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Entry
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- #604004 - MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1; MLC1
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- OMIM
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<p>
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<span class="h4">#604004</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/604004"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS604004"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3715&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1535/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4559" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604004[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2478" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/264cbfbe-cc1a-4d18-b62f-8f76f4903b85/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0080316" 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/604004" 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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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<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> 703536004<br />
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<strong>ICD10CM:</strong> G93.42<br />
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<strong>ORPHA:</strong> 2478<br />
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<strong>DO:</strong> 0080316<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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604004
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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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|
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MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1; MLC1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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VACUOLATING MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS<br />
|
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LVM<br />
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VL<br />
|
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LEUKOENCEPHALOPATHY WITH SWELLING AND CYSTS<br />
|
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VAN DER KNAAP DISEASE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</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>
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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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<a href="/geneMap/22/401?start=-3&limit=10&highlight=401">
|
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22q13.33
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Megalencephalic leukoencephalopathy with subcortical cysts 1
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/604004"> 604004 </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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MLC1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/605908"> 605908 </a>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/604004" 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>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
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|
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<a href="/phenotypicSeries/PS604004" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
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</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>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604004" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/604004" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</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>
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
|
- Autosomal 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 />
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Macrocephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12138000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12138000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1145403003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1145403003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221355&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221355</a>, <a href="https://bioportal.bioontology.org/search?q=C2243051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2243051</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001355</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Macrocephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
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|
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|
|
</div>
|
|
|
|
</div>
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Megalencephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/9740002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">9740002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12138000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12138000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q04.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q04.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221355&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221355</a>, <a href="https://bioportal.bioontology.org/search?q=C2720434&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2720434</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001355</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001355</a>]</span><br /> -
|
|
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
|
|
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
|
|
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
|
|
Delay in motor development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854301&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854301</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span><br /> -
|
|
Mild mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86765009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86765009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F70</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026106&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026106</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001256</a>]</span><br /> -
|
|
