2521 lines
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2521 lines
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Entry
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- #611105 - LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION; LBSL
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- OMIM
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<p>
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<span class="h4">#611105</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/611105"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#inheritance">Inheritance</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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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=16739&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK43417/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8742" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/leukoencephalopathy-with-brainstem-and-spinal-cord-involvement-and-lactate-elevation" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=611105[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137898" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703537008, 735421004<br />
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<strong>ORPHA:</strong> 137898<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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611105
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION; LBSL
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</span>
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MITOCHONDRIAL ASPARTYL-tRNA SYNTHETASE DEFICIENCY
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</h4>
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</div>
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<div>
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<br />
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</div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1438?start=-3&limit=10&highlight=1438">
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1q25.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/611105"> 611105 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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DARS2
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/610956"> 610956 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/611105" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/611105" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/611105" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p />
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
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</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Eyes </em>
|
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</span>
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</div>
|
|
<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
|
<span class="mim-font">
|
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|
|
- Joint contractures (with age) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808088&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808088</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7890003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7890003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M24.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M24.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/718.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">718.4</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/718.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">718.40</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
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|
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<div>
|
|
<span class="mim-font">
|
|
|
|
- Muscle atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88092000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88092000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0541794&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0541794</a>, <a href="https://bioportal.bioontology.org/search?q=C0026846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003202</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003202</a>]</span><br /> -
|
|
Muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26544005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26544005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151786&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151786</a>, <a href="https://bioportal.bioontology.org/search?q=C0030552&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030552</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
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</div>
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</div>
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<div>
|
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<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">
|
|
|
|
- Delayed motor development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854301&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854301</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span><br /> -
|
|
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 /> -
|
|
Tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26079004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26079004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</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 /> -
|
|
Extensor plantar responses <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246586009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246586009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366575004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366575004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034935&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034935</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003487</a>]</span><br /> -
|
|
Hyperreflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
|
|
Cognitive deficits (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/443265004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">443265004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009241</a>, <a href="https://bioportal.bioontology.org/search?q=C0338656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338656</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>]</span><br /> -
|
|
Dysarthria (less common) <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 /> -
