2770 lines
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Entry
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- #620313 - LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3; VWM3
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- OMIM
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<p>
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<span class="h4">#620313</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/620313"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS603896"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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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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</h4>
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<div><a href="https://clinicaltrials.gov/search?cond=LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER" 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=3664&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/NBK1258/" 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.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=135" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0070372" 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/620313" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0070372" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</div>
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 135<br />
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<strong>DO:</strong> 0070372<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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620313
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</span>
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</span>
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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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LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3; VWM3
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</h3>
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</div>
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<div>
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<br />
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/549?start=-3&limit=10&highlight=549">
|
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1p34.1
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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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Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure
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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/620313"> 620313 </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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<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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</td>
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<td>
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<span class="mim-font">
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EIF2B3
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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/606273"> 606273 </a>
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</span>
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</td>
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</tr>
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</table>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/620313" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<a href="/phenotypicSeries/PS603896" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/620313" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/620313" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal 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">
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<strong> GENITOURINARY </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Internal Genitalia (Female) </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Ovarian failure (late-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883450&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883450</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111550004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111550004</a>]</span><br /> -
|
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Secondary amenorrhea (late-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883453&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883453</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86030004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86030004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/156036003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">156036003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N91.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N91.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000869" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000869</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Central Nervous System </em>
|
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</span>
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Leukoencephalopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22811006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22811006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16058431000119104" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16058431000119104</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0270612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0270612</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002352</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002352</a>]</span><br /> -
|
|
Normal-mild developmental delay prior to disease onset <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883459&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883459</a>]</span><br /> -
|
|
Chronic-progressive course with episodes of rapid deterioration following fever or head trauma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858996</a>]</span><br /> -
|
|
Unsteady gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22631008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22631008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231686&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231686</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002317</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002317" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002317</a>]</span><br /> -
|
|
Loss of coordination <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751891&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751891</a>]</span><br /> -
|
|
Deterioration of motor development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751890&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751890</a>]</span><br /> -
|
|
Cognitive deficits <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/443265004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">443265004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009241</a>, <a href="https://bioportal.bioontology.org/search?q=C0338656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338656</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</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 /> -
|
|
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</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 /> -
|
|
Symmetric and diffusely abnormal signal in cerebral hemispheric white matter seen on MRI <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883460&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883460</a>]</span><br /> -
|
|
