3384 lines
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- #540000 - MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS
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<span class="h4">#540000</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="/clinicalSynopsis/540000"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#seeAlso"><strong>See Also</strong></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 style="display: table-cell;">External Links</div>
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</a>
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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><a href="https://clinicaltrials.gov/search?cond=MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES" 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=63&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="#mimGeneReviewsFold" id="mimGeneReviewsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling."><span id="mimGeneReviewsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Gene Reviews</div>
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<div id="mimGeneReviewsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1224/" title="Primary Mitochondrial Disorders Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Primary Mitochondrial Diso…</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">MELAS</a></div>
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</div>
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<div><a href="https://www.diseaseinfosearch.org/x/8697" 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/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes" 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=540000[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=550" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/c007ecbc-edbf-4046-9002-bcb9b496c562/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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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:3687" 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/540000" 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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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div id="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:540000" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 39925003<br />
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<strong>ICD10CM:</strong> E88.41<br />
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<strong>ORPHA:</strong> 550<br />
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<strong>DO:</strong> 3687<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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540000
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</span>
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</span>
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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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MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS
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</span>
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</h3>
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<div>
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<br />
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<p>
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
|
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<span class="mim-font">
|
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MELAS SYNDROME
|
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</span>
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</h4>
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<div>
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<br />
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<a href="/clinicalSynopsis/540000" 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>
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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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- Mitochondrial <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/312239001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">312239001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75056005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75056005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026237</a>, <a href="https://bioportal.bioontology.org/search?q=C0887941&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0887941</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001427" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001427</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001427" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001427</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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- Thin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18043004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18043004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0205168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0205168</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> HEAD & NECK </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> Ears </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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|
- Hearing loss, progressive bilateral sensorineural <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5399972&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5399972</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000408" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000408</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</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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<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
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<span class="mim-font">
|
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|
|
- Bilateral cataracts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95722004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95722004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0521707&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521707</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H26.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H26.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/366" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">366</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/366.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">366.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000518</a>]</span><br /> -
|
|
Hemianopsia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77674003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77674003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018979&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018979</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012377" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012377</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012377" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012377</a>]</span><br /> -
|
|
Cortical blindness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413924001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413924001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68574006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68574006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.61</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.75" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.75</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0155320&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0155320</a>, <a href="https://bioportal.bioontology.org/search?q=C4048268&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4048268</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span><br /> -
|
|
Ophthalmoplegia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16110005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16110005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029089&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029089</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000602" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000602</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000602" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000602</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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|
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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> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Left ventricular hypertrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55827005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55827005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149721&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149721</a>, <a href="https://bioportal.bioontology.org/search?q=C3484363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3484363</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001712</a>]</span><br /> -
|
|
