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- #620315 - LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5; VWM5
- OMIM
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<span class="h4">#620315</span>
<br />
<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">
<a href="/clinicalSynopsis/620315"><strong>Clinical Synopsis</strong></a>
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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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<li role="presentation" style="margin-left: 1em">
<a href="#nomenclature">Nomenclature</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<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>
<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.alliancegenome.org/disease/DOID:0070367" 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>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ORPHA:</strong> 135<br />
<strong>DO:</strong> 0070367<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
620315
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5; VWM5
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
CREE LEUKOENCEPHALOPATHY; CLE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/908?start=-3&limit=10&highlight=908">
3q27.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620315"> 620315 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
EIF2B5
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603945"> 603945 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/620315" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS603896" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/620315" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/620315" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> 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="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Macrocephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hyperventilation (early-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883479&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883479</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68978004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68978004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/786.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">786.01</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002883" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002883</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Vomiting (early-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883470&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883470</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br /> -
Diarrhea (early-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883478&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883478</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Female) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
Mental decline <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883480&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883480</a>]</span><br /> -
Headache <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25064002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25064002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R51.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R51.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R51</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/784.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018681&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018681</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002315</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 /> -
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 /> -
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 /> -
Gait difficulties <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br /> -
Hypotonia (early-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883443&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883443</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Developmental delay (early-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883481</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</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 /> -
Coma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371632003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371632003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405809000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405809000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0543874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0543874</a>, <a href="https://bioportal.bioontology.org/search?q=C3146279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3146279</a>, <a href="https://bioportal.bioontology.org/search?q=C0009421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009421</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</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 (FLAIR images seen on MRI) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883445&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883445</a>]</span><br /> -
Cystic degeneration of cerebral white matter seen on MRI <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883482</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Demyelinating peripheral neuropathy (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23414001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23414001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0270922&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0270922</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007108" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007108</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007108" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007108</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Lethargy (early-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883483</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/214264003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">214264003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R53.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R53.83</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span><br /> -
Paranoia (late-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883484&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883484</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191667009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191667009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F22</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011999" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011999</a>]</span><br /> -
Dementia (late-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848565</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Elevated luteinizing hormone (LH) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4229939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4229939</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011969" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011969</a>]</span><br /> -
Elevated follicle-stimulating hormone (FSH) Decreased estrogen <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5883458&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5883458</a>]</span><br /> -
Decreased progesterone <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1328444&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1328444</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Chronic, progressive disease with episodes of rapid deterioration with loss of motor functioning and possible coma <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 /> -
Episodic deterioration provoked following fever, head trauma, or fright<br /> -
Onset variable from infancy (early-onset) to adulthood (late-onset)<br /> -
Subset of patients with ovarian failure and later onset of neurologic dysfunction<br /> -
Cree leukoencephalopathy is a rapidly fatal infantile variant (onset 3-9 months) in the Canadian Cree and Chippewayan indigenous population<br /> -
In mutational analysis of EIF2B genes in 68 families<br /> -
62% had mutations in EIF2B5<br />
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<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the eukaryotic translation initiation factor 2B, subunit 5 gene (EIF2B5, <a href="/entry/603945#0001">603945.0001</a>)<br />
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<h5>
Leukoencephalopathy with vanishing white matter
- <a href="/phenotypicSeries/PS603896">PS603896</a>
- 5 Entries
</h5>
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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</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<td>
<span class="mim-font">
<a href="/geneMap/1/549?start=-3&limit=10&highlight=549"> 1p34.1 </a>
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<span class="mim-font">
<a href="/entry/620313"> Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure </a>
</span>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<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">
<a href="/entry/620313"> 620313 </a>
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<span class="mim-font">
<a href="/entry/606273"> EIF2B3 </a>
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<span class="mim-font">
<a href="/entry/606273"> 606273 </a>
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<span class="mim-font">
<a href="/geneMap/2/133?start=-3&limit=10&highlight=133"> 2p23.3 </a>
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<td>
<span class="mim-font">
<a href="/entry/620314"> Leukoencephalopathy with vanishing white matter 4, with or without ovarian failure </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
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<span class="mim-font">
<a href="/entry/620314"> 620314 </a>
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<span class="mim-font">
<a href="/entry/606687"> EIF2B4 </a>
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<span class="mim-font">
<a href="/entry/606687"> 606687 </a>
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<span class="mim-font">
<a href="/geneMap/3/908?start=-3&limit=10&highlight=908"> 3q27.1 </a>
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<td>
<span class="mim-font">
<a href="/entry/620315"> Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
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<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
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<span class="mim-font">
<a href="/entry/620315"> 620315 </a>
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<span class="mim-font">