Abnormal white matter with signal intensity close to/same as CSF (T2-weighted or FLAIR images seen on MRI) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883461&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883461</a>]</span><br />
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|
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</span>
|
|
</div>
|
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Mental decline (late-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883462&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883462</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> MISCELLANEOUS </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
|
- Chronic, progressive disease with episodes of rapid deterioration with loss of motor functioning <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90734009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90734009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1547296&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1547296</a>, <a href="https://bioportal.bioontology.org/search?q=C1555457&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1555457</a>, <a href="https://bioportal.bioontology.org/search?q=C0205191&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0205191</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011010</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011010</a>]</span><br /> -
|
|
Cognitive function better preserved than motor function<br /> -
|
|
Onset early childhood-adulthood<br /> -
|
|
Subset of patients with ovarian failure and later onset of neurologic dysfunction<br /> -
|
|
In mutational analysis of EIF2B genes in 68 families, 3 families (4%) had mutations in EIF2B3<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> MOLECULAR BASIS </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<div>
|
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<span class="mim-font">
|
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|
|
- Caused by mutation in the eukaryotic translation initiation factor 2B, subunit 3 gene (EIF2B3, <a href="/entry/606273#0001">606273.0001</a>)<br />
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</span>
|
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</div>
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</div>
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</div>
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<div class="text-right">
|
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
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</div>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<h5>
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Leukoencephalopathy with vanishing white matter
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- <a href="/phenotypicSeries/PS603896">PS603896</a>
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- 5 Entries
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<strong>Location</strong>
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<a href="/geneMap/1/549?start=-3&limit=10&highlight=549"> 1p34.1 </a>
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<span class="mim-font">
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<a href="/entry/620313"> Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/620313"> 620313 </a>
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<a href="/entry/606273"> EIF2B3 </a>
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<span class="mim-font">
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<a href="/entry/606273"> 606273 </a>
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<a href="/geneMap/2/133?start=-3&limit=10&highlight=133"> 2p23.3 </a>
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<span class="mim-font">
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<a href="/entry/620314"> Leukoencephalopathy with vanishing white matter 4, with or without ovarian failure </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<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/620314"> 620314 </a>
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<span class="mim-font">
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<a href="/entry/606687"> EIF2B4 </a>
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<span class="mim-font">
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<a href="/entry/606687"> 606687 </a>
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<a href="/geneMap/3/908?start=-3&limit=10&highlight=908"> 3q27.1 </a>
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<span class="mim-font">
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<a href="/entry/620315"> Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<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/620315"> 620315 </a>
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<span class="mim-font">
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<a href="/entry/603945"> EIF2B5 </a>
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<span class="mim-font">
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<a href="/entry/603945"> 603945 </a>
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<a href="/geneMap/12/932?start=-3&limit=10&highlight=932"> 12q24.31 </a>
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<span class="mim-font">
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<a href="/entry/603896"> Leukoencephalopathy with vanishing white matter 1, with or without ovarian failure </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/603896"> 603896 </a>
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<span class="mim-font">
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<a href="/entry/606686"> EIF2B1 </a>
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<span class="mim-font">
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<a href="/entry/606686"> 606686 </a>
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<a href="/geneMap/14/394?start=-3&limit=10&highlight=394"> 14q24.3 </a>
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<span class="mim-font">
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<a href="/entry/620312"> Leukoencephalopathy with vanishing white matter 2, with or without ovarian failure </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 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/620312"> 620312 </a>
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<span class="mim-font">
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<a href="/entry/606454"> EIF2B2 </a>
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<span class="mim-font">
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<a href="/entry/606454"> 606454 </a>
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that leukoencephalopathy with vanishing white matter-3 (VWM3) is caused by homozygosity or compound heterozygosity for mutation in the EIF2B3 gene (<a href="/entry/606273">606273</a>) on chromosome 1p34.</p>
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<p>Leukoencephalopathy with vanishing white matter-3 (VWM3) is an autosomal recessive leukoencephalopathy characterized by progressive cerebellar ataxia, spasticity, and mental decline. The course is chronic and progressive, with episodes of rapid deterioration following minor head trauma. Affected females may have amenorrhea. Magnetic resonance imaging (MRI) reveals diffuse leukoencephalopathy with lesions having cerebrospinal fluid (CSF)-like signals (summary by <a href="#4" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of VWM, see <a href="/entry/603896">603896</a>.</p>