|
|
Leukoencephalopathy in the periventricular and deep white matter and brainstem, cerebellum, and spinal cord tracts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277799&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277799</a>]</span><br /> -
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Lesions are symmetrical <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277800&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277800</a>]</span><br /> -
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Magnetic resonance spectroscopy shows increased lactate in white matter <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277801&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277801</a>]</span><br />
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<em> Peripheral Nervous System </em>
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- Peripheral axonal neuropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128208007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128208007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1263857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1263857</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003477" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003477</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003477" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003477</a>]</span><br /> -
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Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
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Decreased proprioception and vibration sense <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277802&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277802</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
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Onset between age 2 and 15 years<br /> -
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Slowly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854494</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span><br /> -
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One patient with episodic ataxia and later onset has been reported (as of June 2010)<br />
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<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Caused by mutation in the aspartyl-tRNA synthetase 2 gene (DARS2, <a href="/entry/610956#0001">610956.0001</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) can be caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial aspartyl-tRNA synthetase (DARS2; <a href="/entry/610956">610956</a>) on chromosome 1q25.</p>
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<a id="description" class="mim-anchor"></a>
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<strong>Description</strong>
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<p>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (<a href="#5" class="mim-tip-reference" title="Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S. <strong>Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.</strong> Nature Genet. 39: 534-539, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17384640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17384640</a>] [<a href="https://doi.org/10.1038/ng2013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17384640">Scheper et al., 2007</a>). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17384640" 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 novel leukoencephalopathy with brainstem and spinal cord involvement and high lactate was described by <a href="#9" class="mim-tip-reference" title="van der Knaap, M. S., van der Voorn, P., Barkhof, F., Van Coster, R., Krageloh-Mann, I., Feigenbaum, A., Blaser, S., Vles, J. S. H., Rieckmann, P., Pouwels, P. J. W. <strong>A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.</strong> Ann. Neurol. 53: 252-258, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12557294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12557294</a>] [<a href="https://doi.org/10.1002/ana.10456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12557294">van der Knaap et al. (2003)</a> in 8 patients. They showed a distinct magnetic resonance spectroscopy (MRS) pattern of inhomogeneous cerebral white matter abnormalities and selective involvement of brainstem and spinal tracts. Proton magnetic resonance imaging (MRI) showed increased lactate in the abnormal white matter. Clinically, the patients had slowly progressive pyramidal, cerebellar, and dorsal column dysfunction. Autosomal recessive inheritance was considered likely. Three of the 8 patients were male. The 8 patients included 2 affected sisters and an affected brother and sister. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12557294" 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="Linnankivi, T., Lundbom, N., Autti, T., Hakkinen, A.-M., Koillinen, H., Kuusi, T., Lonnqvist, T., Sainio, K., Valanne, L., Aarimaa, T., Pihko, H. <strong>Five new cases of a recently described leukoencephalopathy with high brain lactate.</strong> Neurology 63: 688-692, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326244</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134658.35601.41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326244">Linnankivi et al. (2004)</a> described 5 additional patients with this entity. MRS showed decreased N-acetylaspartate and increased lactate in the white matter of all patients. A slowly progressive sensory ataxia and tremor manifested at the age of 3 to 16 years and distal spasticity in adolescence. One 13-year-old patient was asymptomatic. Two of the 5 patients were brothers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Serkov, S. V., Pronin, I. N., Bykova, O. V., Maslova, O. I., Arutyunov, N. V., Muravina, T. I., Kornienko, V. N., Fadeeva, L. M., Marks, H., Bonnemann, C., Schiffmann, R., van der Knaap, M. S. <strong>Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.</strong> Neuropediatrics 35: 1-5, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15002045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15002045</a>] [<a href="https://doi.org/10.1055/s-2003-43548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15002045">Serkov et al. (2004)</a> also described 5 new, unrelated patients. The clinical picture was homogeneous with onset in childhood, a slowly progressive course, variable mental deficits, signs of pyramidal and cerebellar dysfunction, and sometimes dorsal column dysfunction. <a href="#6" class="mim-tip-reference" title="Serkov, S. V., Pronin, I. N., Bykova, O. V., Maslova, O. I., Arutyunov, N. V., Muravina, T. I., Kornienko, V. N., Fadeeva, L. M., Marks, H., Bonnemann, C., Schiffmann, R., van der Knaap, M. S. <strong>Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.