<a href="/entry/603945"> EIF2B5 </a>
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<td>
<span class="mim-font">
<a href="/entry/603945"> 603945 </a>
</span>
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<td>
<span class="mim-font">
<a href="/geneMap/12/932?start=-3&limit=10&highlight=932"> 12q24.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603896"> Leukoencephalopathy with vanishing white matter 1, with or without ovarian failure </a>
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</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
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<td>
<span class="mim-font">
<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">
<a href="/entry/603896"> 603896 </a>
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<td>
<span class="mim-font">
<a href="/entry/606686"> EIF2B1 </a>
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<span class="mim-font">
<a href="/entry/606686"> 606686 </a>
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<td>
<span class="mim-font">
<a href="/geneMap/14/394?start=-3&limit=10&highlight=394"> 14q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620312"> Leukoencephalopathy with vanishing white matter 2, with or without ovarian failure </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
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<span class="mim-font">
<a href="/entry/620312"> 620312 </a>
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<span class="mim-font">
<a href="/entry/606454"> EIF2B2 </a>
</span>
</td>
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<span class="mim-font">
<a href="/entry/606454"> 606454 </a>
</span>
</td>
</tr>
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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-5 (VWM5) is caused by homozygous or compound heterozygous mutation in the EIF2B5 gene (<a href="/entry/603945">603945</a>) on chromosome 3q27.</p>
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<strong>Description</strong>
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<p>Leukoencephalopathy with vanishing white matter-5 (VWM5) is a chronic and progressive autosomal recessive leukoencephalopathy characterized by neurologic deterioration usually beginning in late infancy or early childhood; however, juvenile- and adult-onset cases have been reported. Neurologic signs include cerebellar ataxia, spasticity, and relatively preserved mental abilities. The disease is chronic and progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death occurs after a variable period of a few years to a few decades, usually following an episode of fever and coma. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy are diagnostic and show a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage, with increasing amounts of the abnormal white matter vanishing and being replaced by cerebrospinal fluid; autopsy confirms these findings (summary by <a href="#14" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. &lt;strong&gt;Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.&lt;/strong&gt; Nature Genet. 29: 383-388, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11704758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11704758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng764&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11704758">Leegwater et al., 2001</a>). Ovarian dysgenesis may be present in affected females (<a href="#9" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. &lt;strong&gt;Ovarian failure related to eukaryotic initiation factor 2B mutations.&lt;/strong&gt; Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12707859/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12707859&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/375404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12707859">Fogli et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11704758+12707859" 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><p><strong><em>Cree Leukoencephalopathy</em></strong></p><p>
An infantile leukoencephalopathy among the native Cree and Chippewayan indigenous population in Northern Quebec and Manitoba results from homozygosity for an arg195-to-his (R195H; 603945.0005) mutation in the EIF2B5 gene. These patients have disease onset between 3 and 9 months of age, with death in 100% by 21 months of age.</p>
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<strong>Clinical Features</strong>
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<p>Cree leukoencephalopathy, or CLE, is a rapidly fatal leukodystrophy described first by <a href="#3" class="mim-tip-reference" title="Black, D. N., Booth, F., Watters, G. V., Andermann, E., Dumont, C., Halliday, W. C., Hoogstraten, J., Kabay, M. E., Kaplan, P., Meagher-Villemure, K., Michaud, J., O&#x27;Gorman, G. &lt;strong&gt;Leukoencephalopathy among native Indian infants in northern Quebec and Manitoba.&lt;/strong&gt; Ann. Neurol. 24: 490-496, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3239951/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3239951&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410240403&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3239951">Black et al. (1988)</a> in the native Cree and Chippewayan indigenous population of northern Quebec and Manitoba. The onset of CLE is between 3 and 9 months of age, with death in 100% by 21 months of age. Hypotonia often is noted in early infancy followed by relatively sudden onset of seizures, spasticity, hyperventilation, vomiting, and diarrhea, often in a setting of a febrile illness. Onset is followed by developmental regression, lethargy, blindness, and cessation of head growth seen as flattening of the head circumference curve. Computerized tomography of the head shows symmetrically hypodense white matter. Gross neuropathologic examination has shown that white matter is grayish white with translucent zones and subcortical cavitation. Microscopic examination has shown diffuse white matter vacuolation in some cases and astrogliosis with presence of oligodendrocytes and cells described as lipid-laden macrophages (<a href="#1" class="mim-tip-reference" title="Alorainy, I. A., Patenaude, Y. G., O&#x27;Gorman, A. M., Black, D. N., Meagher-Villemure, K. &lt;strong&gt;Cree leukoencephalopathy: neuroimaging findings.&lt;/strong&gt; Radiology 213: 400-406, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10551219/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10551219&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1148/radiology.213.2.r99oc28400&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10551219">Alorainy et al., 1999</a>). Parents of affected children are normal, and because of a high level of consanguinity in this population, CLE is considered autosomal recessive. <a href="#11" class="mim-tip-reference" title="Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R. &lt;strong&gt;Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.&lt;/strong&gt; Ann. Neurol. 52: 506-510, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12325082/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12325082&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12325082">Fogli et al. (2002)</a> investigated microscopically 3 brains of CLE patients and found the same typical foamy oligodendrocytes observed in patients with childhood ataxia with diffuse central hypomyelination (CACH), also called myelinopathia centralis diffusa or vanishing white matter disease (VWM). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3239951+12325082+10551219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Fogli, A., Dionisi-Vici, C., Deodato, F., Bartuli, A., Boespflug-Tanguy, O., Bertini, E. &lt;strong&gt;A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.&lt;/strong&gt; Neurology 59: 1966-1968, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12499492/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12499492&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000041666.76863.47&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12499492">Fogli et al. (2002)</a> reported 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter and mutation in the EIF2B5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499492" 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="Biancheri, R., Rossi, A., Di Rocco, M., Filocamo, M., Pronk, J. C., van der Knaap, M. S., Tortori-Donati, P. &lt;strong&gt;Leukoencephalopathy with vanishing white matter: an adult onset case.&lt;/strong&gt; Neurology 61: 1818-1819, 2003. Note: Erratum: Neurology 62: 1242 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14694060/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14694060&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000098994.35677.3c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14694060">Biancheri et al. (2003)</a> reported adult onset of VWM in a 27-year-old woman, confirmed by mutation in the EIF2B5 gene. At the age of 25 years, an MRI study was performed to evaluate the pituitary gland because of elevated prolactin levels. A diffuse leukoencephalopathy was depicted in the absence of any clinical neurologic signs. Two years later, she developed progressive gait abnormalities consistent with spastic paraparesis and speech difficulties. A second MRI showed worsening of the white matter abnormalities with some cystic degeneration. <a href="#2" class="mim-tip-reference" title="Biancheri, R., Rossi, A., Di Rocco, M., Filocamo, M., Pronk, J. C., van der Knaap, M. S., Tortori-Donati, P. &lt;strong&gt;Leukoencephalopathy with vanishing white matter: an adult onset case.&lt;/strong&gt; Neurology 61: 1818-1819, 2003. Note: Erratum: Neurology 62: 1242 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14694060/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14694060&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000098994.35677.3c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14694060">Biancheri et al. (2003)</a> emphasized the clinical variability of the disorder and the importance of a high level of suspicion for VWM even in cases of adult onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14694060" 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="#16" class="mim-tip-reference" title="Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S. &lt;strong&gt;Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.