3055 lines
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Entry
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- #602473 - ENCEPHALOPATHY, ETHYLMALONIC; EE
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- OMIM
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<span class="h4">#602473</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/602473"><strong>Clinical Synopsis</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="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</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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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<span class="panel-title">
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<span class="small">
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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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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=ENCEPHALOPATHY, ETHYLMALONIC" 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=10672&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/NBK453432/" 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/2662" 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/ethylmalonic-encephalopathy" 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=602473[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="#mimNewbornScreeningFold" id="mimNewbornScreeningToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Information and resources for newborn screening and genetics."><span id="mimNewbornScreeningToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Newborn Screening</div>
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<div id="mimNewbornScreeningFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/C4-OH.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/C4-OH-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
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</div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=51188" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060640" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/602473" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0060640" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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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> 723307008<br />
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<strong>ORPHA:</strong> 51188<br />
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<strong>DO:</strong> 0060640<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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602473
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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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ENCEPHALOPATHY, ETHYLMALONIC; EE
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
|
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</th>
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<th>
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Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/19/776?start=-3&limit=10&highlight=776">
|
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19q13.31
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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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Ethylmalonic encephalopathy
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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/602473"> 602473 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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ETHE1
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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/608451"> 608451 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group mim-changed mim-change">
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<a href="/clinicalSynopsis/602473" 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>
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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/602473" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/602473" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> GROWTH </strong>
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</span>
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Other </em>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</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>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Retinal lesions with tortuous vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865352&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865352</a>]</span><br />
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|
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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>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Orthostatic acrocyanosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865357&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865357</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Chronic diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236071009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236071009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0401151&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0401151</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002028</a>]</span><br />
|
|
<div class="mim-changed mim-change"> - Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /></div>
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
</div>
|
|
|
|
</div>
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Petechiae <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271813007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271813007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50091001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50091001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/423716004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">423716004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R23.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R23.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241144</a>, <a href="https://bioportal.bioontology.org/search?q=C0031256&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031256</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000967</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000967</a>]</span><br /> -
|
|
Orthostatic acrocyanosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865357&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865357</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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</div>
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|
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</div>
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|
|
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|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Developmental regression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/609225004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">609225004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836830&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836830</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span><br />
|
|
- Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br />
|
|
<div class="mim-changed mim-change"> - Impaired intellectual development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747273</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /></div>
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- Pyramidal symptoms <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865350&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865350</a>]</span><br />
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- Extrapyramidal symptoms <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43378000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43378000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span><br />
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<div class="mim-changed mim-change"> - Chorea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271700006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271700006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008489&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008489</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span><br /></div>
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- 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 />
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- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