</strong> Neuropediatrics 35: 1-5, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15002045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15002045</a>] [<a href="https://doi.org/10.1055/s-2003-43548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15002045">Serkov et al. (2004)</a> proposed the acronym LBSL for leukoencephalopathy with involvement of brainstem and spinal cord and increased lactate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15002045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Petzold, G. C., Bohner, G., Klingebiel, R., Amberger, N., van der Knaap, M. S., Zschenderlein, R. <strong>Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate.</strong> J. Neurol. Neurosurg. Psychiat. 77: 889-891, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16788019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16788019</a>] [<a href="https://doi.org/10.1136/jnnp.2005.078568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16788019">Petzold et al. (2006)</a> described sister and brother with adult-onset leukoencephalopathy with brainstem and spinal cord involvement and normal lactate on MRS. Onset had occurred at ages 20 years in the sister and 23 years in the brother with unsteady gait, stiffness in both legs, and bilateral clumsiness. The parents were not consanguineous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16788019" 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="#1" class="mim-tip-reference" title="Isohanni, P., Linnankivi, T., Buzkova, J., Lonnqvist, T., Pihko, H., Valanne, L., Tienari, P. J., Elovaara, I., Pirttila, T., Reunanen, M., Koivisto, K., Marjavaara, S., Suomalainen, A. <strong>DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.</strong> J. Med. Genet. 47: 66-70, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592391</a>] [<a href="https://doi.org/10.1136/jmg.2009.068221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592391">Isohanni et al. (2010)</a> reviewed the clinical features of 5 patients with LBSL reported by <a href="#2" class="mim-tip-reference" title="Linnankivi, T., Lundbom, N., Autti, T., Hakkinen, A.-M., Koillinen, H., Kuusi, T., Lonnqvist, T., Sainio, K., Valanne, L., Aarimaa, T., Pihko, H. <strong>Five new cases of a recently described leukoencephalopathy with high brain lactate.</strong> Neurology 63: 688-692, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326244</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134658.35601.41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326244">Linnankivi et al. (2004)</a> and described 3 new patients. Six patients were of Finnish origin. Overall, the phenotype was somewhat heterogeneous, with most patients showing onset between ages 2 to 15 years. Most had unsteady or delayed motor development, but 2 had normal motor development. The most common features included progressive onset of tremor, ataxia, dysarthria, and spasticity. A novel finding was an axonal peripheral neuropathy with distal weakness and decreased vibration/proprioception. Four patients had normal cognitive function, and 4 had mild defects of speech, learning problems, or visuospatial defects. Two patients were described in detail. One had onset at age 8 years with nocturnal seizures and was found to have abnormalities in the infra- and supratentorial regions on brain MRI. At age 15 years, he developed ataxia, extensor plantar responses, spasticity, and an axonal neuropathy. The other patient had onset at age 19 months of motor delay with ataxia and hypotonia. Spasticity and hyperreflexia became apparent by age 2 years, 3 months. He also had mild speech delay. Brain MRI showed abnormal signals in the supratentorial region. All patients were compound heterozygous for mutations in the DARS2 gene, and <a href="#1" class="mim-tip-reference" title="Isohanni, P., Linnankivi, T., Buzkova, J., Lonnqvist, T., Pihko, H., Valanne, L., Tienari, P. J., Elovaara, I., Pirttila, T., Reunanen, M., Koivisto, K., Marjavaara, S., Suomalainen, A. <strong>DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.</strong> J. Med. Genet. 47: 66-70, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592391</a>] [<a href="https://doi.org/10.1136/jmg.2009.068221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592391">Isohanni et al. (2010)</a> suggested that homozygosity for a DARS2 mutation may be lethal in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19592391+15326244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Miyake, N., Yamashita, S., Kurosawa, K., Miyatake, S., Tsurusaki, Y., Doi, H., Saitsu, H., Matsumoto, N. <strong>A novel homozygous mutation of DARS2 may cause a severe LBSL variant. (Letter)</strong> Clin. Genet. 80: 293-296, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21815884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21815884</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21815884">Miyake et al. (2011)</a> reported 3 Japanese sibs, born of consanguineous parents, with a severe form of LBSL due to a homozygous mutation in the DARS2 gene (<a href="/entry/610956#0012">610956.0012</a>). The 21-year-old proband developed truncal ataxia at age 3 years, followed by nystagmus, slurred speech, tremor, muscle tonus abnormality, and mental retardation; he could speak only 1 or 2 words. Other features in the proband included peripheral muscle atrophy and weakness, joint contractures, hyporeflexia, and disrupted deep sensation. His 2 sibs, who showed onset before age 12 months, died in childhood of respiratory disease. Brain imaging showed leukoencephalopathy of the cerebrum, cerebellum, brainstem, and spinal cord. The wildtype DARS2 mRNA transcript and protein were significantly decreased in patient cells. <a href="#3" class="mim-tip-reference" title="Miyake, N., Yamashita, S., Kurosawa, K., Miyatake, S., Tsurusaki, Y., Doi, H., Saitsu, H., Matsumoto, N. <strong>A novel homozygous mutation of DARS2 may cause a severe LBSL variant. (Letter)</strong> Clin. Genet. 