&lt;/strong&gt; Neurology 62: 1601-1603, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15136690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15136690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000123117.11264.0e&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15136690">Ohtake et al. (2004)</a> reported a Japanese woman, born of consanguineous parents, with adult-onset VWM caused by a homozygous mutation in the EIF2B5 gene (<a href="/entry/603945#0008">603945.0008</a>). The patient had been well until a traffic accident at age 40 years, after which she became progressively disorganized, forgetful, delusional, and emotionally unstable. By age 52 years, she had developed spastic gait, hyperreflexia, and frank dementia with defective planning and confabulation. T2-weighted MRI showed diffuse hyperintense lesions in the cerebral white matter, most prominent in the frontal lobe. Other findings indicated focal rarefaction and cystic degeneration of the white matter, consistent with VWM. <a href="#16" class="mim-tip-reference" title="Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S. &lt;strong&gt;Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.&lt;/strong&gt; Neurology 62: 1601-1603, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15136690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15136690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000123117.11264.0e&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15136690">Ohtake et al. (2004)</a> suggested that patients with adult-onset VWM may present with presenile dementia or psychiatric symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Vermeulen, G., Seidl, R., Mercimek-Mahmutoglu, S., Rotteveel, J. J., Scheper, G. C., van der Knapp, M. S. &lt;strong&gt;Fright is a provoking factor in vanishing white matter disease.&lt;/strong&gt; Ann. Neurol. 57: 560-563, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15786451/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15786451&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20418&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15786451">Vermeulen et al. (2005)</a> reported 2 unrelated patients with VWM disease and mutation in the EIF2B5 gene who experienced episodes of rapid neurologic decline after being frightened. At age 4 years, the first patient witnessed his mother falling down the stairs. He lost consciousness immediately after that and remained in a coma for 10 days. He showed partial recovery afterwards, but permanently lost the ability to walk. At age 18 years, he was severely handicapped, wheelchair-bound, and unable to speak. The second patient was frightened by a dog at age 4 years. He had instantaneous neurologic decline with stupor and spastic hemiparesis. <a href="#22" class="mim-tip-reference" title="Vermeulen, G., Seidl, R., Mercimek-Mahmutoglu, S., Rotteveel, J. J., Scheper, G. C., van der Knapp, M. S. &lt;strong&gt;Fright is a provoking factor in vanishing white matter disease.&lt;/strong&gt; Ann. Neurol. 57: 560-563, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15786451/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15786451&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20418&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15786451">Vermeulen et al. (2005)</a> emphasized the rapid onset of neurologic deterioration in these 2 cases compared to the neurologic decline after infection, which usually occurs over the course of a few days. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15786451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Federico, A., Scali, O., Stromillo, M. L., Di Perri, C., Bianchi, S., Sicurelli, F., De Stefano, N., Malandrini, A., Dotti, M. T. &lt;strong&gt;Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation.&lt;/strong&gt; Neurology 67: 353-355, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16864840/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16864840&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000225077.40532.a5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16864840">Federico et al. (2006)</a> reported a Romanian boy who developed VWM disease at age 3 years and had mutation in the EIF2B5 gene. He had spasticity, hypotonia, and distal muscle weakness. In addition, he had a peripheral demyelinating neuropathy with decreased sensory and motor nerve conduction velocities. Sural nerve biopsy showed a moderate decrease in the myelinated fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16864840" 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="#17" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N&#x27;Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. &lt;strong&gt;Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.&lt;/strong&gt; Neurology 69: 400-402, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17646634/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17646634&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000266388.02772.f8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17646634">Passemard et al. (2007)</a> reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene. In the first family, 2 sibs had acute neurologic deterioration in infancy following viral infections. Brain MRIs showed severe white matter abnormalities and complete disappearance of hemispheric white matter, respectively. Both developed progressive severe macrocephaly after age 3 years. In the second family, 1 of 2 sisters who survived beyond age 3 years developed macrocephaly. <a href="#17" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N&#x27;Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. &lt;strong&gt;Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.&lt;/strong&gt; Neurology 69: 400-402, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17646634/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17646634&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000266388.02772.f8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17646634">Passemard et al. (2007)</a> suggested that altered brain water balance may result in swelling of the diseased white matter and macrocephaly in some patients with VWM disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" 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="Labauge, P., Horzinski, L., Ayrignac, X., Blanc, P., Vukusic, S., Rodriguez, D., Mauguiere, F., Peter, L., Goizet, C., Bouhour, F., Denier, C., Confavreux, C., Obadia, M., Blanc, F., de Seze, J., Fogli, A., Boespflug-Tanguy, O. &lt;strong&gt;Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases.&lt;/strong&gt; Brain 132: 2161-2169, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19625339/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19625339&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awp171&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19625339">Labauge et al. (2009)</a> reviewed the phenotypes of 16 patients from 14 families with adult-onset VWM, defined as onset after age 16 years. The mean age of onset was 31.1 years (range, 16 to 62 years), and there was a decreased male:female ratio (3:13). Initial symptoms were neurologic in 11 patients, psychiatric in 2, and ovarian failure in 2, and 1 patient was initially asymptomatic but diagnosed on brain MRI. Onset of the symptoms was linked to a precipitating factor in 13% of cases, including minor head trauma and delivery. Two (12.5%) patients died during a mean follow-up period of 11.2 years after a stress-induced deterioration. Of the 14 survivors, 62% showed a decline in their cognitive functions, and 79% were severely handicapped or bedridden. One individual remained asymptomatic. Stress worsened clinical symptoms in 38% of the patients. MRI findings included cerebral atrophy (75%), extensive cystic cavitating leukoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted hyperintensities. Thirteen of the families had mutations in the EIF2B5 gene, including the common R113H mutation (<a href="/entry/603945#0004">603945.0004</a>), which was found in 11 (79%) of the 14 families. The last family had a mutation in the EIF2B2 gene (E213G; <a href="/entry/606454#0001">606454.0001</a>). <a href="#12" class="mim-tip-reference" title="Labauge, P., Horzinski, L., Ayrignac, X., Blanc, P., Vukusic, S., Rodriguez, D., Mauguiere, F., Peter, L., Goizet, C., Bouhour, F., Denier, C., Confavreux, C., Obadia, M., Blanc, F., de Seze, J., Fogli, A., Boespflug-Tanguy, O. &lt;strong&gt;Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases.&lt;/strong&gt; Brain 132: 2161-2169, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19625339/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19625339&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awp171&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19625339">Labauge et al. (2009)</a> concluded that VWM may be underestimated as an adult-onset inherited leukoencephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625339" 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 id="nomenclature" class="mim-anchor"></a>
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<p><a href="#4" class="mim-tip-reference" title="Black, D. N., Watters, G. V., Andermann, E., Dumont, C., Kabay, M. E., Kaplan, P., Meagher-Villemure, K., Michaud, J., O&#x27;Gorman, G., Reece, E., Tsoukas, C., Wainberg, M. A. &lt;strong&gt;Encephalitis among Cree children in northern Quebec.&lt;/strong&gt; Ann. Neurol. 24: 483-489, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3239950/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3239950&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410240402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3239950">Black et al. (1988)</a> described an early-onset, progressive encephalopathy in an inbred Canadian Aboriginal community. They termed this disorder Cree encephalitis (<a href="/entry/225750">225750</a>) and distinguished it clinically from Cree leukoencephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3239950" 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 id="pathogenesis" class="mim-anchor"></a>