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- Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br />
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- Hyperintense lesions in the basal ganglia on MRI <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865351&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865351</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007183" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007183</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007183" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007183</a>]</span><br />
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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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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- Lactic acidemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/190882007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">190882007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0347959&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0347959</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003128" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003128</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003128" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003128</a>]</span><br /> -
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Ethylmalonic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865353&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865353</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003219" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003219</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003219" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003219</a>]</span><br /> -
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Methylsuccinic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865354&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865354</a>]</span><br /> -
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Cytochrome c oxidase deficiency in skeletal muscle and brain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3148692&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3148692</a>]</span><br /> -
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Increased serum C4 and C5 acylcarnitine esters <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865356&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865356</a>]</span><br /> -
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Increased urinary isobutyryl glycine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3148693&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3148693</a>]</span><br /> -
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Increased urinary 2-methylbutyryl glycine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3148694&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3148694</a>]</span><br /> -
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Increased urinary thiosulphate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3148695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3148695</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011943</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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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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- Onset in first months of life<br /> -
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Patients are often of Mediterranean origin<br /> -
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Death usually occurs in first decade of life<br />
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</span>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the ETHE1 persulfide dioxygenase gene (ETHE1, <a href="/entry/608451#0001">608451.0001</a>)<br />
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<div class="text-right">
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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-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 ethylmalonic encephalopathy (EE) is caused by homozygous or compound heterozygous mutation in the ETHE1 gene (<a href="/entry/608451">608451</a>), which encodes a mitochondrial matrix protein, on chromosome 19q13.</p>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<p>Ethylmalonic encephalopathy (EE) is an autosomal recessive severe metabolic disorder of infancy affecting the brain, gastrointestinal tract, and peripheral vessels. The disorder is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Brain MRI shows necrotic lesions in deep gray matter structures. Death usually occurs in the first decade of life (summary by <a href="#3" class="mim-tip-reference" title="Drousiotou, A., DiMeo, I., Mineri, R., Georgiou, T., Stylianidou, G., Tiranti, V. <strong>Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches.</strong> Clin. Genet. 79: 385-390, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20528888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20528888</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01457.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20528888">Drousiotou et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20528888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<strong>Clinical Features</strong>
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<p><a href="#2" class="mim-tip-reference" title="Burlina, A., Zacchello, F., Dionisi-Vici, C., Bertini, E., Sabetta, G., Bennett, M. J., Hale, D. E., Schmidt-Sommerfeld, E., Rinaldo, P. <strong>New clinical phenotype of branched-chain acyl-CoA oxidation defect. (Letter)</strong> Lancet 338: 1522-1523, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1683940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1683940</a>] [<a href="https://doi.org/10.1016/0140-6736(91)92338-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1683940">Burlina et al. (1991)</a> first described ethylmalonic encephalopathy as a syndrome characterized by developmental delay, acrocyanosis, petechiae, and chronic diarrhea. Laboratory studies showed ethylmalonic and methylsuccinic aciduria and lactic acidemia. However, in vitro activities of short chain acyl-CoA dehydrogenase (SCAD; <a href="/entry/606885">606885</a>) and 2-methyl-branched chain acyl-CoA dehydrogenase, 2 enzymes whose deficiencies could theoretically produce the biochemical findings observed in ethylmalonic encephalopathy, were found to be normal (<a href="#1" class="mim-tip-reference" title="Burlina, A. B., Dionisi-Vici, C., Bennett, M. J., Gibson, K. M., Servidei, S., Bertini, E., Hale, D. E., Schmidt-Sommerfeld, E., Sabetta, G., Zacchello, F., Rinaldo, P. <strong>A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts.</strong> J. Pediat. 124: 79-86, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8283379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8283379</a>] [<a href="https://doi.org/10.1016/s0022-3476(94)70257-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8283379">Burlina et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1683940+8283379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Nowaczyk, M. J. M., Blaser, S. I., Clarke, J. T. R. <strong>Central nervous system malformations in ethylmalonic encephalopathy.</strong> Am. J. Med. Genet. 75: 292-296, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475600</a>]" pmid="9475600">Nowaczyk et al. (1998)</a> reported the cases of 2 sibs with ethylmalonic encephalopathy and central nervous system malformations. The girl had primary tethered cord. Her younger brother, who was evaluated at the age of 4 years because of a similar phenotype (episodic ataxia, chronic diarrhea, and acrocyanosis), had cerebellar tonsillar ectopia (Chiari I malformation). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9475600" 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="#14" class="mim-tip-reference" title="Tiranti, V., D'Adamo, P., Briem, E., Ferrari, G., Mineri, R., Lamantea, E., Mandel, H., Balestri, P., Garcia-Silva, M.-T., Vollmer, B., Rinaldo, P., Hahn, S. H., Leonard, J., Rahman, S., Dionisi-Vici, C., Garavaglia, B., Gasparini, P., Zeviani, M. <strong>Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.</strong> Am. J. Hum. Genet. 