Diffuse swelling of cerebral white matter <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858855&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858855</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007341" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007341</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007341" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007341</a>]</span><br /> -
|
|
Large subcortical cysts in frontal and temporal lobes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858856&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858856</a>]</span><br /> -
|
|
Diffuse spongiform leukoencephalopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858857</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006943</a>]</span><br /> -
|
|
Vacuolizing myelinopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858858&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858858</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
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- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
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Slow course of functional deterioration compared to severity of MRI findings<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the MLC1 gene (MLC1, <a href="/entry/605908#0001">605908.0001</a>)<br />
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<h5>
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Leukoencephalopathy, megalencephalic
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- <a href="/phenotypicSeries/PS604004">PS604004</a>
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- 5 Entries
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</h5>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/11/1058?start=-3&limit=10&highlight=1058"> 11q24.2 </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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<a href="/entry/613925"> Megalencephalic leukoencephalopathy with subcortical cysts 2A </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 class="mim-font">
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<a href="/entry/613925"> 613925 </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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<a href="/entry/611642"> HEPACAM </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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<a href="/entry/611642"> 611642 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/11/1058?start=-3&limit=10&highlight=1058"> 11q24.2 </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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<a href="/entry/613926"> Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</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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<span class="mim-font">
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<a href="/entry/613926"> 613926 </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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<a href="/entry/611642"> HEPACAM </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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<a href="/entry/611642"> 611642 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/16/240?start=-3&limit=10&highlight=240"> 16p12.3 </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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<a href="/entry/620447"> Megalencephalic leukoencephalopathy with subcortical cysts 3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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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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<a href="/entry/620447"> 620447 </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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<a href="/entry/605948"> GPRC5B </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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<a href="/entry/605948"> 605948 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/18/107?start=-3&limit=10&highlight=107"> 18q11.2 </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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<a href="/entry/620448"> ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting </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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<a href="/entry/620448"> 620448 </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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<a href="/entry/600308"> AQP4 </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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<a href="/entry/600308"> 600308 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/22/401?start=-3&limit=10&highlight=401"> 22q13.33 </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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<a href="/entry/604004"> Megalencephalic leukoencephalopathy with subcortical cysts 1 </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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<a href="/entry/604004"> 604004 </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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<a href="/entry/605908"> MLC1 </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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<a href="/entry/605908"> 605908 </a>
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</span>
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</td>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<br />
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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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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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1) is caused by homozygous or compound heterozygous mutation in the MLC1 gene (<a href="/entry/605908">605908</a>) on chromosome 22q13.</p>
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</span>
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<div>
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<br />
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Megalencephalic leukoencephalopathy with subcortical cysts is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurologic deterioration, including cerebellar ataxia, spasticity, epilepsy, and mild cognitive decline (summary by <a href="#3" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Megalencephalic Leukoencephalopathy with Subcortical Cysts</em></strong></p><p>