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<p>In cell cultures from the brain of an individual with VWM who had compound heterozygosity for mutations in EIF2B5 (T91A, <a href="/entry/603945#0001">603945.0001</a> and W628R, <a href="/entry/603945#0002">603945.0002</a>), <a href="#6" class="mim-tip-reference" title="Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C. &lt;strong&gt;EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.&lt;/strong&gt; Nature Med. 11: 277-283, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15723074/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15723074&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1195&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15723074">Dietrich et al. (2005)</a> observed prompt development of normal-appearing oligodendrocytes despite the extensive demyelination seen in the patient. However, few glial fibrillary acidic protein (GFAP; <a href="/entry/137780">137780</a>)-expressing astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP-expressing astrocytes, and RNA-interference targeting of EIF2B5 severely compromised the induction of GFAP-expressing cells from normal human glial progenitors. <a href="#6" class="mim-tip-reference" title="Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C. &lt;strong&gt;EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.&lt;/strong&gt; Nature Med. 11: 277-283, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15723074/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15723074&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm1195&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15723074">Dietrich et al. (2005)</a> suggested that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15723074" 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="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. &lt;strong&gt;Ovarian failure related to eukaryotic initiation factor 2B mutations.&lt;/strong&gt; Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12707859/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12707859&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/375404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12707859">Fogli et al. (2003)</a> reported 8 patients from 7 families with vanishing white matter leukodystrophy and ovarian failure, an association they termed ovarioleukodystrophy, and mutation in the EIF2B2, EIF2B4, or EIF2B5 gene. The diagnosis of ovarian failure was confirmed by findings of high basal gonadotropin levels and low estrogen and progesterone levels. All the patients had a normal karyotype, and only 1 patient had consanguineous parents. In 3 patients with primary amenorrhea, school difficulties, together with poor fine motor performance, were present prior to the development of a slowly progressive neurologic disease in adolescence. Only 1 patient presented with rapid cognitive decline, including a frontal lobe syndrome. The age at menarche was normal in the 5 patients with secondary amenorrhea. The age at onset of neurologic deterioration correlated positively with the severity of ovarian dysfunction. In at least 1 case ovarian failure preceded neurologic decline. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="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. &lt;strong&gt;Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.&lt;/strong&gt; Neurogenetics 12: 259-261, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21484434/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21484434&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-011-0284-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21484434">Matsukawa et al. (2011)</a> reported 3 unrelated Japanese patients, each born of consanguineous parents, with adult-onset VWM. Each carried a homozygous mutation in the EIF2B2 (V85E; <a href="/entry/606454#0006">606454.0006</a>), EIF2B5 (D270H; <a href="/entry/603945#0012">603945.0012</a>), or EIF2B3 (L27Q; <a href="/entry/606273#0005">606273.0005</a>) gene, respectively. The 2 affected women also had evidence of ovarian failure. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing the mutant subunits was significantly decreased (20-40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. <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>
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<p>Family data indicate that leukoencephalopathy with vanishing white matter has an autosomal recessive inheritance with age-dependent penetrance. <a href="#13" class="mim-tip-reference" title="Leegwater, P. A. J., Konst, A. A. M., Kuyt, B., Sandkuijl, L. A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. &lt;strong&gt;The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27.&lt;/strong&gt; Am. J. Hum. Genet. 65: 728-734, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10441579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10441579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302548&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10441579">Leegwater et al. (1999)</a> performed a genomewide linkage screening in 19 families with different ethnic origins. Significant linkage to 3q27 was observed in a 7-cM interval between markers D3S3730 and D3S3592, with a maximum multipoint lod score of 5.1 calculated from the entire data set. Genealogic studies had suggested that 7 parents in 4 Dutch families with VWM had inherited an allele for the disease from a common ancestor who lived at least 8 generations ago. Analysis of these families provided further evidence for the localization of the gene for VWM to 3q27. The patients shared a haplotype spanning 5 cM between markers D3S1618 and D3S3592. In 1 family of a different ethnic background, the patient had, in the same region, homozygosity for 13 consecutive markers spanning at least 12 cM, suggesting consanguinity between the parents. A healthy sib of this patient had the same homozygous haplotype which suggested that the healthy sib was presymptomatic for the disease. Because of ethical considerations, <a href="#13" class="mim-tip-reference" title="Leegwater, P. A. J., Konst, A. A. M., Kuyt, B., Sandkuijl, L. A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. &lt;strong&gt;The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27.&lt;/strong&gt; Am. J. Hum. Genet. 65: 728-734, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10441579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10441579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302548&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10441579">Leegwater et al. (1999)</a> could not evaluate the apparently healthy sib by MRI and MRS. Both the patient and the asymptomatic sib were adults. <a href="#19" class="mim-tip-reference" title="van der Knaap, M. S., Kamphorst, W., Barth, P. G., Kraaijeveld, C. L., Gut, E., Valk, J. &lt;strong&gt;Phenotypic variation in leukoencephalopathy with vanishing white matter.&lt;/strong&gt; Neurology 51: 540-547, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9710032/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9710032&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.51.2.540&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9710032">Van der Knaap et al. (1998)</a> had described similar phenotypic variation in an affected individual and in the individual's presymptomatic adult sib who had MRI findings typical for VWM. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10441579+9710032" 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 mode of inheritance of VVWM in the families reported by <a href="#14" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. &lt;strong&gt;Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.&lt;/strong&gt; Nature Genet. 29: 383-388, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11704758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11704758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng764&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11704758">Leegwater et al. (2001)</a> was shown to be autosomal recessive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" 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="#14" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. &lt;strong&gt;Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.&lt;/strong&gt; Nature Genet. 29: 383-388, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11704758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11704758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng764&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11704758">Leegwater et al. (2001)</a> identified 16 different mutations in EIF2B5 in 29 patients with leukoencephalopathy with vanishing white matter from 23 families. The mutations occurred in homozygosity or compound heterozygosity; the R113H mutation (<a href="/entry/603945#0004">603945.0004</a>) occurred in 12 families with VWM, with a total allelic frequency of approximately 20% among all patients in this report. None of the 14 missense mutations was present in a control group of 210 chromosomes from European individuals. The 2 mutations that disrupted the open reading frame, one a nonsense mutation (R422X) and the other a deletion/insertion resulting in frameshift, occurred in the heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" 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 a genealogic study and haplotyping, <a href="#14" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. &lt;strong&gt;Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.&lt;/strong&gt; Nature Genet. 29: 383-388, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11704758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11704758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng764&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11704758">Leegwater et al. (2001)</a> showed that single founder was involved for 12 people with VWM in 9 families. This permitted narrowing of the location of the gene to a critical region containing a total of 25 genes and STSs. One of these genes, EIF2B5 (<a href="/entry/603945">603945</a>), contained 16 different mutations in 29 patients from 23 families. In addition, they found 2 distantly related individuals who were homozygous for a missense mutation in EIF2B2 (<a href="/entry/606454">606454</a>), affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration in persons with VWM under stress. Mutant translation initiation factors had not theretofore been implicated in disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" 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="#11" class="mim-tip-reference" title="Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R. &lt;strong&gt;Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.&lt;/strong&gt; Ann. Neurol. 52: 506-510, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12325082/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12325082&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12325082">Fogli et al. (2002)</a> identified a homozygous missense mutation in the EIF2B5 gene (R195H; <a href="/entry/603945#0005">603945.0005</a>) in 3 patients with CLE from 2 Cree families. They speculated on the phenotypic differences between CLE and CACH/VWM. A long presymptomatic phase, despite the presence of severe white matter abnormalities on MRI, has been observed in CACH/VWM, in contrast to the early onset and death by 21 months of age in all cases of CLE. Basal ganglia and thalamic abnormalities described in CLE have not been observed in CACH/VWM. <a href="#11" class="mim-tip-reference" title="Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R. &lt;strong&gt;Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.