74: 239-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14732903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14732903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14732903[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381653" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14732903">Tiranti et al. (2004)</a> stated that since the initial report no more than 30 cases of ethylmalonic encephalopathy had been described worldwide, leading to the assumption that the disorder is very rare. However, the actual incidence of the condition may be significantly underestimated because the biochemical phenotype may be incorrectly attributed to other metabolic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14732903" 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="Drousiotou, A., DiMeo, I., Mineri, R., Georgiou, T., Stylianidou, G., Tiranti, V. <strong>Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches.</strong> Clin. Genet. 79: 385-390, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20528888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20528888</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01457.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20528888">Drousiotou et al. (2011)</a> reported 3 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy. The first patient presented at age 2.5 months with feeding difficulties, failure to thrive, petechiae, and ecchymosis. She was floppy with severe head lag and microcephaly, and showed poor responses to auditory and visual stimuli. Deep tendon reflexes were exaggerated, and there was sustained clonus and bilateral Babinski sign. She subsequently developed chronic diarrhea and seizures. Brain MRI revealed multiple bilateral loci of high intensity in the basal ganglia on T2-weighted images. She showed neurologic regression and was 5.5 years old at the time of the report. Her older brother died at age 6 months of a presumably similar disorder. Ultrasound of the brain showed hyperechogenicity of gyri and sulci. No tissues were available for confirmation of diagnosis. A girl from a second family was born prematurely at 36 weeks' gestation and presented at age 6 months with feeding difficulties, hypotonia, and global developmental delay. She later developed diarrhea, petechiae, ecchymosis, and seizures, and brain MRI showed abnormal signals in the basal ganglia and thinning of the corpus callosum. She died at age 8 months from cardiopulmonary arrest. Laboratory studies of all 3 patients showed increased serum lactate and butyrylcarnitine, and increased urinary ethylmalonic acid, methylsuccinate, and thiosulfate. Western blot analysis from 2 patients showed complete absence of the ETHE1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20528888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Pigeon, N., Campeau, P. M., Cyr, D., Lemieux, B., Clarke, J. T. <strong>Clinical heterogeneity in ethylmalonic encephalopathy.</strong> J. Child Neurol 24: 991-996, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289697</a>] [<a href="https://doi.org/10.1177/0883073808331359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289697">Pigeon et al. (2009)</a> described a pair of monochorionic dichorionic twin sisters with EE. Both patients were born in the breech position and had severe neonatal hyperbilirubinemia. Both presented with psychomotor delay at 15 months of age. Patient 1 had truncal hypotonia and progressive pyramidal symptoms with dystonia and spasticity. During an episode of gastroenteritis at 3.5 years of age, she developed status epilepticus and decreased consciousness. At 10 years of age, she had severely impaired intellectual development, a pyramidal syndrome affecting all 4 limbs, and pseudobulbar palsy. Patient 2 had mild metabolic acidosis during an episode of gastroenteritis at 3.5 years of age. At 10 years of age, she had truncal hypotonia, scoliosis, and mildly to moderately impaired intellectual development. Laboratory testing showed increased urine ethylmalonic acid in both patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289697" 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="Kitzler, T. M., Gupta, I. R., Osterman, B., Poulin, C., Trakadis, Y., Waters, P. J., Buhas, D. C. <strong>Acute and chronic management in an atypical case of ethylmalonic encephalopathy.</strong> JIMD Rep. 45: 57-63, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30349987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30349987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30349987[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/8904_2018_136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30349987">Kitzler et al. (2019)</a> reported a 19-year-old man with EE who presented at 10 years of age with a long-standing history of spastic paraplegia, dysarthria, and Arnold-Chiari malformation. At 16 years of age, he developed acute trismus and worsening spasticity in the setting of an upper respiratory tract infection. Laboratory testing at that time showed elevation of C4 carnitine and moderately elevated ethylmalonic acid on urine organic acids. Brain MRI showed abnormal signal in the basal ganglia and cerebellum, and MRS showed a corresponding lactate peak. He presented again at 17 years of age with metabolic decompensation, encephalopathy, focal seizures, and fever. Laboratory testing showed elevated levels of lactate, thiosulfate, and acylcarnitines C4 and C5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30349987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Govindaraj, P., Parayil Sankaran, B., Nagappa, M., Arvinda, H. R., Deepha, S., Jessiena Ponmalar, J. N., Sinha, S., Gayathri, N., Taly, A. B. <strong>Child neurology: ethylmalonic encephalopathy.</strong> Neurology 94: e1336-e1339, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32111695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32111695</a>] [<a href="https://doi.org/10.1212/WNL.0000000000009144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32111695">Govindaraj et al. (2020)</a> reported a patient with EE who presented at 7 months of age with emesis, altered consciousness, seizures, developmental regression, and hyperammonemia. A brain MRI showed abnormal signal in the dorsal pons. He gradually recovered after this episode, but starting at 3 years and 10 months of age, he had regression of all developmental domains. At 52 months of age, he had contractures, spasticity, dystonia, and chorea. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32111695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Kashima, D. T., Sloan-Heggen, C. M., Gottlieb-Smith, R. J., Barone Pritchard, A. <strong>An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.</strong> Am. J. Med. Genet. 191A: 1614-1618, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36891747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36891747</a>] [<a href="https://doi.org/10.1002/ajmg.a.63176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36891747">Kashima et al. (2023)</a> reported a boy with EE who presented at 19 months of age with developmental delay, mild hyperammonemia, and a wide-based gait. Laboratory testing showed elevated C4 acylcarnitine and a small amount of ethylmalonic acid. At 3 years and 5 months of age, he had abnormal speech articulation and dystonia. A brain MRI was normal. At 4 years and 8 months of age, he did not have spasticity or dystonia and had improved speech articulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36891747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Platt, I., Bisgin, A., Kilavuz, S. <strong>Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.</strong> Neurol. Sci. 44: 3827-3852, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37458841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37458841</a>] [<a href="https://doi.org/10.1007/s10072-023-06904-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37458841">Platt et al. (2023)</a> described clinical features of 70 patients with ethylmalonic encephalopathy, including their 2 patients and 68 patients identified through a literature search. Symptom onset ranged from 1 day to 192 months of age, with first symptoms including diarrhea, developmental delay, hypotonia, petechiae, acrocyanosis, poor feeding, spastic paraparesis, seizure, and/or trismus. Among the 70 patients, 67 had psychomotor retardation, 57 had hypotonia, 57 had developmental delay, 53 had pyramidal signs, 28 had seizures, 27 had spastic paraparesis, 16 had episodic coma, and 17 had dystonia. Other common symptoms included gastrointestinal symptoms, such as failure to thrive and chronic diarrhea, and vascular symptoms, such as petechiae and acrocyanosis. Notably, patients with a relatively milder phenotype compared to those with a more severe phenotype had lower ethylmalonic acid levels and lower C4 acylcarnitine levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37458841" 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="#16" class="mim-tip-reference" title="Viscomi, C., Burlina, A. B., Dweikat, I., Savoiardo, M., Lamperti, C., Hildebrandt, T., Tiranti, V., Zeviani, M. <strong>Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy.</strong> Nature Med. 16: 869-871, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20657580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20657580</a>] [<a href="https://doi.org/10.1038/nm.2188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20657580">Viscomi et al. (2010)</a> treated a 29-month-old Italian boy with ethylmalonic encephalopathy with metronidazole and N-acetylcysteine, a precursor of sulfide-buffering glutathione. The therapy was designed to act against accumulation of toxic hydrogen sulfide. Over the next 8 months, the patient showed increased body weight, a decrease and then disappearance of diarrhea, petechiae, and acrocyanosis, and marked neurologic improvement, with decreased seizures, less severe hypotonia, reversion of brain atrophy, and a reduction in leukodystrophy, although lesions in the neostriatum become more evident. Biochemical abnormalities also lessened. Treatment of 4 additional patients showed similar clinical, biochemical, and MRI improvements. The clinical treatment was performed after <a href="#16" class="mim-tip-reference" title="Viscomi, C., Burlina, A. B., Dweikat, I., Savoiardo, M., Lamperti, C., Hildebrandt, T., Tiranti, V., Zeviani, M. <strong>Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy.</strong> Nature Med. 16: 869-871, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20657580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20657580</a>] [<a href="https://doi.org/10.1038/nm.2188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20657580">Viscomi et al. (2010)</a> obtained favorable results in an Ethe1 -/- mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20657580" 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="Kitzler, T. M., Gupta, I. R., Osterman, B., Poulin, C., Trakadis, Y., Waters, P. J., Buhas, D. C. <strong>Acute and chronic management in an atypical case of ethylmalonic encephalopathy.</strong> JIMD Rep. 45: 57-63, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30349987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30349987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30349987[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/8904_2018_136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30349987">Kitzler et al. (2019)</a> reported a patient with EE who presented at 17 years of age with metabolic decompensation, encephalopathy, focal seizures, and fever. Laboratory testing showed elevated levels of lactate, thiosulfate, and acylcarnitines C4 and C5. He was treated with N-acetylcysteine, metronidazole, and continuous renal replacement therapy, which resulted in improved metabolic and clinical status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30349987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of EE in the families studied by <a href="#14" class="mim-tip-reference" title="Tiranti, V., D'Adamo, P., Briem, E., Ferrari, G., Mineri, R., Lamantea, E., Mandel, H., Balestri, P., Garcia-Silva, M.-T., Vollmer, B., Rinaldo, P., Hahn, S. H., Leonard, J., Rahman, S., Dionisi-Vici, C., Garavaglia, B., Gasparini, P., Zeviani, M. <strong>Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.</strong> Am. J. Hum. Genet. 74: 239-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14732903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14732903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14732903[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381653" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14732903">Tiranti et al. (2004)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14732903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By a combination of homozygosity mapping, integration of physical and functional genomic datasets, and mutational screening, <a href="#14" class="mim-tip-reference" title="Tiranti, V., D'Adamo, P., Briem, E., Ferrari, G., Mineri, R., Lamantea, E., Mandel, H., Balestri, P., Garcia-Silva, M.-T., Vollmer, B., Rinaldo, P., Hahn, S. H., Leonard, J., Rahman, S., Dionisi-Vici, C., Garavaglia, B., Gasparini, P., Zeviani, M. <strong>Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.</strong> Am. J. Hum. Genet. 74: 239-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14732903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14732903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14732903[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381653" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14732903">Tiranti et al. (2004)</a> identified the ETHE1 gene (<a href="/entry/608451">608451</a>) as the site of mutations causing EE. They demonstrated that the ETHE1 protein is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14732903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 14 patients with ethylmalonic encephalopathy, <a href="#9" class="mim-tip-reference" title="Mineri, R., Rimoldi, M., Burlina, A. B., Koskull, S., Perletti, C., Heese, B., von Dobeln, U., Mereghetti, P., Di Meo, I., Invernizzi, F., Zeviani, M., Uziel, G., Tiranti, V. <strong>Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. (Letter)</strong> J. Med. Genet. 45: 473-478, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18593870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18593870</a>] [<a href="https://doi.org/10.1136/jmg.2008.058271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18593870">Mineri et al. (2008)</a> identified homozygosity for mutations in the ETHE1 gene (see, e.g., <a href="/entry/608451#0006">608451.0006</a> and <a href="/entry/608451#0007">608451.0007</a>). At the time of the report, 11 patients were deceased; age of death ranged from 18 months to 3 years. Three patients were alive at 6 months, 7 years, and 13 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18593870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy, <a href="#3" class="mim-tip-reference" title="Drousiotou, A., DiMeo, I., Mineri, R., Georgiou, T., Stylianidou, G., Tiranti, V. <strong>Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches.</strong> Clin. Genet. 79: 385-390, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20528888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20528888</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01457.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20528888">Drousiotou et al. (2011)</a> identified 2 different mutations in the ETHE1 gene (<a href="/entry/608451#0007">608451.0007</a> and <a href="/entry/608451#0008">608451.0008</a>). One was compound heterozygous for the mutations, whereas the other was homozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20528888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Pigeon, N., Campeau, P. M., Cyr, D., Lemieux, B., Clarke, J. T. <strong>Clinical heterogeneity in ethylmalonic encephalopathy.</strong> J. Child Neurol 24: 991-996, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289697</a>] [<a href="https://doi.org/10.1177/0883073808331359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289697">Pigeon et al. (2009)</a> identified compound heterozygous mutations in the ETHE1 gene (L185R, <a href="/entry/608451#0008">608451.0008</a> and Q27K, <a href="/entry/608451#0009">608451.0009</a>) in a pair of Yugoslavian identical twins with ethylmalonic encephalopathy. Functional studies in patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289697" 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="Kitzler, T. M., Gupta, I. R., Osterman, B., Poulin, C., Trakadis, Y., Waters, P. J., Buhas, D. C. <strong>Acute and chronic management in an atypical case of ethylmalonic encephalopathy.</strong> JIMD Rep. 45: 57-63, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30349987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30349987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30349987[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/8904_2018_136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30349987">Kitzler et al. (2019)</a> identified homozygosity for the Q27K mutation in the ETHE1 gene in a 19-year-old patient with ethylmalonic encephalopathy. The mutation was identified by Sanger sequencing of the gene, and both parents were shown to be mutation carriers. Functional studies in patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30349987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Govindaraj, P., Parayil Sankaran, B., Nagappa, M., Arvinda, H. R., Deepha, S., Jessiena Ponmalar, J. N., Sinha, S., Gayathri, N., Taly, A. B. <strong>Child neurology: ethylmalonic encephalopathy.