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See also MLC2A (<a href="/entry/613925">613925</a>), caused by homozygous or compound heterozygous mutation in the HEPACAM gene (<a href="/entry/611642">611642</a>) on chromosome 11q24; MLC2B (<a href="/entry/613926">613926</a>), caused by heterozygous mutation in the HEPACAM gene; MLC3 (<a href="/entry/620447">620447</a>), caused by mutation in the GPRC5B gene (<a href="/entry/605948">605948</a>) on chromosome 16p12; and MLC4 (<a href="/entry/620448">620448</a>), caused by mutation in the AQP4 gene (<a href="/entry/600308">600308</a>) on chromosome 18q11.</p>
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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<p><a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Barth, P. G., Stroink, H., van Nieuwenhuizen, O., Arts, W. F. M., Hoogenraad, F., Valk, J. <strong>Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children.</strong> Ann. Neurol. 37: 324-334, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7695231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7695231</a>] [<a href="https://doi.org/10.1002/ana.410370308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7695231">Van der Knaap et al. (1995)</a> described a syndrome of cerebral leukoencephalopathy and megalencephaly with infantile onset in 8 children, including 2 sibs. Neurologic findings were initially normal or near normal, despite megalencephaly and magnetic resonance imaging (MRI) evidence of severe white matter involvement. Slow progressive ataxia and spasticity developed, while intellectual functioning was preserved for years after onset of the disorder. Epilepsy was present in 6 of the 8 patients, with time of first seizure ranging from 1.5 years to 12 years. All patients were from the Netherlands. Age of presentation varied from 2 months to 10 years in a child who had immigrated. All patients had cysts on MRI. MRI showed cysts in the tips of the temporal lobes and frontoparietal subcortical area. Cerebellar hemispheres were mildly involved and not swollen. Cerebral hemispheric white matter was diffusely abnormal with considerable swelling obliterating the subarachnoid spaces. Central white matter structures, including the corpus callosum, internal capsule, and brainstem, were relatively spared. MRI characteristics also included diffuse abnormality in signal intensity. MRI abnormalities that are characteristic for this disorder are the discrepant severity in comparison to clinical picture, the aspect of white matter abnormalities (diffuse, homogeneous abnormality with swelling), the distribution of the abnormalities (supratentorial, hemispheric white matter involvement with relative sparing of central white matter structures), absence of gray matter involvement, and the presence of cysts with a typical location. MR spectra were relatively mildly abnormal. Screening for inborn errors, especially those that cause either megalencephaly or white matter disease or both, was negative. <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Barth, P. G., Stroink, H., van Nieuwenhuizen, O., Arts, W. F. M., Hoogenraad, F., Valk, J. <strong>Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children.</strong> Ann. Neurol. 37: 324-334, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7695231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7695231</a>] [<a href="https://doi.org/10.1002/ana.410370308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7695231">Van der Knaap et al. (1995)</a> stated that this disease can be defined on the basis of clinical and MRI findings. Four of the patients had parents who were consanguineous, and 2 of the patients had an affected sib. The authors suggested an autosomal recessive mode of inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7695231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="van der Knaap, M. S., Barth, P. G., Vrensen, G. F., Valk, J. <strong>Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course.</strong> Acta Neuropath. 92: 206-212, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841668</a>] [<a href="https://doi.org/10.1007/s004010050510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841668">Van der Knaap et al. (1996)</a> described the results of brain biopsy performed in one of the patients described by <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Barth, P. G., Stroink, H., van Nieuwenhuizen, O., Arts, W. F. M., Hoogenraad, F., Valk, J. <strong>Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children.</strong> Ann. Neurol. 37: 324-334, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7695231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7695231</a>] [<a href="https://doi.org/10.1002/ana.410370308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7695231">van der Knaap et al. (1995)</a>. A spongiform leukoencephalopathy without cortical involvement was revealed. Histopathologic findings placed the disease among the vacuolating myelinopathies, although it is distinct from the well-known forms. Possible pathophysiologic mechanisms are splitting of the outermost myelin lamellae at the intraperiod line or a disturbance of compaction of the outermost myelin lamellae at the intraperiod line. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7695231+8841668" 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="Topcu, M., Gartioux, C., Ribierre, F., Yalcinkaya, C., Tokus, E., Oztekin, N., Beckmann, J. S., Ozguc, M., Seboun, E. <strong>Vacuolating megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel.</strong> Am. J. Hum. Genet. 66: 733-739, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677334[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/10.1086/302758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677334">Topcu et al. (2000)</a> reported on vacuolating megalencephalic leukoencephalopathy characterized by diffuse swelling of the white matter, large subcortical cysts, and megalencephaly with infantile onset. They pointed to additional cases reported by <a href="#1" class="mim-tip-reference" title="Goutieres, F., Boulloche, J., Bourgeois, M., Aicardi, J. <strong>Leukoencephalopathy, megalencephaly, and mild clinical course: a recently individualized familial leukodystrophy: report on five new cases.</strong> J. Child Neurol. 11: 439-444, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9120220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9120220</a>] [<a href="https://doi.org/10.1177/088307389601100604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9120220">Goutieres et al. (1996)</a>, <a href="#7" class="mim-tip-reference" title="Singhal, B. S., Gursahani, R. D., Udani, V. P., Biniwale, A. A. <strong>Megalencephalic leukodystrophy in an Asian Indian ethnic group.