80: 293-296, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21815884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21815884</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21815884">Miyake et al. (2011)</a> noted that homozygosity for pathogenic mutations in the DARS2 gene had not previously been reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21815884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="van Berge, L., Hamilton, E. M., Linnankivi, T., Uziel, G., Steenweg, M. E., Isohanni, P., Wolf, N. I., Krageloh-Mann, I., Brautaset, N. J., Andrews, P. I., de Jong, B. A., al Ghamdi, M., and 11 others. <strong>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.</strong> Brain 137: 1019-29, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24566671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24566671</a>] [<a href="https://doi.org/10.1093/brain/awu026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24566671">Van Berge et al. (2014)</a> reviewed the clinical features of 66 patients with LBSL. Patients exhibited their first neurologic symptoms at an average age of 8 years. Eight patients had adult-onset symptoms. The most common features were cerebellar ataxias, including gait ataxia. Nine patients had delayed development and 3 patients never had independent walking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24566671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Synofzik, M., Schicks, J., Lindig, T., Biskup, S., Schmidt, T., Hansel, J., Lehmann-Horn, F., Schols, L. <strong>Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.</strong> J. Med. Genet. 48: 713-715, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21749991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21749991</a>] [<a href="https://doi.org/10.1136/jmg.2011.090282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21749991">Synofzik et al. (2011)</a> reported a 25-year-old German woman who presented with a 3-year history of paroxysmal exercise-induced gait ataxia. The episodic ataxia occurred up to 5 times a day and lasted for a few seconds to 5 minutes, but the frequency increased to up to 23 times per day over a few years. Other features included mild distal deficits in position and vibration sense, mild leg spasticity, and hyperreflexia, but she never had permanent cerebellar ataxia or gait spasticity. Serum lactate was intermittently increased, and brain MRI showed T2 hyperintense lesions in the cerebellar white matter, deep cerebral white matter, and periventricular region, with some involvement of the pyramidal tracts and dorsal columns. Treatment with acetazolamide resulted in significantly decreased frequency of the attacks. Genetic analysis identified a homozygous mutation in the DARS2 gene (R609W; <a href="/entry/610956#0013">610956.0013</a>) and excluded mutations in known episodic ataxia genes. The findings indicated that this disorder can have a milder phenotype and even present with episodic ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21749991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S. <strong>Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.</strong> Nature Genet. 39: 534-539, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17384640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17384640</a>] [<a href="https://doi.org/10.1038/ng2013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17384640">Scheper et al. (2007)</a> performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which they narrowed to a 1.9-cM region between markers D1S2790 and D1S416 by means of shared haplotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17384640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S. <strong>Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.</strong> Nature Genet. 39: 534-539, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17384640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17384640</a>] [<a href="https://doi.org/10.1038/ng2013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17384640">Scheper et al. (2007)</a> sequenced genes in the candidate region on chromosome 1 linked to LBSL and uncovered mutations in DARS2 (<a href="/entry/610956">610956</a>), which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. Surprisingly, activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17384640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="van Berge, L., Hamilton, E. M., Linnankivi, T., Uziel, G., Steenweg, M. E., Isohanni, P., Wolf, N. I., Krageloh-Mann, I., Brautaset, N. J., Andrews, P. I., de Jong, B. A., al Ghamdi, M., and 11 others. <strong>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.</strong> Brain 137: 1019-29, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24566671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24566671</a>] [<a href="https://doi.org/10.1093/brain/awu026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24566671">Van Berge et al. (2014)</a> reviewed mutations in the DARS2 gene in 120 patients with LBSL. Overall, 60 different mutations were identified, which were located throughout the gene. One hundred and sixteen patients had compound heterozygous mutations and and 4 patients had homozygous mutations. Ninety-four percent (113/120) of the patients were heterozygous for a mutation in the polypyrimidine tract in intron 2, which is just upstream of exon 3. Thirteen different mutations were identified in this region, with 228-20_-21delTTinsC (<a href="/entry/610956#0001">610956.0001</a>) as the most common, in 88 patients. Mutations in the polypyrimidine tract in intron 2 were identified in only compound heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24566671" 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="#9" class="mim-tip-reference" title="van der Knaap, M. S., van der Voorn, P., Barkhof, F., Van Coster, R., Krageloh-Mann, I., Feigenbaum, A., Blaser, S., Vles, J. S. H., Rieckmann, P., Pouwels, P. J. W. <strong>A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.</strong> Ann. Neurol. 53: 252-258, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12557294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12557294</a>] [<a href="https://doi.org/10.1002/ana.10456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12557294">Van der Knaap et al. (2003)</a> postulated autosomal recessive inheritance of LBSL based on the presence of 2 affected sib pairs among their patients. <a href="#2" class="mim-tip-reference" title="Linnankivi, T., Lundbom, N., Autti, T., Hakkinen, A.-M., Koillinen, H., Kuusi, T., Lonnqvist, T., Sainio, K., Valanne, L., Aarimaa, T., Pihko, H. <strong>Five new cases of a recently described leukoencephalopathy with high brain lactate.