Left ventricular dysfunction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/275514001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">275514001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242698&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242698</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005162" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005162</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005162" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005162</a>]</span><br /> -
|
|
Cardiac conduction abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1842820&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1842820</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031546" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031546</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031546" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031546</a>]</span><br /> -
|
|
Wolff-Parkinson-White syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74390002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74390002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I45.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I45.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0043202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0043202</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001716</a>]</span><br /> -
|
|
Heart failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84114007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84114007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42343007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42343007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/428.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/428" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/428.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018802&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018802</a>, <a href="https://bioportal.bioontology.org/search?q=C0018801&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018801</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001635" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001635</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001635" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001635</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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<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br />
|
|
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|
</span>
|
|
</div>
|
|
</div>
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|
</div>
|
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
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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">
|
|
|
|
- Episodic vomiting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838993&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838993</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002572</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002572</a>]</span><br />
|
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|
</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> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Myopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/129565002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">129565002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G72.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G72.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M60-M63" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M60-M63</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/359.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">359.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026848&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026848</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003198</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003198</a>]</span><br /> -
|
|
Reduced muscle mass <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849578&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849578</a>]</span><br /> -
|
|
Ragged-red fibers on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151939</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Episodic sudden headache <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151938&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151938</a>]</span><br /> -
|
|
Intermittent migraine headaches <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0744641&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0744641</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002076" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002076</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002076" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002076</a>]</span><br /> -
|
|
Grand mal seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1217136003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1217136003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G40.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G40.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0494475&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0494475</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002069" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002069</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002069" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002069</a>]</span><br /> -
|
|
Hemiparesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20022000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20022000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018989&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018989</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001269" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001269</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001269" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001269</a>]</span><br /> -
|
|
Stroke-like episodes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857287&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857287</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002401" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002401</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002401" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002401</a>]</span><br /> -
|
|
Dementia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011265</a>, <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
|
|
Encephalopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81308009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81308009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G93.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G93.40</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/348.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.30</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/348.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085584</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001298</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001298</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Lactic acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91273001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91273001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001125&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001125</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 />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ENDOCRINE FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Diabetes mellitus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73211009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73211009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E08-E13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E08-E13</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">250</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011849&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011849</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000819</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000819</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
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- Elevated resting serum lactate, increased with exercise <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151940&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151940</a>]</span><br /> -
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Subsarcolemmal pleomorphic mitochondria on EM <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151941&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151941</a>]</span><br />
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- Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
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The MTTL1 c.3243A-G transition (<a href="/entry/590050#0001">590050.0001</a>) is the most common mutation<br />
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- Caused by mutation in the mitochondrial transfer RNA leucine 1 gene (MTTL1, <a href="/entry/590050#0001">590050.0001</a>)<br /> -
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Caused by mutation in the mitochondrial transfer RNA glutamine gene (MTTQ, <a href="/entry/590030#0003">590030.0003</a>)<br /> -