</strong> Pediat. Neurol. 14: 291-296, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8805171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8805171</a>] [<a href="https://doi.org/10.1016/0887-8994(96)00048-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8805171">Singhal et al. (1996)</a>, <a href="#5" class="mim-tip-reference" title="Mejaski-Bosnjak, V., Besenski, N., Brockmann, K., Pouwels, P. J.W., Frahm, J., Hanefeld, F. A. <strong>Cystic leukoencephalopathy in a megalencephalic child: clinical and magnetic resonance imaging/magnetic resonance spectroscopy findings.</strong> Pediat. Neurol. 16: 347-350, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9258973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9258973</a>] [<a href="https://doi.org/10.1016/s0887-8994(97)00044-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9258973">Mejaski-Bosnjak et al. (1997)</a>, and <a href="#10" class="mim-tip-reference" title="Topcu, M., Saatci, I., Topcuoglu, M. A., Kose, G., Kunak, B. <strong>Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases.</strong> Brain Dev. 20: 142-153, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628190</a>] [<a href="https://doi.org/10.1016/s0387-7604(98)00002-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628190">Topcu et al. (1998)</a>. Family studies in several ethnic groups had suggested autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9258973+9120220+8805171+10677334+9628190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Patrono, C., Di Giacinto, G., Eymard-Pierre, E., Santorelli, F. M., Rodriguez, D., De Stefano, N., Federico, A., Gatti, R., Benigno, V., Megarbane, A., Tabarki, B., Boespflug-Tanguy, O., Bertini, E. <strong>Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.</strong> Neurology 61: 534-537, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939431</a>] [<a href="https://doi.org/10.1212/01.wnl.0000076184.21183.ca" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12939431">Patrono et al. (2003)</a> reported clinical, neuroradiologic, and molecular findings in 18 patients from 15 unrelated families with MLC. Most patients had a delay in reaching autonomous walking and presented with early-onset ataxia. About half of the patients lost the ability to walk by age 11 years, and about half showed learning difficulties in the first years of school. All had macrocephaly, and most had seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939431" 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="Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R. <strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 20: 3266-3277, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>] [<a href="https://doi.org/10.1093/hmg/ddr238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21624973">Lopez-Hernandez et al. (2011)</a> reported a woman with megalencephalic leukoencephalopathy with subcortical cysts-1. She developed macrocephaly within the first few months of life, and thereafter showed slow motor deterioration, epilepsy, and cognitive decline. Brain MRI at age 40 years showed diffuse signal abnormalities in the cerebral white matter, with global atrophy and subcortical cysts in the anterior temporal region. She died at age 57 years following a cranial trauma. Postmortem brain examination showed reduced cerebral white matter with cavitation in the frontal and parietal lobes. Microscopic examination showed preservation of the cerebral cortex, but lack of myelin in the deep white matter with cavitation in the most affected areas. There was a reduction in the number of astrocytes and oligodendrocytes and loss of axons. Many astrocytes lacking myelin contained alpha-beta-crystallin (CRYAB; <a href="/entry/123590">123590</a>), a stress protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21624973" 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>By genome scan of 13 affected Turkish families, <a href="#9" class="mim-tip-reference" title="Topcu, M., Gartioux, C., Ribierre, F., Yalcinkaya, C., Tokus, E., Oztekin, N., Beckmann, J. S., Ozguc, M., Seboun, E. <strong>Vacuolating megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel.</strong> Am. J. Hum. Genet. 66: 733-739, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677334[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/10.1086/302758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677334">Topcu et al. (2000)</a> mapped the disease locus to the telomeric region of 22q, within a 3-cM linkage interval (maximum multipoint lod score of 17 for this interval). Linkage analysis under the genetic-heterogeneity hypothesis showed no genetic heterogeneity. <a href="#9" class="mim-tip-reference" title="Topcu, M., Gartioux, C., Ribierre, F., Yalcinkaya, C., Tokus, E., Oztekin, N., Beckmann, J. S., Ozguc, M., Seboun, E. <strong>Vacuolating megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel.</strong> Am. J. Hum. Genet. 66: 733-739, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677334[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/10.1086/302758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677334">Topcu et al. (2000)</a> found no abnormalities in 3 positional candidate genes: FBLN1 (<a href="/entry/135820">135820</a>), GSTT1 (<a href="/entry/600436">600436</a>), and GSTT2 (<a href="/entry/600437">600437</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677334" 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="Topcu, M., Gartioux, C., Ribierre, F., Yalcinkaya, C., Tokus, E., Oztekin, N., Beckmann, J. S., Ozguc, M., Seboun, E. <strong>Vacuolating megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel.</strong> Am. J. Hum. Genet. 