</strong> Neurology 63: 688-692, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326244</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134658.35601.41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326244">Linnankivi et al. (2004)</a>, <a href="#6" class="mim-tip-reference" title="Serkov, S. V., Pronin, I. N., Bykova, O. V., Maslova, O. I., Arutyunov, N. V., Muravina, T. I., Kornienko, V. N., Fadeeva, L. M., Marks, H., Bonnemann, C., Schiffmann, R., van der Knaap, M. S. <strong>Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.</strong> Neuropediatrics 35: 1-5, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15002045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15002045</a>] [<a href="https://doi.org/10.1055/s-2003-43548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15002045">Serkov et al. (2004)</a>, and <a href="#4" class="mim-tip-reference" title="Petzold, G. C., Bohner, G., Klingebiel, R., Amberger, N., van der Knaap, M. S., Zschenderlein, R. <strong>Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate.</strong> J. Neurol. Neurosurg. Psychiat. 77: 889-891, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16788019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16788019</a>] [<a href="https://doi.org/10.1136/jnnp.2005.078568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16788019">Petzold et al. (2006)</a> likewise thought autosomal recessive inheritance likely <a href="#5" class="mim-tip-reference" title="Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S. <strong>Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.</strong> Nature Genet. 39: 534-539, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17384640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17384640</a>] [<a href="https://doi.org/10.1038/ng2013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17384640">Scheper et al. (2007)</a> proved this to be the case, with affected individuals carrying mutations on both alleles of the DARS2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15002045+15326244+17384640+12557294+16788019" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592391</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19592391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Linnankivi, T., Lundbom, N., Autti, T., Hakkinen, A.-M., Koillinen, H., Kuusi, T., Lonnqvist, T., Sainio, K., Valanne, L., Aarimaa, T., Pihko, H.
|
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<strong>Five new cases of a recently described leukoencephalopathy with high brain lactate.</strong>
|
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Neurology 63: 688-692, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000134658.35601.41" target="_blank">Full Text</a>]
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</p>
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<a id="3" class="mim-anchor"></a>
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<a id="Miyake2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miyake, N., Yamashita, S., Kurosawa, K., Miyatake, S., Tsurusaki, Y., Doi, H., Saitsu, H., Matsumoto, N.
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<strong>A novel homozygous mutation of DARS2 may cause a severe LBSL variant. (Letter)</strong>
|
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Clin. Genet. 80: 293-296, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21815884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21815884</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21815884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2011.01644.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Petzold2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Petzold, G. C., Bohner, G., Klingebiel, R., Amberger, N., van der Knaap, M. S., Zschenderlein, R.
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<strong>Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate.</strong>
|
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J. Neurol. Neurosurg. Psychiat. 77: 889-891, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16788019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16788019</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16788019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jnnp.2005.078568" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Scheper2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S.
|
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<strong>Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.</strong>
|
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Nature Genet. 39: 534-539, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17384640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17384640</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17384640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng2013" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Serkov2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Serkov, S. V., Pronin, I. N., Bykova, O. V., Maslova, O. I., Arutyunov, N. V., Muravina, T. I., Kornienko, V. N., Fadeeva, L. M., Marks, H., Bonnemann, C., Schiffmann, R., van der Knaap, M. S.
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<strong>Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.</strong>
|
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Neuropediatrics 35: 1-5, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15002045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15002045</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15002045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1055/s-2003-43548" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Synofzik2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Synofzik, M., Schicks, J., Lindig, T., Biskup, S., Schmidt, T., Hansel, J., Lehmann-Horn, F., Schols, L.
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<strong>Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.</strong>
|
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J. Med. Genet. 48: 713-715, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21749991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21749991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21749991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2011.090282" target="_blank">Full Text</a>]
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="van Berge2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Berge, L., Hamilton, E. M., Linnankivi, T., Uziel, G., Steenweg, M. E., Isohanni, P., Wolf, N. I., Krageloh-Mann, I., Brautaset, N. J., Andrews, P. I., de Jong, B. A., al Ghamdi, M., and 11 others.