&lt;/strong&gt; Ann. Neurol. 52: 506-510, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12325082/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12325082&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.10339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12325082">Fogli et al. (2002)</a> suggested that the indigenous population of northern Quebec may have evolved an adaptation to an extremely cold environment, rendering them particularly susceptible to dysregulation of protective mechanisms that respond to temperature elevation, such as eIF2B. They concluded that CLE may represent the most severe observed form of eIF2-related disorders, possibly because of an exaggerated response to heat stress induced by a common infectious illness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter, <a href="#8" class="mim-tip-reference" title="Fogli, A., Dionisi-Vici, C., Deodato, F., Bartuli, A., Boespflug-Tanguy, O., Bertini, E. &lt;strong&gt;A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.&lt;/strong&gt; Neurology 59: 1966-1968, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12499492/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12499492&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000041666.76863.47&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12499492">Fogli et al. (2002)</a> identified a homozygous c.925G-C mutation in the EIF2B5 gene, resulting in a leu309-to-val (L309V; <a href="/entry/603945#0006">603945.0006</a>) substitution. The unaffected parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Because of the similarity of cerebral abnormalities in patients with ovarioleukodystrophy to those in patients with VWM, <a href="#9" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. &lt;strong&gt;Ovarian failure related to eukaryotic initiation factor 2B mutations.&lt;/strong&gt; Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12707859/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12707859&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/375404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12707859">Fogli et al. (2003)</a> tested 8 patients with ovarioleukodystrophy for mutations in the 5 EIF2B genes. In 7 of the patients, they identified mutations in the EIF2B2, EIF2B4, and EIF2B5 genes, including 5 novel mutations. The only patient without identified EIF2B mutations had a distinctive neurologic presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" 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="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. &lt;strong&gt;Ovarian failure related to eukaryotic initiation factor 2B mutations.&lt;/strong&gt; Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12707859/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12707859&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/375404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12707859">Fogli et al. (2003)</a> noted that 2 indigenous North American populations, the Cree and the Chippewa, have a particularly severe form of leukodystrophy caused by homozygosity for an arg195-to-his (R195H; <a href="/entry/603945#0005">603945.0005</a>) mutation in the EIF2B5 gene. Patients with this severe EIF2B mutation, as well as patients with the classical form of VWM, do not survive to puberty and therefore do not express ovarian failure. However, <a href="#9" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. &lt;strong&gt;Ovarian failure related to eukaryotic initiation factor 2B mutations.&lt;/strong&gt; Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12707859/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12707859&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/375404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12707859">Fogli et al. (2003)</a> pointed out that several reports had suggested that ovarian dysgenesis may be present in these patients. Two children with neuropathologic abnormalities suggestive of VWM were also found at autopsy to have 'ovarian dysgenesis' (<a href="#5" class="mim-tip-reference" title="Boltshauser, E., Barth, P. G., Troost, D., Martin, E., Stallmach, T. &lt;strong&gt;&#x27;Vanishing white matter&#x27; and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype.&lt;/strong&gt; Neuropediatrics 33: 57-62, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12075484/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12075484&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2002-32363&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12075484">Boltshauser et al., 2002</a>) or 'bilateral streak ovaries' (<a href="#18" class="mim-tip-reference" title="van der Knaap, M. S., Barth, P. G., Gabreels, F. J. M., Franzoni, E., Begeer, J. H., Stroink, H., Rotteveel, J. J., Valk, J. &lt;strong&gt;A new leukoencephalopathy with vanishing white matter.&lt;/strong&gt; Neurology 48: 845-855, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9109866/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9109866&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.48.4.845&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9109866">van der Knaap et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9109866+12707859+12075484" 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="#20" class="mim-tip-reference" title="van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. &lt;strong&gt;eIF2B-related disorders: antenatal onset and involvement of multiple organs.&lt;/strong&gt; Am. J. Hum. Genet. 73: 1199-1207, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14566705/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14566705&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/379524&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14566705">van der Knaap et al. (2003)</a> analyzed the eIF2B genes in 9 patients with antenatal- or early infantile-onset encephalopathy and an early demise. Mutations were found in 8 of the patients, with a total count of 7 different mutations: 2 in EIF2B2, 2 in EIF2B4, and 3 in EIF2B5. In addition to signs of serious encephalopathy, they found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Three of the patients were sisters; 2 other patients were brother and sister. The consistently severe phenotype in affected sibs and in Cree encephalopathy patients suggested an influence of the genotype on the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566705" 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="#17" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N&#x27;Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. &lt;strong&gt;Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.&lt;/strong&gt; Neurology 69: 400-402, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17646634/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17646634&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000266388.02772.f8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17646634">Passemard et al. (2007)</a> reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene (<a href="/entry/603945#0009">603945.0009</a>-<a href="/entry/603945#0011">603945.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" 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>Among 11 unrelated Chinese patients with VWM disease, <a href="#23" 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. &lt;strong&gt;Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.&lt;/strong&gt; J. Hum. Genet. 54: 74-77, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19158808/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19158808&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/jhg.2008.10&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19158808">Wu et al. (2009)</a> found that 6 had mutations in the EIF2B5 gene and 5 had mutations in the EIF2B3 gene. The phenotype was similar to that reported in other populations. <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="#21" class="mim-tip-reference" title="van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S. &lt;strong&gt;Genotype-phenotype correlation in vanishing white matter disease.&lt;/strong&gt; Neurology 75: 1555-1559, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20975056/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20975056&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181f962ae&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20975056">Van der Lei et al. (2010)</a> identified mutations in the EIF2B5 gene in 126 (68%) of 184 patients from a large database of patients with VWM disease. A subset of these patients were chosen for study, including 23 with a homozygous R113H mutation (<a href="/entry/603945#0004">603945.0004</a>), 49 who had R113H in the compound heterozygous state, 8 with a homozygous T91A mutation (<a href="/entry/603945#0001">603945.0001</a>), 9 with R113H/R339any, and 7 with T91A/R339any. Patients homozygous for R113H had a milder disease than patients who were compound heterozygous for R113H and patients homozygous for T91A. Patients with R113H/R339any had a milder phenotype than patients with T91A/R339any. Finally, females tended to have a milder disease than males. <a href="#21" class="mim-tip-reference" title="van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S. &lt;strong&gt;Genotype-phenotype correlation in vanishing white matter disease.&lt;/strong&gt; Neurology 75: 1555-1559, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20975056/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20975056&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e3181f962ae&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20975056">Van der Lei et al. (2010)</a> concluded that the clinical phenotype in VWM is influenced by the combination of both mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20975056" 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="#10" class="mim-tip-reference" title="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. &lt;strong&gt;The effect of genotype on the natural history of eIF2B-related leukodystrophies.&lt;/strong&gt; Neurology 62: 1509-1517, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15136673/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15136673&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000123259.67815.db&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15136673">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=15136673" 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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Alorainy, I. A., Patenaude, Y. G., O'Gorman, A. M., Black, D. N., Meagher-Villemure, K.
<strong>Cree leukoencephalopathy: neuroimaging findings.</strong>
Radiology 213: 400-406, 1999.
