laboratory studies in MSL show low leptin (<a href="/entry/164160">164160</a>), low adiponectin (<a href="/entry/605441">605441</a>), variably increased lactate, and increased FGF21 (<a href="/entry/609436">609436</a>). Some patients may have insulin resistance. The disorder is exclusively associated with a particular MFN2 mutation (R707W; <a href="/entry/608507#0013">608507.0013</a>), usually in the homozygous state, but sometimes in the compound heterozygous state (<a href="#22" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[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/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al., 2017</a>; <a href="#2" class="mim-tip-reference" title="Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others. <strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong> J. Clin. Lipid. 12: 1420-1435, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>] [<a href="https://doi.org/10.1016/j.jacl.2018.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30158064">Capel et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28414270+30158064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p><a href="#20" class="mim-tip-reference" title="Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A. <strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong> Neurology 70: 1678-1681, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18458227">Nicholson et al. (2008)</a> reported a 33-year-old woman (CMT40) with onset of severe axonal peripheral neuropathy at 2 years of age. Other features included hearing loss and kyphosis. She was also noted to have 'lipodystrophy'. <a href="#23" class="mim-tip-reference" title="Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G. <strong>Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.</strong> Hum. Molec. Genet. 24: 5109-5114, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26085578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26085578</a>] [<a href="https://doi.org/10.1093/hmg/ddv229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26085578">Sawyer et al. (2015)</a> reported follow-up of this patient, noting that she developed pronounced cervical and thoracic lipomatosis in her late twenties, as well as fatty nodules on her forearms and chest. MRI showed accumulation of subcutaneous unencapsulated fat, and laboratory studies showed increased lactate. Features of the neuropathy included club foot at birth and progressive muscle weakness, muscle atrophy, areflexia, and distal sensory impairment of the lower limbs during childhood. At age 48, she walked with a cane and needed a wheelchair for longer distances; she was diagnosed with autosomal recessive axonal Charcot-Marie-Tooth disease (see <a href="/entry/617087">617087</a>). Her parents and 2 daughters had minor signs and symptoms of a peripheral neuropathy, but neurophysiology was normal and they were not diagnosed with Charcot-Marie-Tooth disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26085578+18458227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G. <strong>Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.</strong> Hum. Molec. Genet. 24: 5109-5114, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26085578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26085578</a>] [<a href="https://doi.org/10.1093/hmg/ddv229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26085578">Sawyer et al. (2015)</a> reported 2 brothers, born of consanguineous Irish parents, who developed progressive cervical and thoracic lipomatosis as adults. P1 had onset in his twenties and P2 in his mid-forties. P1 had striking unencapsulated lipomas and progressive tongue hypertrophy, resulting in swallowing difficulties. He underwent multiple liposuction surgeries with recurrence of the lesions. P1 developed diabetes mellitus in his early fifties that was controlled with oral hypoglycemic medication. Laboratory studies showed elevated lactate and decreased leptin and adiponectin. P2 developed multiple encapsulated cervical and thoracic lipomas with frequent surgical interventions. Both patients developed axonal peripheral neuropathy as adults, which was more severe in P1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26085578" 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="Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M. <strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong> J. Peripher. Nerv. Syst. 20: 67-71, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>] [<a href="https://doi.org/10.1111/jns.12117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26114802">Carr et al. (2015)</a> reported a 44-year-old man (family 4) with multiple lipomata and facial lipodystrophy associated with early-onset axonal peripheral neuropathy. He presented with foot drop and pes cavus at 24 months of age. Although there was weakness of the upper and lower limbs, he remained ambulatory. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26114802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[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/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al. (2017)</a> reported 4 patients from 3 families of European ancestry with onset of MSL in the first or second decades (range 5 to 13 years). They had striking upper body adipose overgrowth affecting the upper back, head, and neck with concomitant paucity of adipose tissue in the limbs and lower body. P1 was an 18-year-old girl who also had peripheral neuropathy and primary amenorrhea with evidence of partial hypogonadotropic hypogonadism. P2 and P3, a 17-year-old female (P2) and a 16-year-old male (P3), were sibs from a large consanguineous Irish family. They had normal progression through puberty and did not have signs or symptoms of peripheral neuropathy. There was a family history of lipomatosis affecting the upper back, chest, and head and neck across 3 generations, although these family members were not available for study. Some of the affected family members reportedly had severe airway occlusion due to overgrown neck adipose tissue; 1 of these patients had a severe sensorimotor axonal neuropathy. P4 was a 37-year-old woman who developed signs of MSL around 13 years of age. She also had male pattern hair growth, irregular menstrual cycle, and acanthosis nigricans, suggesting insulin resistance, as well as mild symptoms of a peripheral neuropathy. Laboratory studies of all 4 patients showed decreased adiponectin. Two showed increased lactate and decreased leptin. All had moderate to severe insulin resistance, and 2 had fasting hyperglycemia. Two patients had elevated triglycerides associated with hepatic steatosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28414270" 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="Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others. <strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong> J. Clin. Lipid. 12: 1420-1435, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>] [<a href="https://doi.org/10.1016/j.jacl.2018.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30158064">Capel et al. (2018)</a> reported 6 patients from 5 families of French or Portuguese origin with MSL due to a homozygous R707W mutation in the MFN2 gene. The patients, who ranged from 31 to 76 years of age, showed phenotypic heterogeneity in the chronology of onset of disease manifestations and the severity. In 2 patients, neurologic signs of a peripheral neuropathy occurred first during childhood, followed by development of lipomatous masses at 25 and 30 years of age. In 3 patients, lipoma-like masses appeared between 2 and 11 years of age, and mild neurologic signs began in adulthood. One of these individuals presented with acanthosis nigricans, hyperglycemia, and severe insulin resistance at age 10, followed by adipose overgrowth at age 11. In another patient, lipomatous signs appeared at age 35 and neurologic signs at age 65. Fat accumulation variably occurred at the neck, upper back, thorax, proximal upper limbs, chin, and abdomen, whereas the lower limbs and forearms showed lipoatrophy. The lipomatous masses were unencapsulated and difficult to delineate on imaging. Laboratory findings included low serum leptin (<a href="/entry/164160">164160</a>) and low adiponectin (<a href="/entry/605441">605441</a>). Two patients studied had increased serum FGF21 (<a href="/entry/609436">609436</a>). Other abnormalities included increased triglycerides and insulin resistance; 1 patient had diabetes that was treated with diet. All 5 patients studied showed hepatic steatosis. Neurologic findings of a peripheral neuropathy included pes cavus or foot deformities, distal weakness and atrophy of the lower and upper limbs, distal sensory impairment, and hyporeflexia. Electrophysiologic studies were consistent with an axonal sensorimotor polyneuropathy. Bone imaging of 3 patients showed centromedullary cystic lesions of the tibial, peroneal, and femoral epiphyses, metaphyses, and diaphyses. Additional more variable clinical features included deafness, precocious puberty, constipation with diarrhea, and hypothyroidism. None had a history of alcohol abuse. Histologic studies of lipomatous tissue showed white fat with unilocular normal sized adipocytes and rare multilocular adipocytes. Adipose tissue was highly vascularized. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30158064" 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>Early Reports</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="McKusick, V. A. <strong>Medical genetics 1961.</strong> J. Chronic Dis. 15: 417-572, 1962. Fig. 24."None>McKusick (1962)</a> described 3 brothers with a collar of fat around the neck in the submandibular area and involving the nape of the neck. The age of onset was said to be 45, 39, and 29 years in the 3 patients. The mother was said to be definitely unaffected, having died at age 61, but 2 sisters and a maternal aunt were also affected. In advanced stages the process extended into the upper mediastinum. In 3 of those affected, lipomata of conventional type were present (e.g., in the epitrochlear area, back, axillae, and internal aspect of forearm).</p><p><a href="#16" class="mim-tip-reference" title="Lyon, I. P. <strong>Adiposis and lipomatosis: considered in reference to their constitutional relations and symptomatology.</strong> Arch. Intern. Med. 6: 28-120, 1910."None>Lyon (1910)</a> reported a striking case which was familial. <a href="#19" class="mim-tip-reference" title="Michon, P., Rose, F. <strong>Adenolipomatose symetrique familiale.</strong> Bull. Soc. Franc. Derm. Syph. 42: 1005-1007, 1935."None>Michon and Rose (1935)</a> observed familial cases.</p><p>Cervical lipomatosis was associated with gout and hyperlipoproteinemia type IV in the sisters reported by <a href="#11" class="mim-tip-reference" title="Greene, M. L., Glueck, C. J., Fujimoto, W. Y., Seegmiller, J. E. <strong>Benign symmetric lipomatosis (Launois-Bensaude adenolipomatosis) with gout and hyperlipoproteinemia.</strong> Am. J. Med. 48: 239-246, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5416265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5416265</a>] [<a href="https://doi.org/10.1016/0002-9343(70)90120-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5416265">Greene et al. (1970)</a>. Oligomenorrhea, muscle cramps, pes cavus, and extensor plantar reflexes were also described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5416265" 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>Because fat cells are smaller than normal in this disorder, <a href="#7" class="mim-tip-reference" title="Enzi, G., Inelmen, E. M., Baritussio, A., Dorigo, P., Prosdocimi, M., Mazzoleni, F. <strong>Multiple symmetric-lipomatosis: a defect in adrenergic-stimulated lipolysis.</strong> J. Clin. Invest. 60: 1221-1229, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/199616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">199616</a>] [<a href="https://doi.org/10.1172/JCI108881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="199616">Enzi et al. (1977)</a> concluded that lipomata are attributable to neoformation of adipocytes. In their studies of 10 affected males, reduced glucose tolerance and hyperlipoproteinemia were no more frequent than in controls. In lipomatous tissue but not in normal fat tissue from these subjects, in vitro insensitivity to the lipolytic effect of catecholamines was demonstrated. The block appeared to be proximal to cyclic AMP formation because theophylline induced a prompt and significant decrease in intracellular ATP in lipomatous tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=199616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Enzi, G., Angelini, C., Negrin, P., Armani, M., Pierobon, S., Fedele, D. <strong>Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis.</strong> Medicine 64: 388-393, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4058304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4058304</a>] [<a href="https://doi.org/10.1097/00005792-198511000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4058304">Enzi et al. (1985)</a> documented the high frequency of somatic and autonomic neuropathies. In 28 of 33 male patients changes varying from vibratory sensory loss to incapacitating trophic ulcers or Charcot arthropathy were found. High density lipoprotein was increased, consistent with the diagnosis of hyperalphalipoproteinemia, and low density lipoprotein fractions were reduced with a marked enhancement of lipoprotein lipase activity in adipose tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4058304" 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="#21" class="mim-tip-reference" title="Pollock, M., Nicholson, G. I., Nukada, H., Cameron, S., Frankish, P. <strong>Neuropathy in multiple symmetric lipomatosis: Madelung's disease.</strong> Brain 111: 1157-1171, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3179687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3179687</a>] [<a href="https://doi.org/10.1093/brain/111.5.1157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3179687">Pollock et al. (1988)</a> pointed out that, with increasing age, peripheral neuropathy becomes more common in multiple symmetric lipomatosis and is a principal cause of severe disability. The peripheral neuropathy is often attributed to alcoholism, but the pathologic findings of <a href="#21" class="mim-tip-reference" title="Pollock, M., Nicholson, G. I., Nukada, H., Cameron, S., Frankish, P. <strong>Neuropathy in multiple symmetric lipomatosis: Madelung's disease.</strong> Brain 111: 1157-1171, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3179687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3179687</a>] [<a href="https://doi.org/10.1093/brain/111.5.1157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3179687">Pollock et al. (1988)</a> led them to conclude that the neuropathy is in fact an integral part of the syndrome. Biochemical observations suggested a defect in catecholamine-stimulated lipolysis at the level of cell membranes. <a href="#4" class="mim-tip-reference" title="Chalk, C. H., Mills, K. R., Jacobs, J. M., Donaghy, M. <strong>Familial multiple symmetric lipomatosis with peripheral neuropathy.</strong> Neurology 40: 1246-1250, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2166247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2166247</a>] [<a href="https://doi.org/10.1212/wnl.40.8.1246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2166247">Chalk et al. (1990)</a> also thought that alcoholism could be excluded. Sural nerve biopsy in 1 patient showed nerve fiber loss, predominantly affecting large myelinated fibers. The relationship between myelin sheath thickness and axon diameter was normal, arguing that this neuropathy is not due to primary axonal atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3179687+2166247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Zancanaro, C., Sbarbati, A., Morroni, M., Carraro, R., Cigolini, M., Enzi, G., Cinti, S. <strong>Multiple symmetric lipomatosis: ultrastructural investigation of the tissue and preadipocytes in primary culture.</strong> Lab. Invest. 63: 253-258, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2381166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2381166</a>]" pmid="2381166">Zancanaro et al. (1990)</a> presented studies suggesting that multiple symmetric lipomatosis may be a neoplastic disease that originates in brown fat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2381166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Williams, D. W., III, Ginsberg, L. E., Moody, D. M., McCain, B. L. <strong>Madelung disease: MR findings.</strong> Am. J. Neuroradiol. 14: 1070-1073, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8237682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8237682</a>]" pmid="8237682">Williams et al. (1993)</a> described the findings on magnetic resonance imaging in 2 unrelated women, aged 27 and 48 years. <a href="#25" class="mim-tip-reference" title="Tizian, C., Berger, A., Vykoupil, K. F. <strong>Malignant degeneration in Madelung's disease (benign lipomatosis of the neck): case report.</strong> Brit. J. Plast. Surg. 36: 187-189, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6831098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6831098</a>] [<a href="https://doi.org/10.1016/0007-1226(83)90089-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6831098">Tizian et al. (1983)</a> had described malignant degeneration within the lipomatosis tissue. This must be very rare inasmuch as <a href="#26" class="mim-tip-reference" title="Williams, D. W., III, Ginsberg, L. E., Moody, D. M., McCain, B. L. <strong>Madelung disease: MR findings.</strong> Am. J. Neuroradiol. 14: 1070-1073, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8237682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8237682</a>]" pmid="8237682">Williams et al. (1993)</a> could find no other report of this complication. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8237682+6831098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Klopstock, T., Naumann, M., Schalke, B., Bischof, F., Seibel, P., Kottlors, M., Eckert, P., Reiners, K., Toyka, K. V., Reichmann, H. <strong>Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA.</strong> Neurology 44: 862-866, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8190288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8190288</a>] [<a href="https://doi.org/10.1212/wnl.44.5.862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8190288">Klopstock et al. (1994)</a> pointed out that ragged-red fibers are occasionally found in muscle of patients with multiple symmetric lipomatosis, suggesting a mitochondrial abnormality. They studied 11 unrelated patients with this disorder by means of neurophysiology, muscle morphology, muscle biochemistry, Southern blot, and PCR analysis of mitochondrial DNA. All patients were men, aged 41 to 63 years. Clinical or electrophysiologic signs of sensorimotor polyneuropathy were present in 9 patients, 8 of whom had a history of alcoholism. In muscle biopsy specimens, the most prominent feature was pathologic subsarcolemmal accumulations of mitochondria. Biochemical analysis of respiratory chain enzymes revealed a moderate but significant decrease of cytochrome c oxidase activity as compared with age-matched controls. In 1 patient, Southern blot analysis showed multiple deletions of mitochondrial DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8190288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Golsch, S., Worret, W.-I. <strong>Familial multiple lipomatosis with polyneuropathy.</strong> Europ. J. Derm. 5: 283-285, 1995."None>Golsch and Worret (1995)</a> described a family with 9 cases of familial multiple lipomatosis in 3 generations. The oldest living member of the family suffered from a nonalcoholic peripheral neuropathy. Polyneuropathy has been described in association with multiple symmetric lipomatosis and may be an intrinsic part of the disorder.</p><p>In a longitudinal study of 31 patients with MSL (mean follow-up of 14.5 +/- 5.0 years), <a href="#6" class="mim-tip-reference" title="Enzi, G., Busetto, L., Ceschin, E., Coin, A., Digito, M., Pigozzo, S. <strong>Multiple symmetric lipomatosis: clinical aspects and outcome in a long-term longitudinal study.</strong> Int. J. Obes. Relat. Metab. Disord. 26: 253-261, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850759</a>] [<a href="https://doi.org/10.1038/sj.ijo.0801867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850759">Enzi et al. (2002)</a> confirmed the association of the disorder with high ethanol intake. Onset was usually in the fourth or fifth decade. Eight patients (25.8%) died during follow-up, none of whom had signs or symptoms of coronary heart disease. In addition to this high fatality rate, a substantial morbidity related to the occupation of the mediastinal space by the lipomatous tissue and to somatic neuropathy was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850759" 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 MSL in the families reported by <a href="#22" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[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/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al. (2017)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28414270" 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="Enzi, G. <strong>Multiple symmetric lipomatosis: an updated clinical report.</strong> Medicine 63: 56-64, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6318013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6318013</a>] [<a href="https://doi.org/10.1097/00005792-198401000-00004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6318013">Enzi (1984)</a> studied 34 patients with MSL, 3 of whom had other affected family members: a brother in 2 instances and a father and son in the third. The other patients declared that none of their sibs (34 brothers, 28 sisters) or parents was affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6318013" 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="Chalk, C. H., Mills, K. R., Jacobs, J. M., Donaghy, M. <strong>Familial multiple symmetric lipomatosis with peripheral neuropathy.</strong> Neurology 40: 1246-1250, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2166247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2166247</a>] [<a href="https://doi.org/10.1212/wnl.40.8.1246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2166247">Chalk et al. (1990)</a> described coexisting peripheral neuropathy and multiple symmetric lipomatosis in 4 of 7 sibs, 3 female and 1 male. They favored autosomal recessive inheritance because of absence of either condition in 3 other generations of this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2166247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#24" class="mim-tip-reference" title="Taylor, L. M., Beahrs, O. H., Fontana, R. S. <strong>Benign symmetric lipomatosis.</strong> Proc. Staff Meet. Mayo Clin. 36: 96-100, 1961.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13775631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13775631</a>]" pmid="13775631">Taylor et al. (1961)</a> described surgical procedures adopted in a case similar to those reported by <a href="#18" class="mim-tip-reference" title="McKusick, V. A. <strong>Medical genetics 1961.</strong> J. Chronic Dis. 15: 417-572, 1962. Fig. 24."None>McKusick (1962)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13775631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Williams, D. W., III, Ginsberg, L. E., Moody, D. M., McCain, B. L. <strong>Madelung disease: MR findings.</strong> Am. J. Neuroradiol. 14: 1070-1073, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8237682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8237682</a>]" pmid="8237682">Williams et al. (1993)</a> commented that the standard treatment is surgical debulking, but prognosis is guarded because of frequent recurrences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8237682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a longitudinal follow-up of patients with MSL, <a href="#6" class="mim-tip-reference" title="Enzi, G., Busetto, L., Ceschin, E., Coin, A., Digito, M., Pigozzo, S. <strong>Multiple symmetric lipomatosis: clinical aspects and outcome in a long-term longitudinal study.</strong> Int. J. Obes. Relat. Metab. Disord. 26: 253-261, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850759</a>] [<a href="https://doi.org/10.1038/sj.ijo.0801867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850759">Enzi et al. (2002)</a> found that alcohol discontinuation was associated with a slight regression of lipomatous depots and that an increase in ethanol consumption seemed to accelerate the lipomatous growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 33-year-old woman (CMT40) with MSL and early-onset peripheral axonal neuropathy, <a href="#20" class="mim-tip-reference" title="Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A. <strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong> Neurology 70: 1678-1681, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18458227">Nicholson et al. (2008)</a> identified a homozygous missense mutation in the MFN2 gene (R707W; <a href="/entry/608507#0013">608507.0013</a>). Her parents, who were heterozygous for the mutation, showed mild features of a peripheral neuropathy, but were not diagnosed with Charcot-Marie-Tooth disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18458227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 brothers, born of consanguineous Irish parents, with MSL, <a href="#23" class="mim-tip-reference" title="Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G. <strong>Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.</strong> Hum. Molec. Genet. 24: 5109-5114, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26085578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26085578</a>] [<a href="https://doi.org/10.1093/hmg/ddv229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26085578">Sawyer et al. (2015)</a> identified a homozygous R707W mutation in the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homooligomers, and formed smaller oligomeric complexes compared to wildtype MFN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26085578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 44-year-old man (family 4) with MSL and early-onset axonal peripheral neuropathy, <a href="#3" class="mim-tip-reference" title="Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M. <strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong> J. Peripher. Nerv. Syst. 20: 67-71, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>] [<a href="https://doi.org/10.1111/jns.12117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26114802">Carr et al. (2015)</a> identified compound heterozygous mutations in the MFN2 gene: an ex7-8 deletion (<a href="/entry/608507#0018">608507.0018</a>) and R707W. His carrier parents were unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26114802" 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 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, <a href="#22" class="mim-tip-reference" title="Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others. <strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong> eLife 6: e23813, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[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/10.7554/eLife.23813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28414270">Rocha et al. (2017)</a> identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (<a href="/entry/608507#0023">608507.0023</a>). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (<a href="/entry/113730">113730</a>)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also alteration of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28414270" 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 6 patients from 5 families of French or Portuguese descent with MSL, <a href="#2" class="mim-tip-reference" title="Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others. <strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong> J. Clin. Lipid. 12: 1420-1435, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>] [<a href="https://doi.org/10.1016/j.jacl.2018.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30158064">Capel et al. (2018)</a> identified a homozygous R707W mutation in the MFN2 gene. The patients were ascertained from a cohort of 66 individuals with altered fat distribution and lipomas who underwent sequencing of the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (<a href="/entry/300149">300149</a>) and FGF21 (<a href="/entry/609436">609436</a>). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30158064" 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>Associations Pending Confirmation</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., Stenman, G. <strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong> Am. J. Hum. Genet. 52: 551-556, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8447321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8447321</a>]" pmid="8447321">Holme et al. (1993)</a> reported a woman with multiple symmetric lipomas in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (<a href="/entry/590060#0001">590060.0001</a>). Her son, who also carried the mutation, had MERRF syndrome (<a href="/entry/545000">545000</a>); the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. <a href="#12" class="mim-tip-reference" title="Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., Stenman, G. <strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong> Am. J. Hum. Genet. 52: 551-556, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8447321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8447321</a>]" pmid="8447321">Holme et al. (1993)</a> concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8447321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gamez, J., Playan, A., Andreu, A. L., Bruno, C., Navarro, C., Cervera, C., Arbos, M. A., Schwartz, S., Enriquez, J. A., Montoya, J. <strong>Familial multiple symmetric lipomatosis associated with the A8344G mutation of mitochondrial DNA.</strong> Neurology 51: 258-260, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674814</a>] [<a href="https://doi.org/10.1212/wnl.51.1.258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674814">Gamez et al. (1998)</a> identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with multiple symmetric lipomatosis. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure; some of these features are found in MERRF syndrome. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lindner, A., Marbach, F., Tschernitz, S., Ortner, C., Berneburg, M., Felthaus, O., Prantl, L., Kye, M. J., Rappl, G., Altmuller, J., Thiele, H., Schreml, S., Schreml, J. <strong>Calcyphosine-like (CAPSL) is regulated in multiple symmetric lipomatosis and is involved in adipogenesis.</strong> Sci. Rep. 9: 8444, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31186450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31186450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31186450[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/10.1038/s41598-019-44382-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31186450">Lindner et al. (2019)</a> studied a 4-generation family with MSL in which a woman, her son, and her paternal grandmother were affected; the proband's father, an obligate carrier, was not affected. None of the family members were reported to have signs of myopathy or neuropathy. Whole-exome sequencing revealed heterozygosity for an R9X mutation in the CAPSL gene (<a href="/entry/618799">618799</a>) in the 3 affected individuals and the obligate carrier; there was no evidence for involvement of known lipodystrophy- or overgrowth syndrome-associated genes. Analysis of the CAPSL gene in 21 unrelated MSL patients did not reveal any mutations. Adipose tissue from the proband and from 10 patients with sporadic MSL, from both affected and unaffected regions of the body, showed markedly reduced or absent expression of CASL compared to control adipocytes. The authors suggested an association between CAPSL deficiency and the MSL phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31186450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Enzi, G., Angelini, C., Negrin, P., Armani, M., Pierobon, S., Fedele, D. <strong>Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis.</strong> Medicine 64: 388-393, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4058304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4058304</a>] [<a href="https://doi.org/10.1097/00005792-198511000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4058304">Enzi et al. (1985)</a> suggested that MSL is not unusual in Mediterranean areas and that the frequency in Italy is about 1 per 25,000 males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4058304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Brodie, B. C. <strong>Clinical Lectures on Surgery, Delivered at St. George's Hospital.</strong> Philadelphia: Lea and Blanchard (pub.) 1846. Pp. 201-202."None>Brodie (1846)</a> is said to have first described diffuse symmetrical lipomatosis with predilection for the neck. It was called 'Fetthals" (fat neck) by <a href="#17" class="mim-tip-reference" title="Madelung, (NI). <strong>Ueber den Fetthals (diffuses Lipom des Halses).</strong> Arch. Klin. Chir. 37: 106-130, 1888."None>Madelung (1888)</a>.</p>
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<a href="#Launois1898" class="mim-tip-reference" title="Launois, P. E., Bensaude, R. <strong>De l'adeno-lipomatose symetrique.</strong> Bull. Mem. Soc. Med. Hop. Paris 1: 298-318, 1898.">Launois and Bensaude (1898)</a>
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Brodie, B. C.
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<strong>Clinical Lectures on Surgery, Delivered at St. George's Hospital.</strong>
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Philadelphia: Lea and Blanchard (pub.) 1846. Pp. 201-202.
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Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others.
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<strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong>
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J. Clin. Lipid. 12: 1420-1435, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30158064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30158064</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30158064" 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.jacl.2018.07.009" target="_blank">Full Text</a>]
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<a id="Carr2015" class="mim-anchor"></a>
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Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M.
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<strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong>
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J. Peripher. Nerv. Syst. 20: 67-71, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26114802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26114802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26114802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/jns.12117" target="_blank">Full Text</a>]
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<a id="Chalk1990" class="mim-anchor"></a>
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Chalk, C. H., Mills, K. R., Jacobs, J. M., Donaghy, M.
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<strong>Familial multiple symmetric lipomatosis with peripheral neuropathy.</strong>
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Neurology 40: 1246-1250, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2166247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2166247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2166247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.40.8.1246" target="_blank">Full Text</a>]
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<a id="Enzi1985" class="mim-anchor"></a>
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<p class="mim-text-font">
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Enzi, G., Angelini, C., Negrin, P., Armani, M., Pierobon, S., Fedele, D.
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<strong>Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis.</strong>
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Medicine 64: 388-393, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4058304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4058304</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4058304" 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/10.1097/00005792-198511000-00003" target="_blank">Full Text</a>]
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<a id="Enzi2002" class="mim-anchor"></a>
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Enzi, G., Busetto, L., Ceschin, E., Coin, A., Digito, M., Pigozzo, S.