66: 733-739, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677334[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/10.1086/302758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677334">Topcu et al. (2000)</a> enumerated several factors possibly responsible for the difficulties that they encountered in mapping the LVM locus. First, approximately half of the parents were distant cousins; therefore, the chromosomal region homozygous by descent was expected to be small. Second, these families originated from a population in which approximately 30% of the marriages are consanguineous. The number of observed heterozygotes was approximately half of what would be expected on the basis of marker PIC (polymorphism information content) values. Therefore, consanguinity reduced marker informativity by limiting the allele number. Third, the LVM locus mapped to the telomeric end of 22q, a region with poor marker coverage. Fourth, the size of the chromosomal region shared by the affected children appeared to be small, i.e., 3 cM. Although the families originated from rural areas of central and southeastern Anatolia, Turkey, no shared allele or shared haplotype was detected. This suggested either that the genetic markers are still too far from the disease locus to allow detection of an ancient founder effect or the existence of allelic heterogeneity. Although the authors noted mild and severe forms of the disease, both forms appeared to be linked to the same locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677334" 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="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> narrowed the critical region by linkage analysis of 11 informative families with MLC to a region of approximately 250 kb. One family with 2 patients who were sibs did not display linkage to any of the analyzed microsatellite markers on 22qtel, suggesting genetic heterogeneity and the existence of at least a second MLC locus. The maximum 2-point lod score for the 11 families was 6.6 at a recombination fraction of 0.02. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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 7 informative and 6 uninformative families with MLC, <a href="#2" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> identified 12 different mutations in the MLC1 gene (see, e.g., <a href="/entry/605908#0001">605908.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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 13 of 18 patients with MLC, <a href="#6" class="mim-tip-reference" title="Patrono, C., Di Giacinto, G., Eymard-Pierre, E., Santorelli, F. M., Rodriguez, D., De Stefano, N., Federico, A., Gatti, R., Benigno, V., Megarbane, A., Tabarki, B., Boespflug-Tanguy, O., Bertini, E. <strong>Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.</strong> Neurology 61: 534-537, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939431</a>] [<a href="https://doi.org/10.1212/01.wnl.0000076184.21183.ca" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12939431">Patrono et al. (2003)</a> identified 11 mutations in the MLC1 gene. There was no apparent genotype/phenotype correlation. Five patients did not show MLC1 mutations, indicating genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939431" 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 woman with megalencephalic leukoencephalopathy with subcortical cysts-1, <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R. <strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 20: 3266-3277, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>] [<a href="https://doi.org/10.1093/hmg/ddr238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21624973">Lopez-Hernandez et al. (2011)</a> identified a homozygous mutation in the MLC1 gene (S69L; <a href="/entry/605908#0013">605908.0013</a>). Patient brain tissue showed no immunostaining for MLC1, indicating that deficiency of cell surface MLC1 protein expression is the basis for the disorder. In vitro expression of the S69L mutation in HeLa cells showed that the mutant protein was located in intracellular compartments, with reduced surface membrane expression compared to wildtype. The mutant protein also showed reduced stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21624973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunohistochemical analysis, <a href="#8" class="mim-tip-reference" title="Sirisi, S., Folgueira, M., Lopez-Hernandez, T., Minieri, L., Perez-Rius, C., Gaitan-Penas, H., Zang, J., Martinez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estevez, R., Barrallo-Gimeno, A. <strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.</strong> Hum. Molec. Genet. 23: 5069-5086, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24824219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24824219</a>] [<a href="https://doi.org/10.1093/hmg/ddu231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24824219">Sirisi et al. (2014)</a> observed mislocalization of GLIALCAM (HEPACAM; <a href="/entry/611642">611642</a>) in Bergmann glia in the cerebellum of the patient with megalencephalic leukoencephalopathy with subcortical cysts-1 reported by <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R. <strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 20: 3266-3277, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>] [<a href="https://doi.org/10.1093/hmg/ddr238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21624973">Lopez-Hernandez et al. (2011)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21624973+24824219" 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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Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R.
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<strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Hum. Molec. Genet. 20: 3266-3277, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21624973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Sirisi, S., Folgueira, M., Lopez-Hernandez, T., Minieri, L., Perez-Rius, C., Gaitan-Penas, H., Zang, J., Martinez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estevez, R., Barrallo-Gimeno, A.
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Patricia A. Hartz - updated : 10/29/2014
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Cassandra L. Kniffin - updated : 5/30/2012<br>Victor A. McKusick - updated : 4/5/2004<br>Cassandra L. Kniffin - updated : 1/21/2004<br>Victor A. McKusick - updated : 5/4/2001<br>Victor A. McKusick - updated : 5/3/2001<br>Victor A. McKusick - updated : 3/31/2000
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh : 7/9/1999
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alopez : 07/19/2023
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ckniffin : 07/19/2023<br>carol : 05/26/2016<br>mgross : 10/29/2014<br>carol : 5/31/2012<br>ckniffin : 5/30/2012<br>wwang : 4/28/2011<br>wwang : 4/28/2011<br>ckniffin : 4/25/2011<br>terry : 4/5/2004<br>ckniffin : 1/21/2004<br>mgross : 5/7/2001<br>mgross : 5/4/2001<br>mgross : 5/4/2001<br>terry : 5/3/2001<br>mcapotos : 8/1/2000<br>mgross : 4/10/2000<br>mgross : 4/7/2000<br>terry : 3/31/2000<br>alopez : 7/9/1999