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<strong>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.</strong>
|
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Brain 137: 1019-29, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24566671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24566671</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24566671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awu026" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="van der Knaap2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Knaap, M. S., van der Voorn, P., Barkhof, F., Van Coster, R., Krageloh-Mann, I., Feigenbaum, A., Blaser, S., Vles, J. S. H., Rieckmann, P., Pouwels, P. J. W.
|
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<strong>A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.</strong>
|
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Ann. Neurol. 53: 252-258, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12557294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12557294</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12557294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10456" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/26/2011
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/4/2011<br>Cassandra L. Kniffin - updated : 6/15/2010
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</span>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/11/2007
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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carol : 10/06/2022
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<span class="mim-text-font">
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ckniffin : 10/26/2011<br>carol : 10/11/2011<br>ckniffin : 10/4/2011<br>wwang : 6/25/2010<br>ckniffin : 6/15/2010<br>carol : 7/13/2007<br>alopez : 6/11/2007
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<span class="mim-font">
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<strong>#</strong> 611105
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<h3>
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LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION; LBSL
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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MITOCHONDRIAL ASPARTYL-tRNA SYNTHETASE DEFICIENCY
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<strong>SNOMEDCT:</strong> 703537008, 735421004;
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<strong>ORPHA:</strong> 137898;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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Location
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<th>
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Gene/Locus
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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1q25.1
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</td>
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<td>
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<span class="mim-font">
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Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
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</span>
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</td>
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<td>
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<span class="mim-font">
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611105
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<td>
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<span class="mim-font">
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DARS2
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</td>
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<td>
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<span class="mim-font">
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610956
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) can be caused by homozygous or compound heterozygous mutation in the gene encoding mitochondrial aspartyl-tRNA synthetase (DARS2; 610956) on chromosome 1q25.</p>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<span class="mim-text-font">
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<p>A novel leukoencephalopathy with brainstem and spinal cord involvement and high lactate was described by van der Knaap et al. (2003) in 8 patients. They showed a distinct magnetic resonance spectroscopy (MRS) pattern of inhomogeneous cerebral white matter abnormalities and selective involvement of brainstem and spinal tracts. Proton magnetic resonance imaging (MRI) showed increased lactate in the abnormal white matter. Clinically, the patients had slowly progressive pyramidal, cerebellar, and dorsal column dysfunction. Autosomal recessive inheritance was considered likely. Three of the 8 patients were male. The 8 patients included 2 affected sisters and an affected brother and sister. </p><p>Linnankivi et al. (2004) described 5 additional patients with this entity. MRS showed decreased N-acetylaspartate and increased lactate in the white matter of all patients. A slowly progressive sensory ataxia and tremor manifested at the age of 3 to 16 years and distal spasticity in adolescence. One 13-year-old patient was asymptomatic. Two of the 5 patients were brothers. </p><p>Serkov et al. (2004) also described 5 new, unrelated patients. The clinical picture was homogeneous with onset in childhood, a slowly progressive course, variable mental deficits, signs of pyramidal and cerebellar dysfunction, and sometimes dorsal column dysfunction. Serkov et al. (2004) proposed the acronym LBSL for leukoencephalopathy with involvement of brainstem and spinal cord and increased lactate. </p><p>Petzold et al. (2006) described sister and brother with adult-onset leukoencephalopathy with brainstem and spinal cord involvement and normal lactate on MRS. Onset had occurred at ages 20 years in the sister and 23 