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<p><a href="#5" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">Van der Knaap et al. (2002)</a> studied 2 patients (vwm91 and vwm47) with leukoencephalopathy with vanishing white matter and mutation in the EIF2B3 gene. In both patients, MRI showed symmetrically and diffusely abnormal cerebral hemispheric white matter, signal intensity of part or all of the abnormal white matter close to or the same as cerebrospinal fluid (CSF) on T2-weighted and either proton density or FLAIR images, and a fine meshwork of remaining tissue strands visible within the areas of CSF-like white matter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" 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="Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. <strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong> J. Hum. Genet. 54: 74-77, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>] [<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158808">Wu et al. (2009)</a> reported 5 children (patients 7-11) with VWM and mutation in the EIF2B3 gene. Four had normal development before disease onset, and the fifth patient had been mildly delayed. Motor signs were the presenting symptoms in all. Four had moderate to severe motor difficulties (either ambulating with assistance or confined to wheelchair or bed) by age 6 years; the fifth child had mild motor difficulties and could ambulate without assistance, with ataxia or gait disturbance. Cognitive difficulties were mild or moderate. The most severely affected patient had seizures and dysarthria. The disorder was noted to be progressive in all. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" 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="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> reported a 30-year-old Japanese woman (patient 3) with adult-onset leukoencephalopathy with vanishing white matter and mutation in the EIF2B3 gene. She developed secondary amenorrhea at age 28 years, left hemianopia at age 29, and weakness in her left leg after a fall. T1- and T2-weighted MRI showed diffuse hypointense and hyperintense lesions, respectively, in cerebral white matter. Some of the white matter lesions adjacent to the lateral ventricles showed signal intensities identical to those of CSF on FLAIR imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N. <strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong> Neurology 79: 2077-2078, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23115207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23115207</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182749edc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23115207">Ghezzi et al. (2012)</a> described a 66-year-old woman with adult-onset vanishing white matter disease and mutation in the EIF2B3 gene. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances. She had experienced a rapid worsening of her clinical condition in the 10 days prior to evaluation. Neurologic examination demonstrated lower limb hypertonia, spastic paraparesis, brisk reflexes, positive Babinski sign in her right foot, and ideomotor apraxia. Her medical history was significant for premature ovarian failure at age 24 years, subclinical hypothyroidism, and late-onset diabetes. A brain MRI showed symmetric diffuse signal abnormality in the hemispheric white matter in T2-weighted images, sparing the U fibers. Cortical and subcortical atrophy was also present. Adult-onset vanishing white matter disease was diagnosed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23115207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of VWM3 in the families reported by <a href="#6" class="mim-tip-reference" title="Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. <strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong> J. Hum. Genet. 54: 74-77, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>] [<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158808">Wu et al. (2009)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">Van der Knaap et al. (2002)</a> identified mutations in the EIF2B3 gene in 2 patients (vwm91 and vwm47) with vanishing white matter. Patient vwm91 was compound heterozygous for a missense mutation (R225Q; <a href="/entry/606273#0001">606273.0001</a>) and a 2-bp deletion (<a href="/entry/606273#0002">606273.0002</a>). Patient vwm47 was homozygous for an ala87-to-val substitution (A87V; <a href="/entry/606273#0003">606273.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" 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="Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. <strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong> J. Hum. Genet. 54: 74-77, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>] [<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158808">Wu et al. (2009)</a> identified an ile346-to-thr substitution (I346T; <a href="/entry/606273#0004">606273.0004</a>) in the EIF2B3 gene in 4 unrelated Chinese patients with vanishing white matter. Two patients carried the mutation in homozygosity, 1 in compound heterozygosity, and in 1 patient a second mutation could not be identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" 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 30-year-old Japanese woman (patient 3), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter, <a href="#4" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> identified a homozygous c.80T-A transversion in the EIF2B3 gene, resulting in a leu27-to-gln (L27Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" 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 66-year old woman with adult-onset vanishing white matter disease, <a href="#3" class="mim-tip-reference" title="Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N. <strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong> Neurology 79: 2077-2078, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23115207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23115207</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182749edc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23115207">Ghezzi et al. (2012)</a> identified homozygosity for a missense mutation (A87V; <a href="/entry/606273#0003">606273.0003</a>) in EIF2B3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23115207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies with homozygous or compound heterozygous mutations in EIF2B2, EIF2B3, EIF2B4, and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. <a href="#2" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> found that 68 (87%) of 78 families with MRI criteria of leukodystrophy had a mutation in 4 of the EIF2B genes. Forty-two families (62%) had a mutation in the EIF2B5 gene, and 71% had the arg113-to-his mutation (R113H; <a href="/entry/603945#0004">603945.0004</a>). Thirteen families (19%), 10 families (15%), and 3 families (4%) had mutations in the EIF2B2, EIF2B4, and EIF2B3 genes, respectively. No mutations were identified in the EIF2B1 gene. Disease onset ranged from 4 months to 30 years of age, with a mean of 3.9 years, and disease severity ranged from no neurologic signs in 2 to death in 24 individuals; there was no correlation between type of mutated gene and the age at onset or disease severity. However, the EIF2B5 R113H mutation and the EIF2B2 glu213-to-gly mutation (E213G; <a href="/entry/606454#0001">606454.0001</a>) were significantly associated with milder phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Fogli2004" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.">Fogli et al. (2004)</a>
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Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard-Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., Chaunu, M. P., Rodriguez, D., Boespflug-Tanguy, O.