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Caused by mutation in the mitochondrial transfer RNA histidine gene (MTTH, <a href="/entry/590040#0003">590040.0003</a>)<br /> -
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Caused by mutation in the mitochondrial transfer RNA lysine gene (MTTK, <a href="/entry/590060#0002">590060.0002</a>)<br /> -
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Caused by mutation in the mitochondrial transfer RNA cysteine gene (MTTC, <a href="/entry/590020#0001">590020.0001</a>)<br /> -
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Caused by mutation in the mitochondrial transfer RNA serine 1 gene (MTTS1, <a href="/entry/590080#0001">590080.0001</a>)<br /> -
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Caused by mutation in the mitochondrial transfer RNA serine 2 gene (MTTS2, <a href="/entry/590085#0002">590085.0002</a>)<br /> -
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Caused by mutation in the mitochondrial complex I, subunit ND1 gene (MTND1, <a href="/entry/516000#0012">516000.0012</a>)<br /> -
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Caused by mutation in the mitochondrial complex I, subunit ND5 gene (MTND5, <a href="/entry/516005#0004">516005.0004</a>)<br /> -
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Caused by mutation in the mitochondrial complex I, subunit ND6 gene (MTND6, <a href="/entry/516006#0005">516006.0005</a>)<br />
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<p>A number sign (#) is used with this entry because MELAS syndrome can be caused by mutation in several genes, including MTTL1 (<a href="/entry/590050">590050</a>), MTTQ (<a href="/entry/590030">590030</a>), MTTH (<a href="/entry/590040">590040</a>), MTTK (<a href="/entry/590060">590060</a>), MTTC (<a href="/entry/590020">590020</a>), MTTS1 (<a href="/entry/590080">590080</a>), MTND1 (<a href="/entry/516000">516000</a>), MTND5 (<a href="/entry/516005">516005</a>), MTND6 (<a href="/entry/516006">516006</a>), and MTTS2 (<a href="/entry/590085">590085</a>). The most common mutation causing MELAS is a c.3243A-G transition in the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) (summary by <a href="#20" class="mim-tip-reference" title="Malfatti, E., Laforet, P., Jardel, C., Stojkovic, T., Behin, A., Eymard, B., Lombes, A., Benmalek, A., Becane, H.-M., Berber, N., Meune, C., Duboc, D., Wahbi, K. <strong>High risk of severe cardiac adverse events in patients with mitochondrial m.3243A-G mutation.</strong> Neurology 80: 100-105, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827b1a2f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23243073">Malfatti et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243073" 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>MELAS syndrome, comprising mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with a variable clinical phenotype. The disorder is accompanied by features of central nervous system involvement, including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting (<a href="#27" class="mim-tip-reference" title="Pavlakis, S. G., Phillips, P. C., DiMauro, S., De Vivo, D. C., Rowland, L. P. <strong>Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome.</strong> Ann. Neurol. 16: 481-488, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6093682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6093682</a>] [<a href="https://doi.org/10.1002/ana.410160409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6093682">Pavlakis et al., 1984</a>; <a href="#22" class="mim-tip-reference" title="Montagna, P., Gallassi, R., Medori, R., Govoni, E., Zeviani, M., Di Mauro, S., Lugaresi, E., Andermann, F. <strong>MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission.</strong> Neurology 38: 751-754, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3362373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3362373</a>] [<a href="https://doi.org/10.1212/wnl.38.5.751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3362373">Montagna et al., 1988</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6093682+3362373" 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>Other mitochondrial encephalomyopathies include Leigh syndrome (MILS; <a href="/entry/500017">500017</a>), Kearns-Sayre syndrome (KSS; <a href="/entry/530000">530000</a>), MERRF syndrome (<a href="/entry/545000">545000</a>), and Leber optic atrophy (<a href="/entry/535000">535000</a>).</p>
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<p><a href="#7" class="mim-tip-reference" title="Goto, Y., Horai, S., Matsuoka, T., Koga, Y., Nihei, K., Kobayashi, M., Nonaka, I. <strong>Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation.</strong> Neurology 42: 545-550, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1549215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1549215</a>] [<a href="https://doi.org/10.1212/wnl.42.3.545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1549215">Goto et al. (1992)</a> studied MELAS in 21 males and 19 females to characterize the clinical features and biochemical and muscle biopsy findings related to the 3243A-G transition in the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>). The most frequent symptom was episodic sudden headache with vomiting and convulsions, which in 80% of cases affected patients aged 5 to 15 years. They demonstrated the mtDNA mutation in 32 of the 40 patients but concluded that there were no clinical or pathologic differences between the patients with or without the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1549215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Latkany, P., Ciulla, T. A., Cucchillo, P., Malkoff, M. D. <strong>Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation.</strong> Am. J. Ophthal. 128: 112-114, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482110</a>] [<a href="https://doi.org/10.1016/s0002-9394(99)00057-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482110">Latkany et al. (1999)</a> reported the ocular findings in 4 family members with MELAS syndrome caused by the 3243A-G MTTL1 mutation (<a href="/entry/590050#0001">590050.0001</a>). Findings included ophthalmoplegia, neurosensory deafness, reduced photopic and scotopic electroretinogram b-wave amplitudes, myopathy, and macular retinal pigment epithelial atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10482110" 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="De Quick, M., Lammens, M., Dom, R., Carton, H. <strong>MELAS: a family with paternal inheritance.</strong> Ann. Neurol. 29: 456-457, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1929218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1929218</a>] [<a href="https://doi.org/10.1002/ana.410290425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1929218">De Quick et al. (1991)</a> described MELAS syndrome in 2 sisters in whom detailed workup, including muscle biopsy, was normal in the mother but in the father showed a myopathic pattern on EMG and ragged-red fibers on muscle biopsy. Whether coincidence or true transmission from the father was not clear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1929218" 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 sporadic case of MELAS syndrome, <a href="#28" class="mim-tip-reference" title="Ravn, K., Wibrand, F., Hansen, F. J., Horn, N., Rosenberg, T., Schwartz, M. <strong>An mtDNA mutation, 14453G-A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.</strong> Europ. J. Hum. Genet. 9: 805-809, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781695</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781695">Ravn et al. (2001)</a> identified a heteroplasmic mutation in the ND6 gene (14453G-A; <a href="/entry/516006#0005">516006.0005</a>). The patient was a 7-year-old girl with normal development until the age of 2 years. Between 2 and 3 years of age, she had episodes of vomiting followed by ketotic acidosis. She developed myoclonic epilepsy, general weakness, and ataxia with intermittent dystonia. Magnetic resonance scans showed cerebellar hypoplasia and multiple infarctions in both hemispheres. A muscle biopsy revealed lipid storage myopathy with normal mitochondria on electron microscopy. The patient developed episodes of lethargy, lactic acidosis, and alternating uniparesis. Ophthalmologic examination revealed no sign of atrophy of the optic nerve but abolished visual evoked potentials (VEP). The mother was healthy, with no history of a mitochondrial disorder. Mitochondrial enzyme analysis in the patient showed a decreased activity of complex I in muscle. Sequencing of the entire mtDNA, except part of the D loop, revealed heteroplasmy for the 14453G-A mutation in 82% of the mtDNA of the patient's muscle and 78% in blood. The mutation was not detected in the blood of the mother nor in 50 healthy controls. In addition to the 14453G-A mutation, <a href="#28" class="mim-tip-reference" title="Ravn, K., Wibrand, F., Hansen, F. J., Horn, N., Rosenberg, T., Schwartz, M. <strong>An mtDNA mutation, 14453G-A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.</strong> Europ. J. Hum. Genet. 