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[<a href="https://doi.org/10.1148/radiology.213.2.r99oc28400" target="_blank">Full Text</a>]
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Biancheri, R., Rossi, A., Di Rocco, M., Filocamo, M., Pronk, J. C., van der Knaap, M. S., Tortori-Donati, P.
<strong>Leukoencephalopathy with vanishing white matter: an adult onset case.</strong>
Neurology 61: 1818-1819, 2003. Note: Erratum: Neurology 62: 1242 only, 2004.
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Black, D. N., Booth, F., Watters, G. V., Andermann, E., Dumont, C., Halliday, W. C., Hoogstraten, J., Kabay, M. E., Kaplan, P., Meagher-Villemure, K., Michaud, J., O'Gorman, G.
<strong>Leukoencephalopathy among native Indian infants in northern Quebec and Manitoba.</strong>
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[<a href="https://doi.org/10.1002/ana.410240403" target="_blank">Full Text</a>]
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Black, D. N., Watters, G. V., Andermann, E., Dumont, C., Kabay, M. E., Kaplan, P., Meagher-Villemure, K., Michaud, J., O'Gorman, G., Reece, E., Tsoukas, C., Wainberg, M. A.
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[<a href="https://doi.org/10.1002/ana.410240402" target="_blank">Full Text</a>]
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<strong>'Vanishing white matter' and ovarian dysgenesis in an infant with cerebro-oculo-facio-skeletal phenotype.</strong>
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[<a href="https://doi.org/10.1055/s-2002-32363" target="_blank">Full Text</a>]
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Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C.
<strong>EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.</strong>
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Federico, A., Scali, O., Stromillo, M. L., Di Perri, C., Bianchi, S., Sicurelli, F., De Stefano, N., Malandrini, A., Dotti, M. T.
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Fogli, A., Dionisi-Vici, C., Deodato, F., Bartuli, A., Boespflug-Tanguy, O., Bertini, E.
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Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O.
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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.
<strong>The effect of genotype on the natural history of eIF2B-related leukodystrophies.</strong>
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<p class="mim-text-font">
Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R.
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[<a href="https://doi.org/10.1002/ana.10339" target="_blank">Full Text</a>]
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Labauge, P., Horzinski, L., Ayrignac, X., Blanc, P., Vukusic, S., Rodriguez, D., Mauguiere, F., Peter, L., Goizet, C., Bouhour, F., Denier, C., Confavreux, C., Obadia, M., Blanc, F., de Seze, J., Fogli, A., Boespflug-Tanguy, O.
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Leegwater, P. A. J., Konst, A. A. M., Kuyt, B., Sandkuijl, L. A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
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Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
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[<a href="https://doi.org/10.1038/ng764" 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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Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S.
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Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D.
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van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S.
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[<a href="https://doi.org/10.1212/WNL.0b013e3181f962ae" target="_blank">Full Text</a>]
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Vermeulen, G., Seidl, R., Mercimek-Mahmutoglu, S., Rotteveel, J. J., Scheper, G. C., van der Knapp, M. S.
<strong>Fright is a provoking factor in vanishing white matter disease.</strong>
Ann. Neurol. 57: 560-563, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15786451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15786451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15786451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.20418" target="_blank">Full Text</a>]
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<a id="Wu2009" class="mim-anchor"></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.
<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://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>]
[<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank">Full Text</a>]
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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 : 06/14/2023<br>alopez : 04/17/2023<br>alopez : 04/14/2023
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<strong>#</strong> 620315
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<span class="mim-font">
LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5; VWM5
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<em>Alternative titles; symbols</em>
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CREE LEUKOENCEPHALOPATHY; CLE
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<strong>ORPHA:</strong> 135; &nbsp;
<strong>DO:</strong> 0070367; &nbsp;
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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
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Gene/Locus <br /> MIM number
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3q27.1
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Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure
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620315
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Autosomal recessive
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3
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EIF2B5
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603945
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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-5 (VWM5) is caused by homozygous or compound heterozygous mutation in the EIF2B5 gene (603945) on chromosome 3q27.</p>
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<strong>Description</strong>
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<p>Leukoencephalopathy with vanishing white matter-5 (VWM5) is a chronic and progressive autosomal recessive leukoencephalopathy characterized by neurologic deterioration usually beginning in late infancy or early childhood; however, juvenile- and adult-onset cases have been reported. Neurologic signs include cerebellar ataxia, spasticity, and relatively preserved mental abilities. The disease is chronic and progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death occurs after a variable period of a few years to a few decades, usually following an episode of fever and coma. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy are diagnostic and show a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage, with increasing amounts of the abnormal white matter vanishing and being replaced by cerebrospinal fluid; autopsy confirms these findings (summary by Leegwater et al., 2001). Ovarian dysgenesis may be present in affected females (Fogli et al., 2003). </p><p>For a discussion of genetic heterogeneity of VWM, see 603896.</p><p><strong><em>Cree Leukoencephalopathy</em></strong></p><p>
An infantile leukoencephalopathy among the native Cree and Chippewayan indigenous population in Northern Quebec and Manitoba results from homozygosity for an arg195-to-his (R195H; 603945.0005) mutation in the EIF2B5 gene. These patients have disease onset between 3 and 9 months of age, with death in 100% by 21 months of age.</p>
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<strong>Clinical Features</strong>