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<span class="mim-font">
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<strong>#</strong> 604004
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MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1; MLC1
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<em>Alternative titles; symbols</em>
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VACUOLATING MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS<br />
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LVM<br />
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VL<br />
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LEUKOENCEPHALOPATHY WITH SWELLING AND CYSTS<br />
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VAN DER KNAAP DISEASE
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<strong>SNOMEDCT:</strong> 703536004;
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<strong>ICD10CM:</strong> G93.42;
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<strong>ORPHA:</strong> 2478;
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<strong>DO:</strong> 0080316;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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22q13.33
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Megalencephalic leukoencephalopathy with subcortical cysts 1
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604004
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Autosomal recessive
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3
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MLC1
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605908
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1) is caused by homozygous or compound heterozygous mutation in the MLC1 gene (605908) on chromosome 22q13.</p>
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<strong>Description</strong>
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<p>Megalencephalic leukoencephalopathy with subcortical cysts is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurologic deterioration, including cerebellar ataxia, spasticity, epilepsy, and mild cognitive decline (summary by Lopez-Hernandez et al., 2011). </p><p><strong><em>Genetic Heterogeneity of Megalencephalic Leukoencephalopathy with Subcortical Cysts</em></strong></p><p>
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See also MLC2A (613925), caused by homozygous or compound heterozygous mutation in the HEPACAM gene (611642) on chromosome 11q24; MLC2B (613926), caused by heterozygous mutation in the HEPACAM gene; MLC3 (620447), caused by mutation in the GPRC5B gene (605948) on chromosome 16p12; and MLC4 (620448), caused by mutation in the AQP4 gene (600308) on chromosome 18q11.</p>
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<strong>Clinical Features</strong>
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<p>Van der Knaap et al. (1995) described a syndrome of cerebral leukoencephalopathy and megalencephaly with infantile onset in 8 children, including 2 sibs. Neurologic findings were initially normal or near normal, despite megalencephaly and magnetic resonance imaging (MRI) evidence of severe white matter involvement. Slow progressive ataxia and spasticity developed, while intellectual functioning was preserved for years after onset of the disorder. Epilepsy was present in 6 of the 8 patients, with time of first seizure ranging from 1.5 years to 12 years. All patients were from the Netherlands. Age of presentation varied from 2 months to 10 years in a child who had immigrated. All patients had cysts on MRI. MRI showed cysts in the tips of the temporal lobes and frontoparietal subcortical area. Cerebellar hemispheres were mildly involved and not swollen. Cerebral hemispheric white matter was diffusely abnormal with considerable swelling obliterating the subarachnoid spaces. Central white matter structures, including the corpus callosum, internal capsule, and brainstem, were relatively spared. MRI characteristics also included diffuse abnormality in signal intensity. MRI abnormalities that are characteristic for this disorder are the discrepant severity in comparison to clinical picture, the aspect of white matter abnormalities (diffuse, homogeneous abnormality with swelling), the distribution of the abnormalities (supratentorial, hemispheric white matter involvement with relative sparing of central white matter structures), absence of gray matter involvement, and the presence of cysts with a typical location. MR spectra were relatively mildly abnormal. Screening for inborn errors, especially those that cause either megalencephaly or white matter disease or both, was negative. Van der Knaap et al. (1995) stated that this disease can be defined on the basis of clinical and MRI findings. Four of the patients had parents who were consanguineous, and 2 of the patients had an affected sib. The authors suggested an autosomal recessive mode of inheritance. </p><p>Van der Knaap et al. (1996) described the results of brain biopsy performed in one of the patients described by van der Knaap et al. (1995). A spongiform leukoencephalopathy without cortical involvement was revealed. Histopathologic findings placed the disease among the vacuolating myelinopathies, although it is distinct from the well-known forms. Possible pathophysiologic mechanisms are splitting of the outermost myelin lamellae at the intraperiod line or a disturbance of compaction of the outermost myelin lamellae at the intraperiod line. </p><p>Topcu et al. (2000) reported on vacuolating megalencephalic leukoencephalopathy characterized by diffuse swelling of the white matter, large subcortical cysts, and megalencephaly with infantile onset. They pointed to additional cases reported by Goutieres et al. (1996), Singhal et al. (1996), Mejaski-Bosnjak et al. (1997), and Topcu et al. (1998). Family studies in several ethnic groups had suggested autosomal recessive inheritance. </p><p>Patrono et al. (2003) reported clinical, neuroradiologic, and molecular findings in 18 patients from 15 unrelated families with MLC. Most patients had a delay in reaching autonomous walking and presented with early-onset ataxia. About half of the patients lost the ability to walk by age 11 years, and about half showed learning difficulties in the first years of school. All had macrocephaly, and most had seizures. </p><p>Lopez-Hernandez et al. (2011) reported a woman with megalencephalic leukoencephalopathy with subcortical cysts-1. She developed macrocephaly within the first few months of life, and thereafter showed slow motor deterioration, epilepsy, and cognitive decline. Brain MRI at age 40 years showed diffuse signal abnormalities in the cerebral white matter, with global atrophy and subcortical cysts in the anterior temporal region. She died at age 57 years following a cranial trauma. Postmortem brain examination showed reduced cerebral white matter with cavitation in the frontal and parietal lobes. Microscopic examination showed preservation of the cerebral cortex, but lack of myelin in the deep white matter with cavitation in the most affected areas. There was a reduction in the number of astrocytes and oligodendrocytes and loss of axons. Many astrocytes lacking myelin contained alpha-beta-crystallin (CRYAB; 123590), a stress protein. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>By genome scan of 13 affected Turkish families, Topcu et al. (2000) mapped the disease locus to the telomeric region of 22q, within a 3-cM linkage interval (maximum multipoint lod score of 17 for this interval). Linkage analysis under the genetic-heterogeneity hypothesis showed no genetic heterogeneity. Topcu et al. (2000) found no abnormalities in 3 positional candidate genes: FBLN1 (135820), GSTT1 (600436), and GSTT2 (600437). </p><p>Topcu et al. (2000) enumerated several factors possibly responsible for the difficulties that they encountered in mapping the LVM locus. First, approximately half of the parents were distant cousins; therefore, the chromosomal region homozygous by descent was expected to be small. Second, these families originated from a population in which approximately 30% of the marriages are consanguineous. The number of observed heterozygotes was approximately half of what would be expected on the basis of marker PIC (polymorphism information content) values. Therefore, consanguinity reduced marker informativity by limiting the allele number. Third, the LVM locus mapped to the telomeric end of 22q, a region with poor marker coverage. Fourth, the size of the chromosomal region shared by the affected children appeared to be small, i.e., 3 cM. Although the families originated from rural areas of central and southeastern Anatolia, Turkey, no shared allele or shared haplotype was detected. This suggested either that the genetic markers are still too far from the disease locus to allow detection of an ancient founder effect or the existence of allelic heterogeneity. Although the authors noted mild and severe forms of the disease, both forms appeared to be linked to the same locus. </p><p>Leegwater et al. (2001) narrowed the critical region by linkage analysis of 11 informative families with MLC to a region of approximately 250 kb. One family with 2 patients who were sibs did not display linkage to any of the analyzed microsatellite markers on 22qtel, suggesting genetic heterogeneity and the existence of at least a second MLC locus. The maximum 2-point lod score for the 11 families was 6.6 at a recombination fraction of 0.02. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In 7 informative and 6 uninformative families with MLC, Leegwater et al. (2001) identified 12 different mutations in the MLC1 gene (see, e.g., 605908.0001). </p><p>In 13 of 18 patients with MLC, Patrono et al. (2003) identified 11 mutations in the MLC1 gene. There was no apparent genotype/phenotype correlation. Five patients did not show MLC1 mutations, indicating genetic heterogeneity. </p><p>In a woman with megalencephalic leukoencephalopathy with subcortical cysts-1, Lopez-Hernandez et al. (2011) identified a homozygous mutation in the MLC1 gene (S69L; 605908.0013). Patient brain tissue showed no immunostaining for MLC1, indicating that deficiency of cell surface MLC1 protein expression is the basis for the disorder. In vitro expression of the S69L mutation in HeLa cells showed that the mutant protein was located in intracellular compartments, with reduced surface membrane expression compared to wildtype. The mutant protein also showed reduced stability. </p><p>By immunohistochemical analysis, Sirisi et al. (2014) observed mislocalization of GLIALCAM (HEPACAM; 611642) in Bergmann glia in the cerebellum of the patient with megalencephalic leukoencephalopathy with subcortical cysts-1 reported by Lopez-Hernandez et al. (2011). </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<p />
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<p class="mim-text-font">
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Goutieres, F., Boulloche, J., Bourgeois, M., Aicardi, J.
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<strong>Leukoencephalopathy, megalencephaly, and mild clinical course: a recently individualized familial leukodystrophy: report on five new cases.</strong>
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J. Child Neurol. 11: 439-444, 1996.
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[PubMed: 9120220]
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[Full Text: https://doi.org/10.1177/088307389601100604]
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Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S.
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<strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Am. J. Hum. Genet. 68: 831-838, 2001.
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[PubMed: 11254442]
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[Full Text: https://doi.org/10.1086/319519]
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<p class="mim-text-font">
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Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S.
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<strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong>
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Am. J. Hum. Genet. 88: 422-432, 2011.
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[PubMed: 21419380]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.02.009]
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<p class="mim-text-font">
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Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R.
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<strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Hum. Molec. Genet. 20: 3266-3277, 2011.
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[PubMed: 21624973]
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[Full Text: https://doi.org/10.1093/hmg/ddr238]
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