9: 805-809, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781695</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781695">Ravn et al. (2001)</a> identified 2 other homoplasmic mutations in the mtDNA of their patient, 5628T-C in the MTTA gene (<a href="/entry/590000">590000</a>) and 13535A-G in the MTND5 gene (<a href="/entry/516005">516005</a>), which might have contributed to the observed decrease in activity of complex I and the severe phenotype of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bataillard, M., Chatzoglou, E., Rumbach, L., Sternberg, D., Tournade, A., Laforet, P., Jardel, C., Maisonobe, T., Lombes, A. <strong>Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation.</strong> Neurology 56: 405-407, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11171912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11171912</a>] [<a href="https://doi.org/10.1212/wnl.56.3.405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11171912">Bataillard et al. (2001)</a> reported an atypical case of MELAS syndrome associated with a 4332G-A mutation in the MTTQ gene (<a href="/entry/590030#0003">590030.0003</a>). The patient was a 47-year-old male with sensorineural deafness since age 20 years, who presented with an acute stroke in the absence of cardiovascular disease. Although late onset and some neuroradiographic findings were atypical for MELAS, there were extensive basal ganglia calcifications and muscle COX activity was decreased with severely deficient fibers. The 4332G-A mutation was present in 81% of the patient's muscle mtDNA molecules, and absent from his mtDNA blood and skin cells. The mutation was not found in mtDNA blood cells from his mother and brother or in 300 controls. The authors emphasized the genetic heterogeneity of the MELAS syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11171912" 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 several affected members of 3-generation Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS, <a href="#31" class="mim-tip-reference" title="Zeviani, M., Muntoni, F., Savarese, N., Serra, G., Tiranti, V., Carrara, F., Mariotti, C., DiDonato, S. <strong>A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA-lys gene.</strong> Europ. J. Hum. Genet. 1: 80-87, 1993. Note: Erratum: Europ. J. Hum. Genet. 1: 124 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069654</a>] [<a href="https://doi.org/10.1159/000472390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069654">Zeviani et al. (1993)</a> identified a mutation in the MTTK gene (<a href="/entry/590060#0002">590060.0002</a>). The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069654" 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 mother and daughter with MERRF/MELAS overlap syndrome, <a href="#25" class="mim-tip-reference" title="Nakamura, M., Nakano, S., Gato, Y.-i., Ozawa, M., Nagahama, Y., Fukuyama, H., Akiguchi, I., Kaji, R., Kimura, J. <strong>A novel point mutation in the mitochondrial tRNA (ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome.</strong> Biochem. Biophys. Res. Commun. 214: 86-93, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7669057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7669057</a>] [<a href="https://doi.org/10.1006/bbrc.1995.2260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7669057">Nakamura et al. (1995)</a> identified a heteroplasmic mutation in the MTTS1 gene (<a href="/entry/590080#0001">590080.0001</a>). The proband in their study was a mentally retarded 26-year-old woman who had had epileptic attacks since the age of 15 years. At the age of 20 years, clear symptoms of MERRF syndrome developed, including myoclonic seizures, generalized tonic-clonic seizures, and paroxysmal hearing disturbance. She also showed mental deterioration, muscle atrophy weakness, and truncal ataxia. Lactate levels in both blood and cerebrospinal fluid were elevated. The brain CT scan showed cerebral atrophy and bilateral calcification of the basal ganglia. Muscle biopsies showed many ragged-red fibers and abnormal mitochondria with concentric cristae. The mother was a 55-year-old woman who had myoclonic jerks of the arms and generalized seizures since the age of 37 years. At age 47 years, she was moderately demented. Muscle weakness and ataxia were not apparent. The brain CT scan revealed calcification of the basal ganglia and bilateral occipital lobe atrophy. At age 55 years, she developed blindness after an episode of generalized seizure, and thereafter was bedridden and severely demented; the phenotype suggested stroke-like episodes consistent with MELAS syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7669057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Melone, M. A. B., Tessa, A., Petrini, S., Lus, G., Sampaolo, S., di Fede, G., Santorelli, F. M., Cotrufo, R. <strong>Revelation of a new mitochondrial DNA mutation (G12147A) in a MELAS/MERFF (sic) phenotype.</strong> Arch. Neurol. 61: 269-272, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14967777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14967777</a>] [<a href="https://doi.org/10.1001/archneur.61.2.269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14967777">Melone et al. (2004)</a> reported a 20-year-old man who experienced sudden migrainous headache and vomiting, followed by left hemiparesis and lateral homonymous hemianopia. Seizures also occurred. The clinical picture was consistent with MELAS syndrome. At age 25 years, he developed myoclonus and ataxia, suggesting MERRF syndrome. His mother had shown similar stroke-like episodes and had died at age 36 years. Muscle biopsy of the proband showed abnormal mitochondrial proliferation and COX-negative fibers. Genetic analysis identified a heteroplasmic mutation in the MTTH gene (<a href="/entry/590040#0003">590040.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14967777" 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="Kirby, D. M., McFarland, R., Ohtake, A., Dunning, C., Ryan, M. T., Wilson, C., Ketteridge, D., Turnbull, D. M., Thorburn, D. R., Taylor, R. W. <strong>Mutations of the mitochondrial ND1 gene as a cause of MELAS.</strong> J. Med. Genet. 41: 784-789, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466014</a>] [<a href="https://doi.org/10.1136/jmg.2004.020537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466014">Kirby et al. (2004)</a> reported 3 unrelated patients with MELAS syndrome in whom the common 3243A-G mutation of the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts. Targeted sequencing of the mitochondrial tRNA and MTND genes showed that each patient harbored a different mutation in the MTND1 subunit gene of complex I (<a href="/entry/590050#0012">590050.0012</a>-<a href="/entry/590050#0014">590050.0014</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466014" 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="Kisanuki, Y. Y., Gruis, K. L., Smith, T. L., Brown, D. L. <strong>Late-onset mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes with bitemporal lesions.</strong> Arch. Neurol. 63: 1200-1201, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908753</a>] [<a href="https://doi.org/10.1001/archneur.63.8.1200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908753">Kisanuki et al. (2006)</a> identified the common 3243A-G mutation in a 50-year-old man with onset of headaches and seizures associated with bitemporal lesions identified on brain MRI. Other clinical features included long-standing thin habitus, deafness, and diabetes. The authors noted the late onset of classic MELAS symptoms in this patient and suggested a low mitochondrial mutation load in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16908753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Kaufmann, P., Pascual, J. M., Anziska, Y., Gooch, C. L., Engelstad, K., Jhung, S., DiMauro, S., De Vivo, D. C. <strong>Nerve conduction abnormalities in patients with MELAS and the A3243G mutation.</strong> Arch. Neurol. 63: 746-748, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16682545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16682545</a>] [<a href="https://doi.org/10.1001/archneur.63.5.746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16682545">Kaufmann et al. (2006)</a> found that 23 (77%) of 30 MELAS patients ranging in age from 10 to 60 years had abnormal peripheral nerve conduction measures. All patients had the common MTTL1 3243A-G mutation (<a href="/entry/590050#0001">590050.0001</a>). Although only 15 (50%) had outright clinical symptoms of peripheral neuropathy such as imbalance, paresthesias, and numbness, almost all (29 of 30) had abnormal findings on neurologic exam, including reflex testing, sensory exam, distal muscle strength testing, and gait. Nerve conduction tests showed pure sensory anomalies in 10 patients, pure motor anomalies in 5, and a mixed pattern in 8. Twelve patients had axonal neuropathy, 4 demyelinating, and 7 mixed. Lower extremities were more commonly affected (19 of 23) than upper extremities. Twelve patients with abnormal conduction studies had either abnormal fasting glucose levels or increased thyrotropin levels. <a href="#11" class="mim-tip-reference" title="Kaufmann, P., Pascual, J. M., Anziska, Y., Gooch, C. L., Engelstad, K., Jhung, S., DiMauro, S., De Vivo, D. C. <strong>Nerve conduction abnormalities in patients with MELAS and the A3243G mutation.</strong> Arch. Neurol. 