</strong> Neurology 94: e1336-e1339, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32111695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32111695</a>] [<a href="https://doi.org/10.1212/WNL.0000000000009144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32111695">Govindaraj et al. (2020)</a> identified a homozygous mutation (D165H; <a href="/entry/608451#0010">608451.0010</a>) in the ETHE1 gene in an Indian boy with ethylmalonic encephalopathy. The mutation was identified by whole-exome sequencing. Respiratory chain activity testing in patient muscle demonstrated an isolated defect of complex IV activity. ETHE1 protein was reduced in patient muscle tissue, as were proteins associated with respiratory chain complexes I, II, and IV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32111695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 4-year-old boy with ethylmalonic encephalopathy, <a href="#7" class="mim-tip-reference" title="Kashima, D. T., Sloan-Heggen, C. M., Gottlieb-Smith, R. J., Barone Pritchard, A. <strong>An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.</strong> Am. J. Med. Genet. 191A: 1614-1618, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36891747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36891747</a>] [<a href="https://doi.org/10.1002/ajmg.a.63176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36891747">Kashima et al. (2023)</a> identified a homozygous mutation in the ETHE1 gene (D196N; <a href="/entry/608451#0011">608451.0011</a>). The mutation was identified by whole-exome sequencing. Functional studies in patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36891747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Platt, I., Bisgin, A., Kilavuz, S. <strong>Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.</strong> Neurol. Sci. 44: 3827-3852, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37458841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37458841</a>] [<a href="https://doi.org/10.1007/s10072-023-06904-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37458841">Platt et al. (2023)</a> reviewed the biallelic mutations that had been identified in the ETHE1 gene in 45 patients with ethylmalonic encephalopathy. Thirty-two patients had homozygous mutations, and 13 patients had compound heterozygous mutations. Thirty individual mutations were identified, with the most common being R163Q, deletion of exon 4, and R163W. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37458841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a review of clinical features and ETHE1 mutations identified in 70 patients with EE, <a href="#13" class="mim-tip-reference" title="Platt, I., Bisgin, A., Kilavuz, S. <strong>Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.</strong> Neurol. Sci. 44: 3827-3852, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37458841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37458841</a>] [<a href="https://doi.org/10.1007/s10072-023-06904-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37458841">Platt et al. (2023)</a> noted that a milder clinical phenotype was associated with homozygosity for the R163W (<a href="/entry/608451#0001">608451.0001</a>), R163Q, and Q27K (<a href="/entry/608451#0009">608451.0009</a>) mutations and compound heterozygosity for the Q27K and L185R (<a href="/entry/608451#0008">608451.0008</a>) mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37458841" 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>With few exceptions, reported patients with ethylmalonic encephalopathy have been of Mediterranean (<a href="#4" class="mim-tip-reference" title="Garcia-Silva, M. T., Ribes, A., Campos, Y., Garavaglia, B., Arenas, J. <strong>Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria.</strong> Pediat. Neurol. 17: 165-170, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9367300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9367300</a>] [<a href="https://doi.org/10.1016/s0887-8994(97)00048-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9367300">Garcia-Silva et al., 1997</a>; <a href="#6" class="mim-tip-reference" title="Grosso, S., Mostardini, R., Farnetani, M. A., Molinelli, M., Berardi, R., Dionisi-Vici, C., Rizzo, C., Morgese, G., Balestri, P. <strong>Ethylmalonic encephalopathy: further clinical and neuroradiological characterization.</strong> J. Neurol. 249: 1446-1450, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12382164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12382164</a>] [<a href="https://doi.org/10.1007/s00415-002-0880-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12382164">Grosso et al., 2002</a>) or Arab (<a href="#11" class="mim-tip-reference" title="Ozand, P. T., Rashed, M., Millington, D. S., Sakati, N., Hazzaa, S., Rahbeeni, Z., Al Odaib, A., Youssef, N., Mazrou, A., Gascon, G. G., Brismar, J. <strong>Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy.</strong> Brain Dev. 16 (suppl.): 12-22, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726376</a>] [<a href="https://doi.org/10.1016/0387-7604(94)90092-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7726376">Ozand et al., 1994</a>) extraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9367300+12382164+7726376" 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="#15" class="mim-tip-reference" title="Tiranti, V., Viscomi, C., Hildebrandt, T., Di Meo, I., Mineri, R., Tiveron, C., Levitt, M. D., Prelle, A., Fagiolari, G., Rimoldi, M., Zeviani, M. <strong>Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy.</strong> Nature Med. 15: 200-205, 2009. Note: Erratum: Nature Med. 15: 220 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136963</a>] [<a href="https://doi.org/10.1038/nm.1907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136963">Tiranti et al. (2009)</a> found that Ethe1-null mice developed the cardinal features of ethylmalonic encephalopathy, including poor growth, reduced motor activity, early death, low cytochrome c oxidase (COX) in muscle and brain, and increased urinary excretion of ethylmalonic acid. Both mutant mice and humans with the disorder excreted massive amounts of thiosulfate in the urine, and there was an accumulation of thiosulfate and hydrogen sulfide (H2S) in mutant mouse tissue. Hydrogen sulfide is powerful inhibitor of COX and short-chain fatty acid oxidation, and has vasoactive and vasotoxic effects. The findings suggested that ethylmalonic encephalopathy is a disease associated with impaired catabolism of inorganic sulfur leading to accumulation of hydrogen sulfide in key tissues. The toxic effects of this accumulation can account for several features, including ethylmalonic aciduria, COX deficiency, microangiopathy, acrocyanosis, and chronic diarrhea. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1-null mice, but it was markedly increased by ETHE1 overexpression in HeLa cells and E. coli. These findings indicated that ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts.</strong>
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J. Pediat. 124: 79-86, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8283379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8283379</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8283379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>New clinical phenotype of branched-chain acyl-CoA oxidation defect. (Letter)</strong>
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Lancet 338: 1522-1523, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1683940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1683940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1683940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0140-6736(91)92338-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2010.01457.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0887-8994(97)00048-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000009144" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00415-002-0880-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.63176" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/8904_2018_136" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.058271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0387-7604(94)90092-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/0883073808331359" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10072-023-06904-8" target="_blank">Full Text</a>]
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Tiranti, V., D'Adamo, P., Briem, E., Ferrari, G., Mineri, R., Lamantea, E., Mandel, H., Balestri, P., Garcia-Silva, M.-T., Vollmer, B., Rinaldo, P., Hahn, S. H., Leonard, J., Rahman, S., Dionisi-Vici, C., Garavaglia, B., Gasparini, P., Zeviani, M.