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<strong>Multiple symmetric lipomatosis: clinical aspects and outcome in a long-term longitudinal study.</strong>
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Int. J. Obes. Relat. Metab. Disord. 26: 253-261, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850759</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850759" 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/sj.ijo.0801867" target="_blank">Full Text</a>]
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<a id="Enzi1977" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Enzi, G., Inelmen, E. M., Baritussio, A., Dorigo, P., Prosdocimi, M., Mazzoleni, F.
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<strong>Multiple symmetric-lipomatosis: a defect in adrenergic-stimulated lipolysis.</strong>
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J. Clin. Invest. 60: 1221-1229, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/199616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">199616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=199616" 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/10.1172/JCI108881" target="_blank">Full Text</a>]
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<a id="Enzi1984" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Enzi, G.
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<strong>Multiple symmetric lipomatosis: an updated clinical report.</strong>
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Medicine 63: 56-64, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6318013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6318013</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6318013" 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/10.1097/00005792-198401000-00004" target="_blank">Full Text</a>]
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<a id="Gamez1998" class="mim-anchor"></a>
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Gamez, J., Playan, A., Andreu, A. L., Bruno, C., Navarro, C., Cervera, C., Arbos, M. A., Schwartz, S., Enriquez, J. A., Montoya, J.
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<strong>Familial multiple symmetric lipomatosis associated with the A8344G mutation of mitochondrial DNA.</strong>
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Neurology 51: 258-260, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674814</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.51.1.258" target="_blank">Full Text</a>]
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<a id="Golsch1995" class="mim-anchor"></a>
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<div class="">
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Golsch, S., Worret, W.-I.
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<strong>Familial multiple lipomatosis with polyneuropathy.</strong>
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Europ. J. Derm. 5: 283-285, 1995.
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<a id="Greene1970" class="mim-anchor"></a>
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Greene, M. L., Glueck, C. J., Fujimoto, W. Y., Seegmiller, J. E.
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<strong>Benign symmetric lipomatosis (Launois-Bensaude adenolipomatosis) with gout and hyperlipoproteinemia.</strong>
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Am. J. Med. 48: 239-246, 1970.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5416265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5416265</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5416265" 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/10.1016/0002-9343(70)90120-8" target="_blank">Full Text</a>]
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<a id="Holme1993" class="mim-anchor"></a>
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Holme, E., Larsson, N.-G., Oldfors, A., Tulinius, M., Sahlin, P., Stenman, G.
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<strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong>
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Am. J. Hum. Genet. 52: 551-556, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8447321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8447321</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8447321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Klopstock, T., Naumann, M., Schalke, B., Bischof, F., Seibel, P., Kottlors, M., Eckert, P., Reiners, K., Toyka, K. V., Reichmann, H.
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<strong>Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA.</strong>
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Neurology 44: 862-866, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8190288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8190288</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8190288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.44.5.862" target="_blank">Full Text</a>]
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<a id="Launois1898" class="mim-anchor"></a>
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<div class="">
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Launois, P. E., Bensaude, R.
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<strong>De l'adeno-lipomatose symetrique.</strong>
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Bull. Mem. Soc. Med. Hop. Paris 1: 298-318, 1898.
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<a id="Lindner2019" class="mim-anchor"></a>
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Lindner, A., Marbach, F., Tschernitz, S., Ortner, C., Berneburg, M., Felthaus, O., Prantl, L., Kye, M. J., Rappl, G., Altmuller, J., Thiele, H., Schreml, S., Schreml, J.
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<strong>Calcyphosine-like (CAPSL) is regulated in multiple symmetric lipomatosis and is involved in adipogenesis.</strong>
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Sci. Rep. 9: 8444, 2019. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31186450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31186450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31186450[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=31186450" 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/s41598-019-44382-1" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Lyon1910" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Lyon, I. P.
|
|
<strong>Adiposis and lipomatosis: considered in reference to their constitutional relations and symptomatology.</strong>
|
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Arch. Intern. Med. 6: 28-120, 1910.
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Madelung1888" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Madelung, (NI).
|
|
<strong>Ueber den Fetthals (diffuses Lipom des Halses).</strong>
|
|
Arch. Klin. Chir. 37: 106-130, 1888.
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="McKusick1962" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
McKusick, V. A.
|
|
<strong>Medical genetics 1961.</strong>
|
|
J. Chronic Dis. 15: 417-572, 1962. Fig. 24.
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Michon1935" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Michon, P., Rose, F.
|
|
<strong>Adenolipomatose symetrique familiale.</strong>
|
|
Bull. Soc. Franc. Derm. Syph. 42: 1005-1007, 1935.
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Nicholson2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J.-M., Ouvrier, R. A.
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<strong>Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.</strong>
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Neurology 70: 1678-1681, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18458227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18458227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18458227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000311275.89032.22" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Pollock1988" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Pollock, M., Nicholson, G. I., Nukada, H., Cameron, S., Frankish, P.
|
|
<strong>Neuropathy in multiple symmetric lipomatosis: Madelung's disease.</strong>
|
|
Brain 111: 1157-1171, 1988.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3179687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3179687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3179687" 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/111.5.1157" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Rocha2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rocha, N., Bulger, D. A., Frontini, A., Titheradge, H., Gribsholt, S. B., Knox, R., Page, M., Harris, J., Payne, F., Adams, C., Sleigh, A., Crawford, J., and 19 others.
|
|
<strong>Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression.</strong>
|
|
eLife 6: e23813, 2017.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28414270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28414270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28414270[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=28414270" 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/10.7554/eLife.23813" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Sawyer2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sawyer, S. L., Cheuk-Him Ng, A., Innes, A. M., Wagner, J. D., Dyment, D. A., Tetreault, M., Care4Rare Canada Consortium, Majewski, J., Boycott, K. M., Screaton, R. A., Nicholson, G.
|
|
<strong>Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.</strong>
|
|
Hum. Molec. Genet. 24: 5109-5114, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26085578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26085578</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26085578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv229" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Taylor1961" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Taylor, L. M., Beahrs, O. H., Fontana, R. S.
|
|
<strong>Benign symmetric lipomatosis.</strong>
|
|
Proc. Staff Meet. Mayo Clin. 36: 96-100, 1961.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13775631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13775631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13775631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Tizian1983" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tizian, C., Berger, A., Vykoupil, K. F.
|
|
<strong>Malignant degeneration in Madelung's disease (benign lipomatosis of the neck): case report.</strong>
|
|
Brit. J. Plast. Surg. 36: 187-189, 1983.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6831098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6831098</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6831098" 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/10.1016/0007-1226(83)90089-9" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Williams1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Williams, D. W., III, Ginsberg, L. E., Moody, D. M., McCain, B. L.