63: 746-748, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16682545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16682545</a>] [<a href="https://doi.org/10.1001/archneur.63.5.746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16682545">Kaufmann et al. (2006)</a> concluded that peripheral nerve abnormalities in patients with MELAS are common and likely reflect the high energy demand of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16682545" 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 questionnaire-based survey, <a href="#26" class="mim-tip-reference" title="Parsons, T., Weimer, L., Engelstad, K., Linker, A., Battista, V., Wei, Y., Hirano, M., Dimauro, S., De Vivo, D. C., Kaufmann, P. <strong>Autonomic symptoms in carriers of the m.3243A-G mitochondrial DNA mutation.</strong> Arch. Neurol. 67: 976-979, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697048</a>] [<a href="https://doi.org/10.1001/archneurol.2010.174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20697048">Parsons et al. (2010)</a> found that 28 (80%) of 35 patients with MELAS due to the 3243A-G mutation (<a href="/entry/590050#0001">590050.0001</a>) and 33 (62%) of 53 carrier relatives reported autonomic symptoms compared to 2 (12%) of 16 controls. Gastrointestinal symptoms, orthostatic dizziness, and cold or discolored hands and feet were the most common complaints among mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20697048" 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="#29" class="mim-tip-reference" title="Testai, F. D., Gorelick, P. B. <strong>Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.</strong> Arch. Neurol. 67: 19-24, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20065125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20065125</a>] [<a href="https://doi.org/10.1001/archneurol.2009.309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20065125">Testai and Gorelick (2010)</a> reviewed the pathophysiology of stroke in patients with MELAS. Although the etiology is not completely explained, there is likely a role for mitochondrial angiopathy, vascular dysfunction, and hyperemia, as well as mitochondrial-mediated cytopathic mechanisms, which may result in energy failure. Neuronal hyperexcitability may also play a role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20065125" 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 retrospective study, <a href="#20" class="mim-tip-reference" title="Malfatti, E., Laforet, P., Jardel, C., Stojkovic, T., Behin, A., Eymard, B., Lombes, A., Benmalek, A., Becane, H.-M., Berber, N., Meune, C., Duboc, D., Wahbi, K. <strong>High risk of severe cardiac adverse events in patients with mitochondrial m.3243A-G mutation.</strong> Neurology 80: 100-105, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827b1a2f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23243073">Malfatti et al. (2013)</a> found that 38 of 41 individuals with the MTTL1 c.3243A-G mutation had symptoms consistent with MELAS, whereas 3 were asymptomatic. The symptomatic patients had onset between 24 and 40 years of variable features, including sensorineural deafness, myopathy, cognitive impairment, neuropathy, ophthalmoplegia, diabetes, and stroke-like episodes. Cardiac investigations identified left ventricular hypertrophy and/or left ventricular dysfunction in 18 patients, along with Wolff-Parkinson-White syndrome in 7, conduction system disease in 4, and atrial fibrillation in 1. Over a median 5-year follow-up period, 11 patients died, including 3 due to heart failure. Seven patients had life-threatening adverse events, including 6 hospitalizations for severe heart failure and 1 resuscitated cardiac arrest. One patient had a heart transplant. <a href="#20" class="mim-tip-reference" title="Malfatti, E., Laforet, P., Jardel, C., Stojkovic, T., Behin, A., Eymard, B., Lombes, A., Benmalek, A., Becane, H.-M., Berber, N., Meune, C., Duboc, D., Wahbi, K. <strong>High risk of severe cardiac adverse events in patients with mitochondrial m.3243A-G mutation.</strong> Neurology 80: 100-105, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827b1a2f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23243073">Malfatti et al. (2013)</a> concluded that, after central neurologic disease, cardiac disease has the greatest impact on prognosis in patients with the c.3243A-G mutation. Left ventricular hypertrophy was the only independent prognostic risk factor for adverse cardiac events, suggesting that these patients should be closely monitored. The severity of cardiac disease and adverse events did not correlate with mutation load in blood or urine or with ragged-red fibers on muscle biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Janssen, A. J. M., Schuelke, M., Smeitink, J. A. M., Trijbels, F. J. M., Sengers, R. C. A., Lucke, B., Wintjes, L. T. M., Morava, E., van Engelen, B. G. M., Smits, B. W., Hol, F. A., Siers, M. H., ter Laak, H., van der Knaap, M. S., van Spronsen, F. J., Rodenburg, R. J. T., van den Heuvel, L. P. <strong>Muscle 3243A-G mutation load and capacity of the mitochondrial energy-generating system.</strong> Ann. Neurol. 63: 473-481, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306232</a>] [<a href="https://doi.org/10.1002/ana.21328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306232">Janssen et al. (2008)</a> defined the 'mitochondrial energy-generating system' (MEGS) capacity as a measurement encompassing mitochondrial enzymatic reactions from oxidation of pyruvate to the export of ATP, which can be used as an indicator for overall mitochondrial function. In an analysis of muscle tissue from 24 MELAS patients with the MTTL1 3243A-G mutation (<a href="/entry/590050#0001">590050.0001</a>), MEGS capacity correlated better with mutation load than did analysis of individual respiratory chain enzyme activities, including complex I, III, and IV. The sensitivity and specificity of measurement using MEGS reached 78% and 100%, respectively, for a mitochondriopathy, which was significantly more accurate than measuring individual enzyme activities alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306232" 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="Lam, C. W., Lau, C. H., Williams, J. C., Chan, Y. W., Wong, L. J. C. <strong>Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate therapy.</strong> Europ. J. Pediat. 156: 562-564, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9243242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9243242</a>] [<a href="https://doi.org/10.1007/s004310050663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9243242">Lam et al. (1997)</a> reported the case of a boy in whom MELAS appeared to be precipitated by valproate therapy. He had mild mental retardation and a right-sided convulsion at the age of 12 years. About 1 year later he experienced a similar seizure and was then treated with sodium valproate (200 mg 3 times daily). Eight days after initiation of valproate, he developed right hemiparesis and hypotonia and had 2 seizures. The serum levels of valproate were not excessive, but when no improvement occurred an idiosyncratic drug reaction was suspected and valproate was discontinued. Blood lactate and pyruvate were found to be elevated. Brain CT scan showed a left parietooccipital infarct and bilateral basal ganglia calcification. Muscle biopsy showed ragged-red fibers. Electron microscopy of muscle showed increased numbers of mitochondria and atypical mitochondria in the subsarcolemmal region, some with inclusion bodies. A 3243A-G mutation was detected in mitochondrial DNA from this patient. This mutation predisposed the patient to the detrimental effects of valproate on oxidative phosphorylation. The findings of <a href="#16" class="mim-tip-reference" title="Lam, C. W., Lau, C. H., Williams, J. C., Chan, Y. W., Wong, L. J. C. <strong>Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate therapy.</strong> Europ. J. Pediat. 156: 562-564, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9243242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9243242</a>] [<a href="https://doi.org/10.1007/s004310050663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9243242">Lam et al. (1997)</a> supported the suggestion that valproate should not be given to patients suspected of having mitochondrial diseases. In addition, for patients whose seizures worsen with valproate therapy, an inborn error of mitochondrial metabolism should be suspected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9243242" 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 patient with MELAS due to the 3243A-G mutation (<a href="/entry/590050#0001">590050.0001</a>), <a href="#3" class="mim-tip-reference" title="Costello, D. J., Sims, K. B. <strong>Efficacy of lamotrigine in disabling myoclonus in a patient with an mtDNA A3243G mutation.</strong> Neurology 72: 1279-1280, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19349610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19349610</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345663.71421.1d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19349610">Costello and Sims (2009)</a> reported safe and effective treatment of symptomatic myoclonus with lamotrigine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19349610" 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="#19" class="mim-tip-reference" title="Ma, H., Folmes, C. D. L., Wu, J., Morey, R., Mora-Castilla, S., Ocampo, A., Ma, L., Poulton, J., Wang, X., Ahmed, R., Kang, E., Lee, Y., and 14 others. <strong>Metabolic rescue in pluripotent cells from patients with mtDNA disease.