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<strong>Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14732903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14732903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14732903[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14732903" 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/10.1086/381653" target="_blank">Full Text</a>]
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Tiranti, V., Viscomi, C., Hildebrandt, T., Di Meo, I., Mineri, R., Tiveron, C., Levitt, M. D., Prelle, A., Fagiolari, G., Rimoldi, M., Zeviani, M.
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<strong>Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136963</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136963" 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/nm.1907" target="_blank">Full Text</a>]
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Viscomi, C., Burlina, A. B., Dweikat, I., Savoiardo, M., Lamperti, C., Hildebrandt, T., Tiranti, V., Zeviani, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20657580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20657580</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20657580" 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/nm.2188" target="_blank">Full Text</a>]
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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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Hilary J. Vernon - updated : 10/21/2024
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 5/18/2011<br>Cassandra L. Kniffin - updated : 10/4/2010<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Victor A. McKusick - updated : 2/5/2004
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Creation Date:
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Victor A. McKusick : 3/25/1998
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carol : 10/22/2024
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carol : 10/21/2024<br>carol : 01/20/2022<br>alopez : 07/15/2021<br>carol : 09/22/2016<br>carol : 06/09/2015<br>alopez : 7/24/2013<br>wwang : 6/3/2011<br>ckniffin : 5/18/2011<br>wwang : 10/8/2010<br>ckniffin : 10/4/2010<br>wwang : 10/13/2008<br>ckniffin : 10/6/2008<br>terry : 2/14/2005<br>alopez : 2/9/2004<br>terry : 2/5/2004<br>carol : 4/30/2002<br>alopez : 5/5/1998<br>alopez : 3/25/1998
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<strong>#</strong> 602473
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ENCEPHALOPATHY, ETHYLMALONIC; EE
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<strong>SNOMEDCT:</strong> 723307008;
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<strong>ORPHA:</strong> 51188;
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<strong>DO:</strong> 0060640;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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19q13.31
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Ethylmalonic encephalopathy
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602473
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Autosomal recessive
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3
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ETHE1
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608451
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<p>A number sign (#) is used with this entry because of evidence that ethylmalonic encephalopathy (EE) is caused by homozygous or compound heterozygous mutation in the ETHE1 gene (608451), which encodes a mitochondrial matrix protein, on chromosome 19q13.</p>
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<p>Ethylmalonic encephalopathy (EE) is an autosomal recessive severe metabolic disorder of infancy affecting the brain, gastrointestinal tract, and peripheral vessels. The disorder is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Brain MRI shows necrotic lesions in deep gray matter structures. Death usually occurs in the first decade of life (summary by Drousiotou et al., 2011). </p>
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<strong>Clinical Features</strong>
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<p>Burlina et al. (1991) first described ethylmalonic encephalopathy as a syndrome characterized by developmental delay, acrocyanosis, petechiae, and chronic diarrhea. Laboratory studies showed ethylmalonic and methylsuccinic aciduria and lactic acidemia. However, in vitro activities of short chain acyl-CoA dehydrogenase (SCAD; 606885) and 2-methyl-branched chain acyl-CoA dehydrogenase, 2 enzymes whose deficiencies could theoretically produce the biochemical findings observed in ethylmalonic encephalopathy, were found to be normal (Burlina et al., 1994). </p><p>Nowaczyk et al. (1998) reported the cases of 2 sibs with ethylmalonic encephalopathy and central nervous system malformations. The girl had primary tethered cord. Her younger brother, who was evaluated at the age of 4 years because of a similar phenotype (episodic ataxia, chronic diarrhea, and acrocyanosis), had cerebellar tonsillar ectopia (Chiari I malformation). </p><p>Tiranti et al. (2004) stated that since the initial report no more than 30 cases of ethylmalonic encephalopathy had been described worldwide, leading to the assumption that the disorder is very rare. However, the actual incidence of the condition may be significantly underestimated because the biochemical phenotype may be incorrectly attributed to other metabolic disorders. </p><p>Drousiotou et al. (2011) reported 3 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy. The first patient presented at age 2.5 months with feeding difficulties, failure to thrive, petechiae, and ecchymosis. She was floppy with severe head lag and microcephaly, and showed poor responses to auditory and visual stimuli. Deep tendon reflexes were exaggerated, and there was sustained clonus and bilateral Babinski sign. She subsequently developed chronic diarrhea and seizures. Brain MRI revealed multiple bilateral loci of high intensity in the basal ganglia on T2-weighted images. She showed neurologic regression and was 