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<strong>Madelung disease: MR findings.</strong>
|
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Am. J. Neuroradiol. 14: 1070-1073, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8237682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8237682</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8237682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Zancanaro1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zancanaro, C., Sbarbati, A., Morroni, M., Carraro, R., Cigolini, M., Enzi, G., Cinti, S.
|
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<strong>Multiple symmetric lipomatosis: ultrastructural investigation of the tissue and preadipocytes in primary culture.</strong>
|
|
Lab. Invest. 63: 253-258, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2381166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2381166</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2381166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 05/26/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 03/03/2020<br>Cassandra L. Kniffin - updated : 11/17/2014
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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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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/02/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 06/01/2023<br>ckniffin : 05/30/2023<br>ckniffin : 05/26/2023<br>carol : 03/03/2020<br>carol : 06/07/2018<br>carol : 11/19/2014<br>mcolton : 11/17/2014<br>ckniffin : 11/17/2014<br>ckniffin : 11/17/2014<br>terry : 12/7/2010<br>carol : 9/23/2010<br>terry : 9/23/2010<br>carol : 9/22/2010<br>terry : 9/21/2010<br>joanna : 7/7/1997<br>alopez : 6/2/1997<br>jamie : 2/4/1997<br>jamie : 2/4/1997<br>mimadm : 11/5/1994<br>davew : 8/18/1994<br>carol : 7/28/1994<br>pfoster : 4/22/1994<br>warfield : 4/12/1994<br>carol : 1/28/1993
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 151800
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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LIPOMATOSIS, MULTIPLE SYMMETRIC, WITH OR WITHOUT AXONAL PERIPHERAL NEUROPATHY; MSL
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</span>
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</h3>
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<div>
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<br />
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<div >
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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LIPOMATOSIS, FAMILIAL BENIGN CERVICAL<br />
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LIPODYSTROPHY, CEPHALOTHORACIC
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</span>
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</h4>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 238902007;
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<strong>ORPHA:</strong> 2398;
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<strong>DO:</strong> 14116;
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
|
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</th>
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<th>
|
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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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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1p36.22
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Lipomatosis, multiple symmetric, with or without peripheral neuropathy
|
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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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151800
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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<td>
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MFN2
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608507
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that multiple symmetric lipomatosis (MSL) with or without axonal peripheral neuropathy is caused by homozygous or compound heterozygous mutation in the MFN2 gene (608507) on chromosome 1p36.</p><p>Biallelic mutation in the MFN2 gene causes autosomal recessive axonal Charcot-Marie-Tooth disease type 2A2B (CMT2A2B; 617087) without lipomatosis.</p>
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<strong>Description</strong>
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<p>Multiple symmetric lipomatosis (MSL) is an autosomal recessive metabolic disorder characterized by the growth of unencapsulated masses of adipose tissue with predilection for the cervical and thoracic regions. The lipoma growth is striking and disfiguring, and growth around the neck may cause difficulty swallowing or breathing. The age at onset ranges from childhood to young adulthood. Most, but not all, patients develop axonal peripheral neuropathy, which can appear at any age and varies in severity. Laboratory studies in MSL show low leptin (164160), low adiponectin (605441), variably increased lactate, and increased FGF21 (609436). Some patients may have insulin resistance. The disorder is exclusively associated with a particular MFN2 mutation (R707W; 608507.0013), usually in the homozygous state, but sometimes in the compound heterozygous state (Rocha et al., 2017; Capel et al., 2018). </p>
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<strong>Clinical Features</strong>
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<p>Nicholson et al. (2008) reported a 33-year-old woman (CMT40) with onset of severe axonal peripheral neuropathy at 2 years of age. Other features included hearing loss and kyphosis. She was also noted to have 'lipodystrophy'. Sawyer et al. (2015) reported follow-up of this patient, noting that she developed pronounced cervical and thoracic lipomatosis in her late twenties, as well as fatty nodules on her forearms and chest. MRI showed accumulation of subcutaneous unencapsulated fat, and laboratory studies showed increased lactate. Features of the neuropathy included club foot at birth and progressive muscle weakness, muscle atrophy, areflexia, and distal sensory impairment of the lower limbs during childhood. At age 48, she walked with a cane and needed a wheelchair for longer distances; she was diagnosed with autosomal recessive axonal Charcot-Marie-Tooth disease (see 617087). Her parents and 2 daughters had minor signs and symptoms of a peripheral neuropathy, but neurophysiology was normal and they were not diagnosed with Charcot-Marie-Tooth disease. </p><p>Sawyer et al. (2015) reported 2 brothers, born of consanguineous Irish parents, who developed progressive cervical and thoracic lipomatosis as adults. P1 had onset in his twenties and P2 in his mid-forties. P1 had striking unencapsulated lipomas and progressive tongue hypertrophy, resulting in swallowing difficulties. He underwent multiple liposuction surgeries with recurrence of the lesions. P1 developed diabetes mellitus in his early fifties that was controlled with oral hypoglycemic medication. Laboratory studies showed elevated lactate and decreased leptin and adiponectin. P2 developed multiple encapsulated cervical and thoracic lipomas with frequent surgical interventions. Both patients developed axonal peripheral neuropathy as adults, which was more severe in P1. </p><p>Carr et al. (2015) reported a 44-year-old man (family 4) with multiple lipomata and facial lipodystrophy associated with early-onset axonal peripheral neuropathy. He presented with foot drop and pes cavus at 24 months of age. Although there was weakness of the upper and lower limbs, he remained ambulatory. </p><p>Rocha et al. (2017) reported 4 patients from 3 families of European ancestry with onset of MSL in the first or second decades (range 5 to 13 years). They had striking upper body adipose overgrowth affecting the upper back, head, and neck with concomitant paucity of adipose tissue in the limbs and lower body. P1 was an 18-year-old girl who also had peripheral neuropathy and primary amenorrhea with evidence of partial hypogonadotropic hypogonadism. P2 and P3, a 17-year-old female (P2) and a 16-year-old male (P3), were sibs from a large consanguineous Irish family. They had normal progression through puberty and did not have signs or symptoms of peripheral neuropathy. There was a family history of lipomatosis affecting the upper back, chest, and head and neck across 3 generations, although these family members were not available for study. Some of the affected family members reportedly had severe airway occlusion due to overgrown neck adipose tissue; 1 of these patients had a severe sensorimotor axonal neuropathy. P4 was a 37-year-old woman who developed signs of MSL around 13 years of age. She also had male pattern hair growth, irregular menstrual cycle, and acanthosis nigricans, suggesting insulin resistance, as well as mild symptoms of a peripheral neuropathy. Laboratory