</strong> Nature 524: 234-238, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26176921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26176921</a>] [<a href="https://doi.org/10.1038/nature14546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26176921">Ma et al. (2015)</a> generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A-G (<a href="/entry/590050#0001">590050.0001</a>), causing MELAS, and 8993T-G (<a href="/entry/516060#0001">516060.0001</a>) and 13513G-A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wildtype or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T-G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wildtype mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wildtype mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. <a href="#19" class="mim-tip-reference" title="Ma, H., Folmes, C. D. L., Wu, J., Morey, R., Mora-Castilla, S., Ocampo, A., Ma, L., Poulton, J., Wang, X., Ahmed, R., Kang, E., Lee, Y., and 14 others. <strong>Metabolic rescue in pluripotent cells from patients with mtDNA disease.</strong> Nature 524: 234-238, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26176921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26176921</a>] [<a href="https://doi.org/10.1038/nature14546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26176921">Ma et al. (2015)</a> concluded that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wildtype mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26176921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Ciafaloni1992" class="mim-tip-reference" title="Ciafaloni, E., Ricci, E., Shanske, S., Moraes, C. T., Silvestri, G., Hirano, M., Simonetti, S., Angelini, C., Donati, M. A., Garcia, C., Martinuzzi, A., Mosewich, R., Servidei, S., Zammarchi, E., Bonilla, E., DeVivo, D. C., Rowland, L. P., Schon, E. A., DiMauro, S. <strong>MELAS: clinical features, biochemistry, and molecular genetics.</strong> Ann. Neurol. 31: 391-398, 1992.">Ciafaloni et al. (1992)</a>; <a href="#Danks1988" class="mim-tip-reference" title="Danks, R. A., Dorevitch, M., Cummins, J. T., Byrne, E. <strong>Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): adolescent onset with severe cerebral edema.</strong> Aust. New Zeal. J. Med. 18: 69-72, 1988.">Danks et al. (1988)</a>; <a href="#Enter1991" class="mim-tip-reference" title="Enter, C., Muller-Hocker, J., Zierz, S., Kurlemann, G., Pongratz, D., Forster, C., Obermaier-Kusser, B., Gerbitz, K.-D. <strong>A specific point mutation in the mitochondrial genome of Caucasians with MELAS.</strong> Hum. Genet. 88: 233-236, 1991.">Enter et al. (1991)</a>; <a href="#Goto1990" class="mim-tip-reference" title="Goto, Y., Nonaka, I., Horai, S. <strong>A mutation in the tRNA-leu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.</strong> Nature 348: 651-653, 1990.">Goto et al. (1990)</a>; <a href="#Goto1991" class="mim-tip-reference" title="Goto, Y., Nonaka, I., Horai, S. <strong>A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).</strong> Biochim. Biophys. Acta 1097: 238-240, 1991.">Goto et al. (1991)</a>; <a href="#Kobayashi1990" class="mim-tip-reference" title="Kobayashi, Y., Momoi, M. Y., Tominaga, K., Momoi, T., Nihei, K., Yanagisawa, M., Kagawa, Y., Ohta, S. <strong>A point mutation in the mitochondrial tRNA-leu (UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).</strong> Biochem. Biophys. Res. Commun. 173: 816-822, 1990.">Kobayashi et al. (1990)</a>; <a href="#Kobayashi1991" class="mim-tip-reference" title="Kobayashi, Y., Momoi, M. Y., Tominaga, K., Shimoizumi, H., Nihei, K., Yanagisawa, M., Kagawa, Y., Ohta, S. <strong>Respiration-deficient cells are caused by a single point mutation in the mitochondrial tRNA-leu (UUR) gene in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS).</strong> Am. J. Hum. Genet. 49: 590-599, 1991.">Kobayashi et al. (1991)</a>; <a href="#Lertrit1992" class="mim-tip-reference" title="Lertrit, P., Noer, A. S., Jean-Francois, M. J. B., Kapsa, R., Dennett, X., Thyagarajan, D., Lethlean, K., Byrne, E., Marzuki, S. <strong>A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I.</strong> Am. J. Hum. Genet. 51: 457-468, 1992.">Lertrit et al. (1992)</a>; <a href="#Moraes1992" class="mim-tip-reference" title="Moraes, C. T., Ricci, E., Bonilla, E., DiMauro, S., Schon, E. A. <strong>The mitochondrial tRNA-leu(UUR) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle.</strong> Am. J. Hum. Genet. 50: 934-949, 1992.">Moraes et al. (1992)</a>; <a href="#Mosewich1993" class="mim-tip-reference" title="Mosewich, R. K., Donat, J. R., DiMauro, S., Ciafaloni, E., Shanske, S., Erasmus, M., George, D. <strong>The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke.</strong> Arch. Neurol. 50: 275-278, 1993.">Mosewich et al. (1993)</a>; <a href="#Yoneda1992" class="mim-tip-reference" title="Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O., Attardi, G. <strong>Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy.</strong> Proc. Nat. Acad. Sci. 89: 11164-11168, 1992.">Yoneda et al. (1992)</a>
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Ciafaloni, E., Ricci, E., Shanske, S., Moraes, C. T., Silvestri, G., Hirano, M., Simonetti, S., Angelini, C., Donati, M. A., Garcia, C., Martinuzzi, A., Mosewich, R., Servidei, S., Zammarchi, E., Bonilla, E., DeVivo, D. C., Rowland, L. P., Schon, E. A., DiMauro, S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1586140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1586140</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1586140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410310408" target="_blank">Full Text</a>]
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Danks, R. A., Dorevitch, M., Cummins, J. T., Byrne, E.
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<strong>Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): adolescent onset with severe cerebral edema.</strong>
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[<a href="https://doi.org/10.1111/j.1445-5994.1988.tb02245.x" target="_blank">Full Text</a>]
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Enter, C., Muller-Hocker, J., Zierz, S., Kurlemann, G., Pongratz, D., Forster, C., Obermaier-Kusser, B., Gerbitz, K.-D.
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<strong>A specific point mutation in the mitochondrial genome of Caucasians with MELAS.</strong>
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[<a href="https://doi.org/10.1007/BF00206080" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.42.3.545" target="_blank">Full Text</a>]
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Goto, Y., Nonaka, I., Horai, S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2102678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2102678</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2102678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Goto, Y., Nonaka, I., Horai, S.
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<strong>A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1932147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1932147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1932147" 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/10.1016/0925-4439(91)90042-8" target="_blank">Full Text</a>]
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Janssen, A. J. M., Schuelke, M., Smeitink, J. A. M., Trijbels, F. J. M., Sengers, R. C. A., Lucke, B., Wintjes, L. T. M., Morava, E., van Engelen, B. G. M., Smits, B. W., Hol, F. A., Siers, M. H., ter Laak, H., van der Knaap, M. S., van Spronsen, F. J., Rodenburg, R. J. T., van den Heuvel, L. P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306232</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306232" 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/10.1001/archneur.63.5.746" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.020537" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.63.8.1200" target="_blank">Full Text</a>]
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Testai, F. D., Gorelick, P. B.
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<strong>Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.</strong>
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Arch. Neurol. 67: 19-24, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20065125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20065125</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20065125" 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/10.1001/archneurol.2009.309" target="_blank">Full Text</a>]
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Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O., Attardi, G.
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<strong>Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy.</strong>
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Proc. Nat. Acad. Sci. 89: 11164-11168, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1454794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1454794</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1454794" 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/10.1073/pnas.89.23.11164" target="_blank">Full Text</a>]
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Zeviani, M., Muntoni, F., Savarese, N., Serra, G., Tiranti, V., Carrara, F., Mariotti, C., DiDonato, S.