years in the brother with unsteady gait, stiffness in both legs, and bilateral clumsiness. The parents were not consanguineous. </p><p>Isohanni et al. (2010) reviewed the clinical features of 5 patients with LBSL reported by Linnankivi et al. (2004) and described 3 new patients. Six patients were of Finnish origin. Overall, the phenotype was somewhat heterogeneous, with most patients showing onset between ages 2 to 15 years. Most had unsteady or delayed motor development, but 2 had normal motor development. The most common features included progressive onset of tremor, ataxia, dysarthria, and spasticity. A novel finding was an axonal peripheral neuropathy with distal weakness and decreased vibration/proprioception. Four patients had normal cognitive function, and 4 had mild defects of speech, learning problems, or visuospatial defects. Two patients were described in detail. One had onset at age 8 years with nocturnal seizures and was found to have abnormalities in the infra- and supratentorial regions on brain MRI. At age 15 years, he developed ataxia, extensor plantar responses, spasticity, and an axonal neuropathy. The other patient had onset at age 19 months of motor delay with ataxia and hypotonia. Spasticity and hyperreflexia became apparent by age 2 years, 3 months. He also had mild speech delay. Brain MRI showed abnormal signals in the supratentorial region. All patients were compound heterozygous for mutations in the DARS2 gene, and Isohanni et al. (2010) suggested that homozygosity for a DARS2 mutation may be lethal in humans. </p><p>Miyake et al. (2011) reported 3 Japanese sibs, born of consanguineous parents, with a severe form of LBSL due to a homozygous mutation in the DARS2 gene (610956.0012). The 21-year-old proband developed truncal ataxia at age 3 years, followed by nystagmus, slurred speech, tremor, muscle tonus abnormality, and mental retardation; he could speak only 1 or 2 words. Other features in the proband included peripheral muscle atrophy and weakness, joint contractures, hyporeflexia, and disrupted deep sensation. His 2 sibs, who showed onset before age 12 months, died in childhood of respiratory disease. Brain imaging showed leukoencephalopathy of the cerebrum, cerebellum, brainstem, and spinal cord. The wildtype DARS2 mRNA transcript and protein were significantly decreased in patient cells. Miyake et al. (2011) noted that homozygosity for pathogenic mutations in the DARS2 gene had not previously been reported. </p><p>Van Berge et al. (2014) reviewed the clinical features of 66 patients with LBSL. Patients exhibited their first neurologic symptoms at an average age of 8 years. Eight patients had adult-onset symptoms. The most common features were cerebellar ataxias, including gait ataxia. Nine patients had delayed development and 3 patients never had independent walking. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Synofzik et al. (2011) reported a 25-year-old German woman who presented with a 3-year history of paroxysmal exercise-induced gait ataxia. The episodic ataxia occurred up to 5 times a day and lasted for a few seconds to 5 minutes, but the frequency increased to up to 23 times per day over a few years. Other features included mild distal deficits in position and vibration sense, mild leg spasticity, and hyperreflexia, but she never had permanent cerebellar ataxia or gait spasticity. Serum lactate was intermittently increased, and brain MRI showed T2 hyperintense lesions in the cerebellar white matter, deep cerebral white matter, and periventricular region, with some involvement of the pyramidal tracts and dorsal columns. Treatment with acetazolamide resulted in significantly decreased frequency of the attacks. Genetic analysis identified a homozygous mutation in the DARS2 gene (R609W; 610956.0013) and excluded mutations in known episodic ataxia genes. The findings indicated that this disorder can have a milder phenotype and even present with episodic ataxia. </p>
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<p>Scheper et al. (2007) performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which they narrowed to a 1.9-cM region between markers D1S2790 and D1S416 by means of shared haplotypes. </p>
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<p>Scheper et al. (2007) sequenced genes in the candidate region on chromosome 1 linked to LBSL and uncovered mutations in DARS2 (610956), which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. Surprisingly, activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays. </p><p>Van Berge et al. (2014) reviewed mutations in the DARS2 gene in 120 patients with LBSL. Overall, 60 different mutations were identified, which were located throughout the gene. One hundred and sixteen patients had compound heterozygous mutations and and 4 patients had homozygous mutations. Ninety-four percent (113/120) of the patients were heterozygous for a mutation in the polypyrimidine tract in intron 2, which is just upstream of exon 3. Thirteen different mutations were identified in this region, with 228-20_-21delTTinsC (610956.0001) as the most common, in 88 patients. Mutations in the polypyrimidine tract in intron 2 were identified in only compound heterozygous state. </p>
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<p>Van der Knaap et al. (2003) postulated autosomal recessive inheritance of LBSL based on the presence of 2 affected sib pairs among their patients. Linnankivi et al. (2004), Serkov et al. (2004), and Petzold et al. (2006) likewise thought autosomal recessive inheritance likely Scheper et al. (2007) proved this to be the case, with affected individuals carrying mutations on both alleles of the DARS2 gene. </p>
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<strong>REFERENCES</strong>
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Isohanni, P., Linnankivi, T., Buzkova, J., Lonnqvist, T., Pihko, H., Valanne, L., Tienari, P. J., Elovaara, I., Pirttila, T., Reunanen, M., Koivisto, K., Marjavaara, S., Suomalainen, A.