studies of all 4 patients showed decreased adiponectin. Two showed increased lactate and decreased leptin. All had moderate to severe insulin resistance, and 2 had fasting hyperglycemia. Two patients had elevated triglycerides associated with hepatic steatosis. </p><p>Capel et al. (2018) reported 6 patients from 5 families of French or Portuguese origin with MSL due to a homozygous R707W mutation in the MFN2 gene. The patients, who ranged from 31 to 76 years of age, showed phenotypic heterogeneity in the chronology of onset of disease manifestations and the severity. In 2 patients, neurologic signs of a peripheral neuropathy occurred first during childhood, followed by development of lipomatous masses at 25 and 30 years of age. In 3 patients, lipoma-like masses appeared between 2 and 11 years of age, and mild neurologic signs began in adulthood. One of these individuals presented with acanthosis nigricans, hyperglycemia, and severe insulin resistance at age 10, followed by adipose overgrowth at age 11. In another patient, lipomatous signs appeared at age 35 and neurologic signs at age 65. Fat accumulation variably occurred at the neck, upper back, thorax, proximal upper limbs, chin, and abdomen, whereas the lower limbs and forearms showed lipoatrophy. The lipomatous masses were unencapsulated and difficult to delineate on imaging. Laboratory findings included low serum leptin (164160) and low adiponectin (605441). Two patients studied had increased serum FGF21 (609436). Other abnormalities included increased triglycerides and insulin resistance; 1 patient had diabetes that was treated with diet. All 5 patients studied showed hepatic steatosis. Neurologic findings of a peripheral neuropathy included pes cavus or foot deformities, distal weakness and atrophy of the lower and upper limbs, distal sensory impairment, and hyporeflexia. Electrophysiologic studies were consistent with an axonal sensorimotor polyneuropathy. Bone imaging of 3 patients showed centromedullary cystic lesions of the tibial, peroneal, and femoral epiphyses, metaphyses, and diaphyses. Additional more variable clinical features included deafness, precocious puberty, constipation with diarrhea, and hypothyroidism. None had a history of alcohol abuse. Histologic studies of lipomatous tissue showed white fat with unilocular normal sized adipocytes and rare multilocular adipocytes. Adipose tissue was highly vascularized. </p><p><strong><em>Early Reports</em></strong></p><p>
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McKusick (1962) described 3 brothers with a collar of fat around the neck in the submandibular area and involving the nape of the neck. The age of onset was said to be 45, 39, and 29 years in the 3 patients. The mother was said to be definitely unaffected, having died at age 61, but 2 sisters and a maternal aunt were also affected. In advanced stages the process extended into the upper mediastinum. In 3 of those affected, lipomata of conventional type were present (e.g., in the epitrochlear area, back, axillae, and internal aspect of forearm).</p><p>Lyon (1910) reported a striking case which was familial. Michon and Rose (1935) observed familial cases.</p><p>Cervical lipomatosis was associated with gout and hyperlipoproteinemia type IV in the sisters reported by Greene et al. (1970). Oligomenorrhea, muscle cramps, pes cavus, and extensor plantar reflexes were also described. </p><p>Because fat cells are smaller than normal in this disorder, Enzi et al. (1977) concluded that lipomata are attributable to neoformation of adipocytes. In their studies of 10 affected males, reduced glucose tolerance and hyperlipoproteinemia were no more frequent than in controls. In lipomatous tissue but not in normal fat tissue from these subjects, in vitro insensitivity to the lipolytic effect of catecholamines was demonstrated. The block appeared to be proximal to cyclic AMP formation because theophylline induced a prompt and significant decrease in intracellular ATP in lipomatous tissue. </p><p>Enzi et al. (1985) documented the high frequency of somatic and autonomic neuropathies. In 28 of 33 male patients changes varying from vibratory sensory loss to incapacitating trophic ulcers or Charcot arthropathy were found. High density lipoprotein was increased, consistent with the diagnosis of hyperalphalipoproteinemia, and low density lipoprotein fractions were reduced with a marked enhancement of lipoprotein lipase activity in adipose tissue. </p><p>Pollock et al. (1988) pointed out that, with increasing age, peripheral neuropathy becomes more common in multiple symmetric lipomatosis and is a principal cause of severe disability. The peripheral neuropathy is often attributed to alcoholism, but the pathologic findings of Pollock et al. (1988) led them to conclude that the neuropathy is in fact an integral part of the syndrome. Biochemical observations suggested a defect in catecholamine-stimulated lipolysis at the level of cell membranes. Chalk et al. (1990) also thought that alcoholism could be excluded. Sural nerve biopsy in 1 patient showed nerve fiber loss, predominantly affecting large myelinated fibers. The relationship between myelin sheath thickness and axon diameter was normal, arguing that this neuropathy is not due to primary axonal atrophy. </p><p>Zancanaro et al. (1990) presented studies suggesting that multiple symmetric lipomatosis may be a neoplastic disease that originates in brown fat. </p><p>Williams et al. (1993) described the findings on magnetic resonance imaging in 2 unrelated women, aged 27 and 48 years. Tizian et al. (1983) had described malignant degeneration within the lipomatosis tissue. This must be very rare inasmuch as Williams et al. (1993) could find no other report of this complication. </p><p>Klopstock et al. (1994) pointed out that ragged-red fibers are occasionally found in muscle of patients with multiple symmetric lipomatosis, suggesting a mitochondrial abnormality. They studied 11 unrelated patients with this disorder by means of neurophysiology, muscle morphology, muscle biochemistry, Southern blot, and PCR analysis of mitochondrial DNA. All patients were men, aged 41 to 63 years. Clinical or electrophysiologic signs of sensorimotor polyneuropathy were present in 9 patients, 8 of whom had a history of alcoholism. In muscle biopsy specimens, the most prominent feature was pathologic subsarcolemmal accumulations of mitochondria. Biochemical analysis of respiratory chain enzymes revealed a moderate but significant decrease of cytochrome c oxidase activity as compared with age-matched controls. In 1 patient, Southern blot analysis showed multiple deletions of mitochondrial DNA. </p><p>Golsch and Worret (1995) described a family with 9 cases of familial multiple lipomatosis in 3 generations. The oldest living member of the family suffered from a nonalcoholic peripheral neuropathy. Polyneuropathy has been described in association with multiple symmetric lipomatosis and may be an intrinsic part of the disorder.</p><p>In a longitudinal study of 31 patients with MSL (mean follow-up of 14.5 +/- 5.0 years), Enzi et al. (2002) confirmed the association of the disorder with high ethanol intake. Onset was usually in the fourth or fifth decade. Eight patients (25.8%) died during follow-up, none of whom had signs or symptoms of coronary heart disease. In addition to this high fatality rate, a substantial morbidity related to the occupation of the mediastinal space by the lipomatous tissue and to somatic neuropathy was observed. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of MSL in the families reported by Rocha et al. (2017) was consistent with autosomal recessive inheritance. </p><p>Enzi (1984) studied 34 patients with MSL, 3 of whom had other affected family members: a brother in 2 instances and a father and son in the third. The other patients declared that none of their sibs (34 brothers, 28 sisters) or parents was affected. </p><p>Chalk et al. (1990) described coexisting peripheral neuropathy and multiple symmetric lipomatosis in 4 of 7 sibs, 3 female and 1 male. They favored autosomal recessive inheritance because of absence of either condition in 3 other generations of this family. </p>
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<strong>Clinical Management</strong>
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<p>Taylor et al. (1961) described surgical procedures adopted in a case similar to those reported by McKusick (1962). </p><p>Williams et al. (1993) commented that the standard treatment is surgical debulking, but prognosis is guarded because of frequent recurrences. </p><p>In a longitudinal follow-up of patients with MSL, Enzi et al. (2002) found that alcohol discontinuation was associated with a slight regression of lipomatous depots and that an increase in ethanol consumption seemed to accelerate the lipomatous growth. </p>
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<strong>Molecular Genetics</strong>