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<strong>A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA-lys gene.</strong>
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Europ. J. Hum. Genet. 1: 80-87, 1993. Note: Erratum: Europ. J. Hum. Genet. 1: 124 only, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069654</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069654" 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/10.1159/000472390" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 01/20/2016
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Cassandra L. Kniffin - updated : 12/29/2014<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Cassandra L. Kniffin - updated : 4/7/2010<br>Cassandra L. Kniffin - updated : 11/11/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 11/8/2006<br>Victor A. McKusick - updated : 2/24/2005<br>Jane Kelly - updated : 1/12/2005<br>Cassandra L. Kniffin - updated : 6/2/2004<br>Cassandra L. Kniffin - updated : 8/15/2002<br>Michael B. Petersen - updated : 7/8/2002
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Victor A. McKusick : 9/24/1992
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carol : 05/16/2024<br>carol : 05/14/2024<br>alopez : 01/20/2016<br>carol : 1/13/2015<br>mcolton : 12/29/2014<br>mcolton : 12/29/2014<br>ckniffin : 12/29/2014<br>carol : 11/19/2014<br>mcolton : 11/17/2014<br>ckniffin : 11/17/2014<br>carol : 9/17/2013<br>carol : 4/3/2013<br>carol : 8/2/2011<br>ckniffin : 8/2/2011<br>wwang : 2/16/2011<br>ckniffin : 1/21/2011<br>wwang : 4/13/2010<br>ckniffin : 4/7/2010<br>wwang : 12/3/2009<br>ckniffin : 11/11/2009<br>wwang : 4/13/2009<br>ckniffin : 4/6/2009<br>carol : 6/27/2007<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>wwang : 11/9/2006<br>ckniffin : 11/8/2006<br>wwang : 7/11/2005<br>ckniffin : 6/30/2005<br>terry : 3/30/2005<br>tkritzer : 2/24/2005<br>tkritzer : 1/12/2005<br>tkritzer : 10/15/2004<br>tkritzer : 6/3/2004<br>ckniffin : 6/3/2004<br>ckniffin : 6/2/2004<br>carol : 8/23/2002<br>ckniffin : 8/15/2002<br>mgross : 7/8/2002<br>alopez : 7/26/1999<br>alopez : 7/23/1997<br>mark : 9/25/1996<br>mimman : 2/8/1996<br>pfoster : 4/27/1994<br>carol : 5/26/1993<br>carol : 5/17/1993<br>carol : 4/28/1993<br>carol : 3/2/1993<br>carol : 3/1/1993
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MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE EPISODES; MELAS
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MELAS SYNDROME
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<strong>SNOMEDCT:</strong> 39925003;
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<strong>ICD10CM:</strong> E88.41;
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<strong>ORPHA:</strong> 550;
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<p>A number sign (#) is used with this entry because MELAS syndrome can be caused by mutation in several genes, including MTTL1 (590050), MTTQ (590030), MTTH (590040), MTTK (590060), MTTC (590020), MTTS1 (590080), MTND1 (516000), MTND5 (516005), MTND6 (516006), and MTTS2 (590085). The most common mutation causing MELAS is a c.3243A-G transition in the MTTL1 gene (590050.0001) (summary by Malfatti et al., 2013). </p>
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<p>MELAS syndrome, comprising mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with a variable clinical phenotype. The disorder is accompanied by features of central nervous system involvement, including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting (Pavlakis et al., 1984; Montagna et al., 1988). </p><p>Other mitochondrial encephalomyopathies include Leigh syndrome (MILS; 500017), Kearns-Sayre syndrome (KSS; 530000), MERRF syndrome (545000), and Leber optic atrophy (535000).</p>
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<p>Goto et al. (1992) studied MELAS in 21 males and 19 females to characterize the clinical features and biochemical and muscle biopsy findings related to the 3243A-G transition in the MTTL1 gene (590050.0001). The most frequent symptom was episodic sudden headache with vomiting and convulsions, which in 80% of cases affected patients aged 5 to 15 years. They demonstrated the mtDNA mutation in 32 of the 40 patients but concluded that there were no clinical or pathologic differences between the patients with or without the mutation. </p><p>Latkany et al. (1999) reported the ocular findings in 4 family members with MELAS syndrome caused by the 3243A-G MTTL1 mutation (590050.0001). Findings included ophthalmoplegia, neurosensory deafness, reduced photopic and scotopic electroretinogram b-wave amplitudes, myopathy, and macular retinal pigment epithelial atrophy. </p><p>De Quick et al. (1991) described MELAS syndrome in 2 sisters in whom detailed workup, including muscle biopsy, was normal in the mother but in the father showed a myopathic pattern on EMG and ragged-red fibers on muscle biopsy. Whether coincidence or true transmission from the father was not clear. </p><p>In a sporadic case of MELAS syndrome, Ravn et al. (2001) identified a heteroplasmic mutation in the ND6 gene (14453G-A; 516006.0005). The patient was a 7-year-old girl with normal development until the age of 2 years. Between 2 and 3 years of age, she had episodes of vomiting followed by ketotic acidosis. She developed myoclonic epilepsy, general weakness, and ataxia with intermittent dystonia. Magnetic resonance scans showed cerebellar hypoplasia and multiple infarctions in both hemispheres. A muscle biopsy revealed lipid storage myopathy with normal mitochondria on electron microscopy. The patient developed episodes of lethargy, lactic acidosis, and alternating uniparesis. Ophthalmologic examination revealed no sign of atrophy of the optic nerve but abolished visual evoked potentials (VEP). The mother was healthy, with no history of a mitochondrial disorder. Mitochondrial enzyme analysis in the patient showed a decreased activity of complex I in muscle. Sequencing of the entire mtDNA, except part of the D loop, revealed heteroplasmy for the 14453G-A mutation in 82% of the mtDNA of the patient's muscle and 78% in blood. The mutation was not detected in the blood of the mother nor in 50 healthy controls. In addition to the 14453G-A mutation, Ravn et al. (2001) identified 2 other homoplasmic mutations in the mtDNA of their patient, 5628T-C in the MTTA gene (590000) and 13535A-G in the MTND5 gene (516005), which might have contributed to the observed decrease in activity of complex I and the severe phenotype of the patient. </p><p>Bataillard et al. (2001) reported an atypical case of MELAS syndrome associated with a 4332G-A mutation in the MTTQ gene (590030.0003). The patient was a 47-year-old male with sensorineural deafness since age 20 years, who presented with an acute stroke in the absence of cardiovascular disease. Although late onset and some neuroradiographic findings were atypical for MELAS, there were extensive basal ganglia calcifications and muscle COX activity was decreased with severely deficient fibers. The 4332G-A mutation was present in 81% of the patient's muscle mtDNA molecules, and absent from his mtDNA blood and skin cells. The mutation was not found in mtDNA blood cells from his mother and brother or in 300 controls. The authors emphasized the genetic heterogeneity of the MELAS syndrome. </p><p>In several affected members of 3-generation Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS, Zeviani et al. (1993) identified a mutation in the MTTK gene (590060.0002). The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes. </p><p>In a mother and daughter with MERRF/MELAS overlap syndrome, Nakamura et al. (1995) identified a