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<p>Cree leukoencephalopathy, or CLE, is a rapidly fatal leukodystrophy described first by Black et al. (1988) in the native Cree and Chippewayan indigenous population of northern Quebec and Manitoba. The onset of CLE is between 3 and 9 months of age, with death in 100% by 21 months of age. Hypotonia often is noted in early infancy followed by relatively sudden onset of seizures, spasticity, hyperventilation, vomiting, and diarrhea, often in a setting of a febrile illness. Onset is followed by developmental regression, lethargy, blindness, and cessation of head growth seen as flattening of the head circumference curve. Computerized tomography of the head shows symmetrically hypodense white matter. Gross neuropathologic examination has shown that white matter is grayish white with translucent zones and subcortical cavitation. Microscopic examination has shown diffuse white matter vacuolation in some cases and astrogliosis with presence of oligodendrocytes and cells described as lipid-laden macrophages (Alorainy et al., 1999). Parents of affected children are normal, and because of a high level of consanguinity in this population, CLE is considered autosomal recessive. Fogli et al. (2002) investigated microscopically 3 brains of CLE patients and found the same typical foamy oligodendrocytes observed in patients with childhood ataxia with diffuse central hypomyelination (CACH), also called myelinopathia centralis diffusa or vanishing white matter disease (VWM). </p><p>Fogli et al. (2002) reported 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter and mutation in the EIF2B5 gene. </p><p>Biancheri et al. (2003) reported adult onset of VWM in a 27-year-old woman, confirmed by mutation in the EIF2B5 gene. At the age of 25 years, an MRI study was performed to evaluate the pituitary gland because of elevated prolactin levels. A diffuse leukoencephalopathy was depicted in the absence of any clinical neurologic signs. Two years later, she developed progressive gait abnormalities consistent with spastic paraparesis and speech difficulties. A second MRI showed worsening of the white matter abnormalities with some cystic degeneration. Biancheri et al. (2003) emphasized the clinical variability of the disorder and the importance of a high level of suspicion for VWM even in cases of adult onset. </p><p>Ohtake et al. (2004) reported a Japanese woman, born of consanguineous parents, with adult-onset VWM caused by a homozygous mutation in the EIF2B5 gene (603945.0008). The patient had been well until a traffic accident at age 40 years, after which she became progressively disorganized, forgetful, delusional, and emotionally unstable. By age 52 years, she had developed spastic gait, hyperreflexia, and frank dementia with defective planning and confabulation. T2-weighted MRI showed diffuse hyperintense lesions in the cerebral white matter, most prominent in the frontal lobe. Other findings indicated focal rarefaction and cystic degeneration of the white matter, consistent with VWM. Ohtake et al. (2004) suggested that patients with adult-onset VWM may present with presenile dementia or psychiatric symptoms. </p><p>Vermeulen et al. (2005) reported 2 unrelated patients with VWM disease and mutation in the EIF2B5 gene who experienced episodes of rapid neurologic decline after being frightened. At age 4 years, the first patient witnessed his mother falling down the stairs. He lost consciousness immediately after that and remained in a coma for 10 days. He showed partial recovery afterwards, but permanently lost the ability to walk. At age 18 years, he was severely handicapped, wheelchair-bound, and unable to speak. The second patient was frightened by a dog at age 4 years. He had instantaneous neurologic decline with stupor and spastic hemiparesis. Vermeulen et al. (2005) emphasized the rapid onset of neurologic deterioration in these 2 cases compared to the neurologic decline after infection, which usually occurs over the course of a few days. </p><p>Federico et al. (2006) reported a Romanian boy who developed VWM disease at age 3 years and had mutation in the EIF2B5 gene. He had spasticity, hypotonia, and distal muscle weakness. In addition, he had a peripheral demyelinating neuropathy with decreased sensory and motor nerve conduction velocities. Sural nerve biopsy showed a moderate decrease in the myelinated fibers. </p><p>Passemard et al. (2007) reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene. In the first family, 2 sibs had acute neurologic deterioration in infancy following viral infections. Brain MRIs showed severe white matter abnormalities and complete disappearance of hemispheric white matter, respectively. Both developed progressive severe macrocephaly after age 3 years. In the second family, 1 of 2 sisters who survived beyond age 3 years developed macrocephaly. Passemard et al. (2007) suggested that altered brain water balance may result in swelling of the diseased white matter and macrocephaly in some patients with VWM disease. </p><p>Labauge et al. (2009) reviewed the phenotypes of 16 patients from 14 families with adult-onset VWM, defined as onset after age 16 years. The mean age of onset was 31.1 years (range, 16 to 62 years), and there was a decreased male:female ratio (3:13). Initial symptoms were neurologic in 11 patients, psychiatric in 2, and ovarian failure in 2, and 1 patient was initially asymptomatic but diagnosed on brain MRI. Onset of the symptoms was linked to a precipitating factor in 13% of cases, including minor head trauma and delivery. Two (12.5%) patients died during a mean follow-up period of 11.2 years after a stress-induced deterioration. Of the 14 survivors, 62% showed a decline in their cognitive functions, and 79% were severely handicapped or bedridden. One individual remained asymptomatic. Stress worsened clinical symptoms in 38% of the patients. MRI findings included cerebral atrophy (75%), extensive cystic cavitating leukoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted hyperintensities. Thirteen of the families had mutations in the EIF2B5 gene, including the common R113H mutation (603945.0004), which was found in 11 (79%) of the 14 families. The last family had a mutation in the EIF2B2 gene (E213G; 606454.0001). Labauge et al. (2009) concluded that VWM may be underestimated as an adult-onset inherited leukoencephalopathy. </p>
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<strong>Nomenclature</strong>
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<p>Black et al. (1988) described an early-onset, progressive encephalopathy in an inbred Canadian Aboriginal community. They termed this disorder Cree encephalitis (225750) and distinguished it clinically from Cree leukoencephalopathy. </p>
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<strong>Pathogenesis</strong>
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<p>In cell cultures from the brain of an individual with VWM who had compound heterozygosity for mutations in EIF2B5 (T91A, 603945.0001 and W628R, 603945.0002), Dietrich et al. (2005) observed prompt development of normal-appearing oligodendrocytes despite the extensive demyelination seen in the patient. However, few glial fibrillary acidic protein (GFAP; 137780)-expressing astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP-expressing astrocytes, and RNA-interference targeting of EIF2B5 severely compromised the induction of GFAP-expressing cells from normal human glial progenitors. Dietrich et al. (2005) suggested that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy. </p><p>Fogli et al. (2003) reported 8 patients from 7 families with vanishing white matter leukodystrophy and ovarian failure, an association they termed ovarioleukodystrophy, and mutation in the EIF2B2, EIF2B4, or EIF2B5 gene. The diagnosis of ovarian failure was confirmed by findings of high basal gonadotropin levels and low estrogen and progesterone levels. All the patients had a normal karyotype, and only 1 patient had consanguineous parents. In 3 patients with primary amenorrhea, school difficulties, together with poor fine motor performance, were present prior to the development of a slowly progressive neurologic disease in adolescence. Only 1 patient presented with rapid cognitive decline, including a frontal lobe syndrome. The age at menarche was normal in the 5 patients with secondary amenorrhea. The age at onset of neurologic deterioration correlated positively with the severity of ovarian dysfunction. In at least 1 case ovarian failure preceded neurologic decline. </p><p>Matsukawa et al. (2011) reported 3 unrelated Japanese patients, each born of consanguineous parents, with adult-onset VWM. Each carried a homozygous mutation in the EIF2B2 (V85E; 606454.0006), EIF2B5 (D270H; 603945.0012), or EIF2B3 (L27Q; 606273.0005) gene, respectively. The 2 affected women also had evidence of ovarian failure. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing the mutant subunits was significantly decreased (20-40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. </p>
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<strong>Mapping</strong>