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<p>In a 33-year-old woman (CMT40) with MSL and early-onset peripheral axonal neuropathy, Nicholson et al. (2008) identified a homozygous missense mutation in the MFN2 gene (R707W; 608507.0013). Her parents, who were heterozygous for the mutation, showed mild features of a peripheral neuropathy, but were not diagnosed with Charcot-Marie-Tooth disease. </p><p>In 2 brothers, born of consanguineous Irish parents, with MSL, Sawyer et al. (2015) identified a homozygous R707W mutation in the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homooligomers, and formed smaller oligomeric complexes compared to wildtype MFN2. </p><p>In a 44-year-old man (family 4) with MSL and early-onset axonal peripheral neuropathy, Carr et al. (2015) identified compound heterozygous mutations in the MFN2 gene: an ex7-8 deletion (608507.0018) and R707W. His carrier parents were unaffected. </p><p>In 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, Rocha et al. (2017) identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (608507.0023). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (113730)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also alteration of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific. </p><p>In 6 patients from 5 families of French or Portuguese descent with MSL, Capel et al. (2018) identified a homozygous R707W mutation in the MFN2 gene. The patients were ascertained from a cohort of 66 individuals with altered fat distribution and lipomas who underwent sequencing of the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (300149) and FGF21 (609436). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Holme et al. (1993) reported a woman with multiple symmetric lipomas in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome (545000); the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation. </p><p>Gamez et al. (1998) identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with multiple symmetric lipomatosis. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure; some of these features are found in MERRF syndrome. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss. </p><p>Lindner et al. (2019) studied a 4-generation family with MSL in which a woman, her son, and her paternal grandmother were affected; the proband's father, an obligate carrier, was not affected. None of the family members were reported to have signs of myopathy or neuropathy. Whole-exome sequencing revealed heterozygosity for an R9X mutation in the CAPSL gene (618799) in the 3 affected individuals and the obligate carrier; there was no evidence for involvement of known lipodystrophy- or overgrowth syndrome-associated genes. Analysis of the CAPSL gene in 21 unrelated MSL patients did not reveal any mutations. Adipose tissue from the proband and from 10 patients with sporadic MSL, from both affected and unaffected regions of the body, showed markedly reduced or absent expression of CASL compared to control adipocytes. The authors suggested an association between CAPSL deficiency and the MSL phenotype. </p>
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<strong>Population Genetics</strong>
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<p>Enzi et al. (1985) suggested that MSL is not unusual in Mediterranean areas and that the frequency in Italy is about 1 per 25,000 males. </p>
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<strong>History</strong>
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<p>Brodie (1846) is said to have first described diffuse symmetrical lipomatosis with predilection for the neck. It was called 'Fetthals" (fat neck) by Madelung (1888).</p>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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<span class="mim-text-font">
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Launois and Bensaude (1898)
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<strong>REFERENCES</strong>
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<p class="mim-text-font">
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Brodie, B. C.
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<strong>Clinical Lectures on Surgery, Delivered at St. George's Hospital.</strong>
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Philadelphia: Lea and Blanchard (pub.) 1846. Pp. 201-202.
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Capel, E., Vatier, C., Cervera, P., Stojkovic, T., Disse, E., Cottereau, A.-S., Auclair, M., Verpont, M.-C., Mosbah, H., Gourdy, P., Barraud, S., Miquel, A., and 12 others.
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<strong>MFN2-associated lipomatosis: clinical spectrum and impact on adipose tissue.</strong>
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J. Clin. Lipid. 12: 1420-1435, 2018.
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[PubMed: 30158064]
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[Full Text: https://doi.org/10.1016/j.jacl.2018.07.009]
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Carr, A. S, Polke, J. M., Wilson, J., Pelayo-Negro, A. L., Laura, M., Nanji, T., Holt, J., Vaughan, J., Rankin, J., Sweeney, M. G., Blake, J., Houlden, H., Reilly, M. M.
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<strong>MFN2 deletion of exons 7 and 8: founder mutation in the UK population.</strong>
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J. Peripher. Nerv. Syst. 20: 67-71, 2015.
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[PubMed: 26114802]
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[Full Text: https://doi.org/10.1111/jns.12117]
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Chalk, C. H., Mills, K. R., Jacobs, J. M., Donaghy, M.
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<strong>Familial multiple symmetric lipomatosis with peripheral neuropathy.</strong>
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Neurology 40: 1246-1250, 1990.
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[PubMed: 2166247]
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[Full Text: https://doi.org/10.1212/wnl.40.8.1246]
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Enzi, G., Angelini, C., Negrin, P., Armani, M., Pierobon, S., Fedele, D.
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<strong>Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis.</strong>
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Medicine 64: 388-393, 1985.
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[PubMed: 4058304]
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[Full Text: https://doi.org/10.1097/00005792-198511000-00003]
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<p class="mim-text-font">
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Enzi, G., Busetto, L., Ceschin, E., Coin, A., Digito, M., Pigozzo, S.
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<strong>Multiple symmetric lipomatosis: clinical aspects and outcome in a long-term longitudinal study.</strong>
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Int. J. Obes. Relat. Metab. Disord. 26: 253-261, 2002.
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[PubMed: 11850759]
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[Full Text: https://doi.org/10.1038/sj.ijo.0801867]
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Enzi, G., Inelmen, E. M., Baritussio, A., Dorigo, P., Prosdocimi, M., Mazzoleni, F.
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<strong>Multiple symmetric-lipomatosis: a defect in adrenergic-stimulated lipolysis.</strong>
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J. Clin. Invest. 60: 1221-1229, 1977.
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[PubMed: 199616]
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[Full Text: https://doi.org/10.1172/JCI108881]
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</p>
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<strong>Benign symmetric lipomatosis (Launois-Bensaude adenolipomatosis) with gout and hyperlipoproteinemia.</strong>
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<strong>Multiple symmetric lipomas with high levels of mtDNA with the tRNA(Lys) A-G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.</strong>
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<strong>Malignant degeneration in Madelung's disease (benign lipomatosis of the neck): case report.</strong>
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Williams, D. W., III, Ginsberg, L. E., Moody, D. M., McCain, B. L.
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Zancanaro, C., Sbarbati, A., Morroni, M., Carraro, R., Cigolini, M., Enzi, G., Cinti, S.
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<strong>Multiple symmetric lipomatosis: ultrastructural investigation of the tissue and preadipocytes in primary culture.</strong>
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[PubMed: 2381166]
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