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<strong>The effect of genotype on the natural history of eIF2B-related leukodystrophies.</strong>
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Neurology 62: 1509-1517, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136673</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000123259.67815.db" target="_blank">Full Text</a>]
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<strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong>
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Europ. J. Hum. Genet. 12: 561-566, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N.
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<strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong>
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Neurology 79: 2077-2078, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23115207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23115207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23115207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3182749edc" target="_blank">Full Text</a>]
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Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S.
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<strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong>
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Neurogenetics 12: 259-261, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank">Full Text</a>]
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van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C.
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<strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong>
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Ann. Neurol. 51: 264-270, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10112" target="_blank">Full Text</a>]
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Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y.
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<strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong>
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J. Hum. Genet. 54: 74-77, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank">Full Text</a>]
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Kelly A. Przylepa - updated : 12/13/2023
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Anne M. Stumpf - updated : 06/14/2023
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Anne M. Stumpf : 04/06/2023
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alopez : 12/13/2023
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alopez : 06/14/2023<br>alopez : 04/17/2023
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LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3; VWM3
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<strong>ORPHA:</strong> 135;
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<strong>DO:</strong> 0070372;
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Phenotype
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Phenotype <br /> MIM number
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1p34.1
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Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure
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Autosomal recessive
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3
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EIF2B3
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606273
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<p>A number sign (#) is used with this entry because of evidence that leukoencephalopathy with vanishing white matter-3 (VWM3) is caused by homozygosity or compound heterozygosity for mutation in the EIF2B3 gene (606273) on chromosome 1p34.</p>
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<p>Leukoencephalopathy with vanishing white matter-3 (VWM3) is an autosomal recessive leukoencephalopathy characterized by progressive cerebellar ataxia, spasticity, and mental decline. The course is chronic and progressive, with episodes of rapid deterioration following minor head trauma. Affected females may have amenorrhea. Magnetic resonance imaging (MRI) reveals diffuse leukoencephalopathy with lesions having cerebrospinal fluid (CSF)-like signals (summary by Matsukawa et al., 2011). </p><p>For a discussion of genetic heterogeneity of VWM, see 603896.</p>
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<p>Van der Knaap et al. (2002) studied 2 patients (vwm91 and vwm47) with leukoencephalopathy with vanishing white matter and mutation in the EIF2B3 gene. In both patients, MRI showed symmetrically and diffusely abnormal cerebral hemispheric white matter, signal intensity of part or all of the abnormal white matter close to or the same as cerebrospinal fluid (CSF) on T2-weighted and either proton density or FLAIR images, and a fine meshwork of remaining tissue strands visible within the areas of CSF-like white matter. </p><p>Wu et al. (2009) reported 5 children (patients 7-11) with VWM and mutation in the EIF2B3 gene. Four had normal development before disease onset, and the fifth patient had been mildly delayed. Motor signs were the presenting symptoms in all. Four had moderate to severe motor difficulties (either ambulating with assistance or confined to wheelchair or bed) by age 6 years; the fifth child had mild motor difficulties and could ambulate without assistance, with ataxia or gait disturbance. Cognitive difficulties were mild or moderate. The most severely affected patient had seizures and dysarthria. The disorder was noted to be progressive in all. </p><p>Matsukawa et al. (2011) reported a 30-year-old Japanese woman (patient 3) with adult-onset leukoencephalopathy with vanishing white matter and mutation in the EIF2B3 gene. She developed secondary amenorrhea at age 28 years, left hemianopia at age 29, and weakness in her left leg after a fall. T1- and T2-weighted MRI showed diffuse hypointense and hyperintense lesions, respectively, in cerebral white matter. Some of the white matter lesions adjacent to the lateral ventricles showed signal intensities identical to those of CSF on FLAIR imaging. </p><p>Ghezzi et al. (2012) described a 66-year-old woman with adult-onset vanishing white matter disease and mutation in the EIF2B3 gene. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances. She had experienced a rapid worsening of her clinical condition in the 10 days prior to evaluation. Neurologic examination demonstrated lower limb hypertonia, spastic paraparesis, brisk reflexes, positive Babinski sign in her right foot, and ideomotor apraxia. Her medical history was significant for premature ovarian failure at age 24 years, subclinical hypothyroidism, and late-onset diabetes. A brain MRI showed symmetric diffuse signal abnormality in the hemispheric white matter in T2-weighted images, sparing the U fibers. Cortical and subcortical atrophy was also present. Adult-onset vanishing white matter disease was diagnosed. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of VWM3 in the families reported by Wu et al. (2009) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>Van der Knaap et al. (2002) identified mutations in the EIF2B3 gene in 2 patients (vwm91 and vwm47) with vanishing white matter. Patient vwm91 was compound heterozygous for a missense mutation (R225Q; 606273.0001) and a 2-bp deletion (606273.0002). Patient vwm47 was homozygous for an ala87-to-val substitution (A87V; 606273.0003). </p><p>Wu et al. (2009) identified an ile346-to-thr substitution (I346T; 606273.0004) in the EIF2B3 gene in 4 unrelated Chinese patients with vanishing white matter. Two patients carried the mutation in homozygosity, 1 in compound heterozygosity, and in 1 patient a second mutation could not be identified. </p><p>In a 30-year-old Japanese woman (patient 3), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter, Matsukawa et al. (2011) identified a homozygous c.80T-A transversion in the EIF2B3 gene, resulting in a leu27-to-gln (L27Q) substitution. </p><p>In a 66-year old woman with adult-onset vanishing white matter disease, Ghezzi et al. (2012) identified homozygosity for a missense mutation (A87V; 606273.0003) in EIF2B3. </p>
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<p>Fogli et al. (2004) measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies with homozygous or compound heterozygous mutations in EIF2B2, EIF2B3, EIF2B4, and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease. </p>
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<p>Fogli et al. (2004) found that 68 (87%) of 78 families with MRI criteria of leukodystrophy had a mutation in 4 of the EIF2B genes. Forty-two families (62%) had a mutation in the EIF2B5 gene, and 71% had the arg113-to-his mutation (R113H; 603945.0004). Thirteen families (19%), 10 families (15%), and 3 families (4%) had mutations in the EIF2B2, EIF2B4, and EIF2B3 genes, respectively. No mutations were identified in the EIF2B1 gene. Disease onset ranged from 4 months to 30 years of age, with a mean of 3.9 years, and disease severity ranged from no neurologic signs in 2 to death in 24 individuals; there was no correlation between type of mutated gene and the age at onset or disease severity. However, the EIF2B5 R113H mutation and the EIF2B2 glu213-to-gly mutation (E213G; 606454.0001) were significantly associated with milder phenotypes. </p>
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<strong>See Also:</strong>
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Fogli et al. (2004)
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<strong>REFERENCES</strong>
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Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard-Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., Chaunu, M. P., Rodriguez, D., Boespflug-Tanguy, O.
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<strong>The effect of genotype on the natural history of eIF2B-related leukodystrophies.</strong>
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Neurology 62: 1509-1517, 2004.
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[PubMed: 15136673]
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[Full Text: https://doi.org/10.1212/01.wnl.0000123259.67815.db]
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Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O.
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<strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong>
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Europ. J. Hum. Genet. 12: 561-566, 2004.
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[PubMed: 15054402]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201189]
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Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N.
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<strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong>
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Neurology 79: 2077-2078, 2012.
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[PubMed: 23115207]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3182749edc]
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Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S.
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<strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong>
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Neurogenetics 12: 259-261, 2011.
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[PubMed: 21484434]
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[Full Text: https://doi.org/10.1007/s10048-011-0284-7]
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van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C.
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<strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong>
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Ann. Neurol. 51: 264-270, 2002.
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[PubMed: 11835386]
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[Full Text: https://doi.org/10.1002/ana.10112]
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Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y.
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<strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong>
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J. Hum. Genet. 54: 74-77, 2009.
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[PubMed: 19158808]
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[Full Text: https://doi.org/10.1038/jhg.2008.10]
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Kelly A. Przylepa - updated : 12/13/2023<br>Anne M. Stumpf - updated : 06/14/2023
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alopez : 12/13/2023<br>alopez : 06/14/2023<br>alopez : 04/17/2023
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