5.5 years old at the time of the report. Her older brother died at age 6 months of a presumably similar disorder. Ultrasound of the brain showed hyperechogenicity of gyri and sulci. No tissues were available for confirmation of diagnosis. A girl from a second family was born prematurely at 36 weeks' gestation and presented at age 6 months with feeding difficulties, hypotonia, and global developmental delay. She later developed diarrhea, petechiae, ecchymosis, and seizures, and brain MRI showed abnormal signals in the basal ganglia and thinning of the corpus callosum. She died at age 8 months from cardiopulmonary arrest. Laboratory studies of all 3 patients showed increased serum lactate and butyrylcarnitine, and increased urinary ethylmalonic acid, methylsuccinate, and thiosulfate. Western blot analysis from 2 patients showed complete absence of the ETHE1 protein. </p><p>Pigeon et al. (2009) described a pair of monochorionic dichorionic twin sisters with EE. Both patients were born in the breech position and had severe neonatal hyperbilirubinemia. Both presented with psychomotor delay at 15 months of age. Patient 1 had truncal hypotonia and progressive pyramidal symptoms with dystonia and spasticity. During an episode of gastroenteritis at 3.5 years of age, she developed status epilepticus and decreased consciousness. At 10 years of age, she had severely impaired intellectual development, a pyramidal syndrome affecting all 4 limbs, and pseudobulbar palsy. Patient 2 had mild metabolic acidosis during an episode of gastroenteritis at 3.5 years of age. At 10 years of age, she had truncal hypotonia, scoliosis, and mildly to moderately impaired intellectual development. Laboratory testing showed increased urine ethylmalonic acid in both patients. </p><p>Kitzler et al. (2019) reported a 19-year-old man with EE who presented at 10 years of age with a long-standing history of spastic paraplegia, dysarthria, and Arnold-Chiari malformation. At 16 years of age, he developed acute trismus and worsening spasticity in the setting of an upper respiratory tract infection. Laboratory testing at that time showed elevation of C4 carnitine and moderately elevated ethylmalonic acid on urine organic acids. Brain MRI showed abnormal signal in the basal ganglia and cerebellum, and MRS showed a corresponding lactate peak. He presented again at 17 years of age with metabolic decompensation, encephalopathy, focal seizures, and fever. Laboratory testing showed elevated levels of lactate, thiosulfate, and acylcarnitines C4 and C5. </p><p>Govindaraj et al. (2020) reported a patient with EE who presented at 7 months of age with emesis, altered consciousness, seizures, developmental regression, and hyperammonemia. A brain MRI showed abnormal signal in the dorsal pons. He gradually recovered after this episode, but starting at 3 years and 10 months of age, he had regression of all developmental domains. At 52 months of age, he had contractures, spasticity, dystonia, and chorea. </p><p>Kashima et al. (2023) reported a boy with EE who presented at 19 months of age with developmental delay, mild hyperammonemia, and a wide-based gait. Laboratory testing showed elevated C4 acylcarnitine and a small amount of ethylmalonic acid. At 3 years and 5 months of age, he had abnormal speech articulation and dystonia. A brain MRI was normal. At 4 years and 8 months of age, he did not have spasticity or dystonia and had improved speech articulation. </p><p>Platt et al. (2023) described clinical features of 70 patients with ethylmalonic encephalopathy, including their 2 patients and 68 patients identified through a literature search. Symptom onset ranged from 1 day to 192 months of age, with first symptoms including diarrhea, developmental delay, hypotonia, petechiae, acrocyanosis, poor feeding, spastic paraparesis, seizure, and/or trismus. Among the 70 patients, 67 had psychomotor retardation, 57 had hypotonia, 57 had developmental delay, 53 had pyramidal signs, 28 had seizures, 27 had spastic paraparesis, 16 had episodic coma, and 17 had dystonia. Other common symptoms included gastrointestinal symptoms, such as failure to thrive and chronic diarrhea, and vascular symptoms, such as petechiae and acrocyanosis. Notably, patients with a relatively milder phenotype compared to those with a more severe phenotype had lower ethylmalonic acid levels and lower C4 acylcarnitine levels. </p>
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<strong>Clinical Management</strong>
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<p>Viscomi et al. (2010) treated a 29-month-old Italian boy with ethylmalonic encephalopathy with metronidazole and N-acetylcysteine, a precursor of sulfide-buffering glutathione. The therapy was designed to act against accumulation of toxic hydrogen sulfide. Over the next 8 months, the patient showed increased body weight, a decrease and then disappearance of diarrhea, petechiae, and acrocyanosis, and marked neurologic improvement, with decreased seizures, less severe hypotonia, reversion of brain atrophy, and a reduction in leukodystrophy, although lesions in the neostriatum become more evident. Biochemical abnormalities also lessened. Treatment of 4 additional patients showed similar clinical, biochemical, and MRI improvements. The clinical treatment was performed after Viscomi et al. (2010) obtained favorable results in an Ethe1 -/- mouse model. </p><p>Kitzler et al. (2019) reported a patient with EE who presented at 17 years of age with metabolic decompensation, encephalopathy, focal seizures, and fever. Laboratory testing showed elevated levels of lactate, thiosulfate, and acylcarnitines C4 and C5. He was treated with N-acetylcysteine, metronidazole, and continuous renal replacement therapy, which resulted in improved metabolic and clinical status. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of EE in the families studied by Tiranti et al. (2004) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>By a combination of homozygosity mapping, integration of physical and functional genomic datasets, and mutational screening, Tiranti et al. (2004) identified the ETHE1 gene (608451) as the site of mutations causing EE. They demonstrated that the ETHE1 protein is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism. </p><p>In 14 patients with ethylmalonic encephalopathy, Mineri et al. (2008) identified homozygosity for mutations in the ETHE1 gene (see, e.g., 608451.0006 and 608451.0007). At the time of the report, 11 patients were deceased; age of death ranged from 18 months to 3 years. Three patients were alive at 6 months, 7 years, and 13 years, respectively. </p><p>In 2 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy, Drousiotou et al. (2011) identified 2 different mutations in the ETHE1 gene (608451.0007 and 608451.0008). One was compound heterozygous for the mutations, whereas the other was homozygous for 1 of the mutations. </p><p>Pigeon et al. (2009) identified compound heterozygous mutations in the ETHE1 gene (L185R, 608451.0008 and Q27K, 608451.0009) in a pair of Yugoslavian identical twins with ethylmalonic encephalopathy. Functional studies in patient cells were not performed. </p><p>Kitzler et al. (2019) identified homozygosity for the Q27K mutation in the ETHE1 gene in a 19-year-old patient with ethylmalonic encephalopathy. The mutation was identified by Sanger sequencing of the gene, and both parents were shown to be mutation carriers. Functional studies in patient cells were not performed. </p><p>Govindaraj et al. (2020) identified a homozygous mutation (D165H; 608451.0010) in the ETHE1 gene in an Indian boy with ethylmalonic encephalopathy. The mutation was identified by whole-exome sequencing. Respiratory chain activity testing in patient muscle demonstrated an isolated defect of complex IV activity. ETHE1 protein was reduced in patient muscle tissue, as were proteins associated with respiratory chain complexes I, II, and IV. </p><p>In a 4-year-old boy with ethylmalonic encephalopathy, Kashima et al. (2023) identified a homozygous mutation in the ETHE1 gene (D196N; 608451.0011). The mutation was identified by whole-exome sequencing. Functional studies in patient cells were not performed. </p><p>Platt et al. (2023) reviewed the biallelic mutations that had been identified in the ETHE1 gene in 45 patients with ethylmalonic encephalopathy. Thirty-two patients had homozygous mutations, and 13 patients had compound heterozygous mutations. Thirty individual mutations were identified, with the most common being R163Q, deletion of exon 4, and R163W. </p>
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<p>In a review of clinical features and ETHE1 mutations identified in 70 patients with EE, Platt et al. (2023) noted that a milder clinical phenotype was associated with homozygosity for the R163W (608451.0001), R163Q, and Q27K (608451.0009) mutations and compound heterozygosity for the Q27K and L185R (608451.0008) mutations. </p>
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<p>With few exceptions, reported patients with ethylmalonic encephalopathy have been of Mediterranean (Garcia-Silva et al., 1997; Grosso et al., 2002) or Arab (Ozand et al., 1994) extraction. </p>
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<p>Tiranti et al. (2009) found that Ethe1-null mice developed the cardinal features of ethylmalonic encephalopathy, including poor growth, reduced motor activity, early death, low cytochrome c oxidase (COX) in muscle and brain, and increased urinary excretion of ethylmalonic acid. Both mutant mice and humans with the disorder excreted massive amounts of thiosulfate in the urine, and there was an accumulation of thiosulfate and hydrogen sulfide (H2S) in mutant mouse tissue. Hydrogen sulfide is powerful inhibitor of COX and short-chain fatty acid oxidation, and has vasoactive and vasotoxic effects. The findings suggested that ethylmalonic encephalopathy is a disease associated with impaired catabolism of inorganic sulfur leading to accumulation of hydrogen sulfide in key tissues. The toxic effects of this accumulation can account for several features, including ethylmalonic aciduria, COX deficiency, microangiopathy, acrocyanosis, and chronic diarrhea. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1-null mice, but it was markedly increased by ETHE1 overexpression in HeLa cells and E. coli. These findings indicated that ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy. </p>
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<strong>REFERENCES</strong>
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Burlina, A. B., Dionisi-Vici, C., Bennett, M. J., Gibson, K. M., Servidei, S., Bertini, E., Hale, D. E., Schmidt-Sommerfeld, E., Sabetta, G., Zacchello, F., Rinaldo, P.
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<strong>A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts.</strong>
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J. Pediat. 124: 79-86, 1994.
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[PubMed: 8283379]
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[Full Text: https://doi.org/10.1016/s0022-3476(94)70257-8]
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Burlina, A., Zacchello, F., Dionisi-Vici, C., Bertini, E., Sabetta, G., Bennett, M. J., Hale, D. E., Schmidt-Sommerfeld, E., Rinaldo, P.
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<strong>New clinical phenotype of branched-chain acyl-CoA oxidation defect. (Letter)</strong>
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Lancet 338: 1522-1523, 1991.
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[PubMed: 1683940]
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[Full Text: https://doi.org/10.1016/0140-6736(91)92338-3]
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<p class="mim-text-font">
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Drousiotou, A., DiMeo, I., Mineri, R., Georgiou, T., Stylianidou, G., Tiranti, V.
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<strong>Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches.</strong>
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Clin. Genet. 79: 385-390, 2011.
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[PubMed: 20528888]
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