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<p>Family data indicate that leukoencephalopathy with vanishing white matter has an autosomal recessive inheritance with age-dependent penetrance. Leegwater et al. (1999) performed a genomewide linkage screening in 19 families with different ethnic origins. Significant linkage to 3q27 was observed in a 7-cM interval between markers D3S3730 and D3S3592, with a maximum multipoint lod score of 5.1 calculated from the entire data set. Genealogic studies had suggested that 7 parents in 4 Dutch families with VWM had inherited an allele for the disease from a common ancestor who lived at least 8 generations ago. Analysis of these families provided further evidence for the localization of the gene for VWM to 3q27. The patients shared a haplotype spanning 5 cM between markers D3S1618 and D3S3592. In 1 family of a different ethnic background, the patient had, in the same region, homozygosity for 13 consecutive markers spanning at least 12 cM, suggesting consanguinity between the parents. A healthy sib of this patient had the same homozygous haplotype which suggested that the healthy sib was presymptomatic for the disease. Because of ethical considerations, Leegwater et al. (1999) could not evaluate the apparently healthy sib by MRI and MRS. Both the patient and the asymptomatic sib were adults. Van der Knaap et al. (1998) had described similar phenotypic variation in an affected individual and in the individual's presymptomatic adult sib who had MRI findings typical for VWM. </p>
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<strong>Inheritance</strong>
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<p>The mode of inheritance of VVWM in the families reported by Leegwater et al. (2001) was shown to be autosomal recessive. </p>
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<strong>Molecular Genetics</strong>
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<p>Leegwater et al. (2001) identified 16 different mutations in EIF2B5 in 29 patients with leukoencephalopathy with vanishing white matter from 23 families. The mutations occurred in homozygosity or compound heterozygosity; the R113H mutation (603945.0004) occurred in 12 families with VWM, with a total allelic frequency of approximately 20% among all patients in this report. None of the 14 missense mutations was present in a control group of 210 chromosomes from European individuals. The 2 mutations that disrupted the open reading frame, one a nonsense mutation (R422X) and the other a deletion/insertion resulting in frameshift, occurred in the heterozygous state. </p><p>By a genealogic study and haplotyping, Leegwater et al. (2001) showed that single founder was involved for 12 people with VWM in 9 families. This permitted narrowing of the location of the gene to a critical region containing a total of 25 genes and STSs. One of these genes, EIF2B5 (603945), contained 16 different mutations in 29 patients from 23 families. In addition, they found 2 distantly related individuals who were homozygous for a missense mutation in EIF2B2 (606454), affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration in persons with VWM under stress. Mutant translation initiation factors had not theretofore been implicated in disease. </p><p>Fogli et al. (2002) identified a homozygous missense mutation in the EIF2B5 gene (R195H; 603945.0005) in 3 patients with CLE from 2 Cree families. They speculated on the phenotypic differences between CLE and CACH/VWM. A long presymptomatic phase, despite the presence of severe white matter abnormalities on MRI, has been observed in CACH/VWM, in contrast to the early onset and death by 21 months of age in all cases of CLE. Basal ganglia and thalamic abnormalities described in CLE have not been observed in CACH/VWM. Fogli et al. (2002) suggested that the indigenous population of northern Quebec may have evolved an adaptation to an extremely cold environment, rendering them particularly susceptible to dysregulation of protective mechanisms that respond to temperature elevation, such as eIF2B. They concluded that CLE may represent the most severe observed form of eIF2-related disorders, possibly because of an exaggerated response to heat stress induced by a common infectious illness. </p><p>In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter, Fogli et al. (2002) identified a homozygous c.925G-C mutation in the EIF2B5 gene, resulting in a leu309-to-val (L309V; 603945.0006) substitution. The unaffected parents were heterozygous for the mutation. </p><p>Because of the similarity of cerebral abnormalities in patients with ovarioleukodystrophy to those in patients with VWM, Fogli et al. (2003) tested 8 patients with ovarioleukodystrophy for mutations in the 5 EIF2B genes. In 7 of the patients, they identified mutations in the EIF2B2, EIF2B4, and EIF2B5 genes, including 5 novel mutations. The only patient without identified EIF2B mutations had a distinctive neurologic presentation. </p><p>Fogli et al. (2003) noted that 2 indigenous North American populations, the Cree and the Chippewa, have a particularly severe form of leukodystrophy caused by homozygosity for an arg195-to-his (R195H; 603945.0005) mutation in the EIF2B5 gene. Patients with this severe EIF2B mutation, as well as patients with the classical form of VWM, do not survive to puberty and therefore do not express ovarian failure. However, Fogli et al. (2003) pointed out that several reports had suggested that ovarian dysgenesis may be present in these patients. Two children with neuropathologic abnormalities suggestive of VWM were also found at autopsy to have 'ovarian dysgenesis' (Boltshauser et al., 2002) or 'bilateral streak ovaries' (van der Knaap et al., 1997). </p><p>van der Knaap et al. (2003) analyzed the eIF2B genes in 9 patients with antenatal- or early infantile-onset encephalopathy and an early demise. Mutations were found in 8 of the patients, with a total count of 7 different mutations: 2 in EIF2B2, 2 in EIF2B4, and 3 in EIF2B5. In addition to signs of serious encephalopathy, they found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Three of the patients were sisters; 2 other patients were brother and sister. The consistently severe phenotype in affected sibs and in Cree encephalopathy patients suggested an influence of the genotype on the phenotype. </p><p>Passemard et al. (2007) reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene (603945.0009-603945.0011). </p><p>Among 11 unrelated Chinese patients with VWM disease, Wu et al. (2009) found that 6 had mutations in the EIF2B5 gene and 5 had mutations in the EIF2B3 gene. The phenotype was similar to that reported in other populations. </p><p>Van der Lei et al. (2010) identified mutations in the EIF2B5 gene in 126 (68%) of 184 patients from a large database of patients with VWM disease. A subset of these patients were chosen for study, including 23 with a homozygous R113H mutation (603945.0004), 49 who had R113H in the compound heterozygous state, 8 with a homozygous T91A mutation (603945.0001), 9 with R113H/R339any, and 7 with T91A/R339any. Patients homozygous for R113H had a milder disease than patients who were compound heterozygous for R113H and patients homozygous for T91A. Patients with R113H/R339any had a milder phenotype than patients with T91A/R339any. Finally, females tended to have a milder disease than males. Van der Lei et al. (2010) concluded that the clinical phenotype in VWM is influenced by the combination of both mutations. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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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>REFERENCES</strong>
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<p class="mim-text-font">
Alorainy, I. A., Patenaude, Y. G., O'Gorman, A. M., Black, D. N., Meagher-Villemure, K.
<strong>Cree leukoencephalopathy: neuroimaging findings.</strong>
Radiology 213: 400-406, 1999.
[PubMed: 10551219]
[Full Text: https://doi.org/10.1148/radiology.213.2.r99oc28400]
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Biancheri, R., Rossi, A., Di Rocco, M., Filocamo, M., Pronk, J. C., van der Knaap, M. S., Tortori-Donati, P.
<strong>Leukoencephalopathy with vanishing white matter: an adult onset case.</strong>
Neurology 61: 1818-1819, 2003. Note: Erratum: Neurology 62: 1242 only, 2004.
[PubMed: 14694060]
[Full Text: https://doi.org/10.1212/01.wnl.0000098994.35677.3c]
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<p class="mim-text-font">
Black, D. N., Booth, F., Watters, G. V., Andermann, E., Dumont, C., Halliday, W. C., Hoogstraten, J., Kabay, M. E., Kaplan, P., Meagher-Villemure, K., Michaud, J., O'Gorman, G.
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