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<strong>DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.</strong>
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J. Med. Genet. 47: 66-70, 2010.
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[PubMed: 19592391]
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[Full Text: https://doi.org/10.1136/jmg.2009.068221]
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Linnankivi, T., Lundbom, N., Autti, T., Hakkinen, A.-M., Koillinen, H., Kuusi, T., Lonnqvist, T., Sainio, K., Valanne, L., Aarimaa, T., Pihko, H.
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<strong>Five new cases of a recently described leukoencephalopathy with high brain lactate.</strong>
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Neurology 63: 688-692, 2004.
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[PubMed: 15326244]
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[Full Text: https://doi.org/10.1212/01.wnl.0000134658.35601.41]
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Miyake, N., Yamashita, S., Kurosawa, K., Miyatake, S., Tsurusaki, Y., Doi, H., Saitsu, H., Matsumoto, N.
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<strong>A novel homozygous mutation of DARS2 may cause a severe LBSL variant. (Letter)</strong>
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Clin. Genet. 80: 293-296, 2011.
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[PubMed: 21815884]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2011.01644.x]
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Petzold, G. C., Bohner, G., Klingebiel, R., Amberger, N., van der Knaap, M. S., Zschenderlein, R.
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<strong>Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate.</strong>
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J. Neurol. Neurosurg. Psychiat. 77: 889-891, 2006.
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[PubMed: 16788019]
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[Full Text: https://doi.org/10.1136/jnnp.2005.078568]
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Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S.
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<strong>Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.</strong>
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Nature Genet. 39: 534-539, 2007.
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[PubMed: 17384640]
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[Full Text: https://doi.org/10.1038/ng2013]
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Serkov, S. V., Pronin, I. N., Bykova, O. V., Maslova, O. I., Arutyunov, N. V., Muravina, T. I., Kornienko, V. N., Fadeeva, L. M., Marks, H., Bonnemann, C., Schiffmann, R., van der Knaap, M. S.
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<strong>Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate.</strong>
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Neuropediatrics 35: 1-5, 2004.
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[PubMed: 15002045]
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[Full Text: https://doi.org/10.1055/s-2003-43548]
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Synofzik, M., Schicks, J., Lindig, T., Biskup, S., Schmidt, T., Hansel, J., Lehmann-Horn, F., Schols, L.
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<strong>Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.</strong>
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J. Med. Genet. 48: 713-715, 2011.
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[PubMed: 21749991]
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[Full Text: https://doi.org/10.1136/jmg.2011.090282]
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van Berge, L., Hamilton, E. M., Linnankivi, T., Uziel, G., Steenweg, M. E., Isohanni, P., Wolf, N. I., Krageloh-Mann, I., Brautaset, N. J., Andrews, P. I., de Jong, B. A., al Ghamdi, M., and 11 others.
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<strong>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.</strong>
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Brain 137: 1019-29, 2014.
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[PubMed: 24566671]
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[Full Text: https://doi.org/10.1093/brain/awu026]
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van der Knaap, M. S., van der Voorn, P., Barkhof, F., Van Coster, R., Krageloh-Mann, I., Feigenbaum, A., Blaser, S., Vles, J. S. H., Rieckmann, P., Pouwels, P. J. W.
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<strong>A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.</strong>
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Ann. Neurol. 53: 252-258, 2003.
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[PubMed: 12557294]
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[Full Text: https://doi.org/10.1002/ana.10456]
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Cassandra L. Kniffin - updated : 10/26/2011<br>Cassandra L. Kniffin - updated : 10/4/2011<br>Cassandra L. Kniffin - updated : 6/15/2010
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