heteroplasmic mutation in the MTTS1 gene (590080.0001). The proband in their study was a mentally retarded 26-year-old woman who had had epileptic attacks since the age of 15 years. At the age of 20 years, clear symptoms of MERRF syndrome developed, including myoclonic seizures, generalized tonic-clonic seizures, and paroxysmal hearing disturbance. She also showed mental deterioration, muscle atrophy weakness, and truncal ataxia. Lactate levels in both blood and cerebrospinal fluid were elevated. The brain CT scan showed cerebral atrophy and bilateral calcification of the basal ganglia. Muscle biopsies showed many ragged-red fibers and abnormal mitochondria with concentric cristae. The mother was a 55-year-old woman who had myoclonic jerks of the arms and generalized seizures since the age of 37 years. At age 47 years, she was moderately demented. Muscle weakness and ataxia were not apparent. The brain CT scan revealed calcification of the basal ganglia and bilateral occipital lobe atrophy. At age 55 years, she developed blindness after an episode of generalized seizure, and thereafter was bedridden and severely demented; the phenotype suggested stroke-like episodes consistent with MELAS syndrome. </p><p>Melone et al. (2004) reported a 20-year-old man who experienced sudden migrainous headache and vomiting, followed by left hemiparesis and lateral homonymous hemianopia. Seizures also occurred. The clinical picture was consistent with MELAS syndrome. At age 25 years, he developed myoclonus and ataxia, suggesting MERRF syndrome. His mother had shown similar stroke-like episodes and had died at age 36 years. Muscle biopsy of the proband showed abnormal mitochondrial proliferation and COX-negative fibers. Genetic analysis identified a heteroplasmic mutation in the MTTH gene (590040.0003). </p><p>Kirby et al. (2004) reported 3 unrelated patients with MELAS syndrome in whom the common 3243A-G mutation of the MTTL1 gene (590050.0001) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts. Targeted sequencing of the mitochondrial tRNA and MTND genes showed that each patient harbored a different mutation in the MTND1 subunit gene of complex I (590050.0012-590050.0014, respectively). </p><p>Kisanuki et al. (2006) identified the common 3243A-G mutation in a 50-year-old man with onset of headaches and seizures associated with bitemporal lesions identified on brain MRI. Other clinical features included long-standing thin habitus, deafness, and diabetes. The authors noted the late onset of classic MELAS symptoms in this patient and suggested a low mitochondrial mutation load in the brain. </p><p>Kaufmann et al. (2006) found that 23 (77%) of 30 MELAS patients ranging in age from 10 to 60 years had abnormal peripheral nerve conduction measures. All patients had the common MTTL1 3243A-G mutation (590050.0001). Although only 15 (50%) had outright clinical symptoms of peripheral neuropathy such as imbalance, paresthesias, and numbness, almost all (29 of 30) had abnormal findings on neurologic exam, including reflex testing, sensory exam, distal muscle strength testing, and gait. Nerve conduction tests showed pure sensory anomalies in 10 patients, pure motor anomalies in 5, and a mixed pattern in 8. Twelve patients had axonal neuropathy, 4 demyelinating, and 7 mixed. Lower extremities were more commonly affected (19 of 23) than upper extremities. Twelve patients with abnormal conduction studies had either abnormal fasting glucose levels or increased thyrotropin levels. Kaufmann et al. (2006) concluded that peripheral nerve abnormalities in patients with MELAS are common and likely reflect the high energy demand of the nervous system. </p><p>In a questionnaire-based survey, Parsons et al. (2010) found that 28 (80%) of 35 patients with MELAS due to the 3243A-G mutation (590050.0001) and 33 (62%) of 53 carrier relatives reported autonomic symptoms compared to 2 (12%) of 16 controls. Gastrointestinal symptoms, orthostatic dizziness, and cold or discolored hands and feet were the most common complaints among mutation carriers. </p><p>Testai and Gorelick (2010) reviewed the pathophysiology of stroke in patients with MELAS. Although the etiology is not completely explained, there is likely a role for mitochondrial angiopathy, vascular dysfunction, and hyperemia, as well as mitochondrial-mediated cytopathic mechanisms, which may result in energy failure. Neuronal hyperexcitability may also play a role. </p><p>In a retrospective study, Malfatti et al. (2013) found that 38 of 41 individuals with the MTTL1 c.3243A-G mutation had symptoms consistent with MELAS, whereas 3 were asymptomatic. The symptomatic patients had onset between 24 and 40 years of variable features, including sensorineural deafness, myopathy, cognitive impairment, neuropathy, ophthalmoplegia, diabetes, and stroke-like episodes. Cardiac investigations identified left ventricular hypertrophy and/or left ventricular dysfunction in 18 patients, along with Wolff-Parkinson-White syndrome in 7, conduction system disease in 4, and atrial fibrillation in 1. Over a median 5-year follow-up period, 11 patients died, including 3 due to heart failure. Seven patients had life-threatening adverse events, including 6 hospitalizations for severe heart failure and 1 resuscitated cardiac arrest. One patient had a heart transplant. Malfatti et al. (2013) concluded that, after central neurologic disease, cardiac disease has the greatest impact on prognosis in patients with the c.3243A-G mutation. Left ventricular hypertrophy was the only independent prognostic risk factor for adverse cardiac events, suggesting that these patients should be closely monitored. The severity of cardiac disease and adverse events did not correlate with mutation load in blood or urine or with ragged-red fibers on muscle biopsy. </p>
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<p>Janssen et al. (2008) defined the 'mitochondrial energy-generating system' (MEGS) capacity as a measurement encompassing mitochondrial enzymatic reactions from oxidation of pyruvate to the export of ATP, which can be used as an indicator for overall mitochondrial function. In an analysis of muscle tissue from 24 MELAS patients with the MTTL1 3243A-G mutation (590050.0001), MEGS capacity correlated better with mutation load than did analysis of individual respiratory chain enzyme activities, including complex I, III, and IV. The sensitivity and specificity of measurement using MEGS reached 78% and 100%, respectively, for a mitochondriopathy, which was significantly more accurate than measuring individual enzyme activities alone. </p>
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<p>Lam et al. (1997) reported the case of a boy in whom MELAS appeared to be precipitated by valproate therapy. He had mild mental retardation and a right-sided convulsion at the age of 12 years. About 1 year later he experienced a similar seizure and was then treated with sodium valproate (200 mg 3 times daily). Eight days after initiation of valproate, he developed right hemiparesis and hypotonia and had 2 seizures. The serum levels of valproate were not excessive, but when no improvement occurred an idiosyncratic drug reaction was suspected and valproate was discontinued. Blood lactate and pyruvate were found to be elevated. Brain CT scan showed a left parietooccipital infarct and bilateral basal ganglia calcification. Muscle biopsy showed ragged-red fibers. Electron microscopy of muscle showed increased numbers of mitochondria and atypical mitochondria in the subsarcolemmal region, some with inclusion bodies. A 3243A-G mutation was detected in mitochondrial DNA from this patient. This mutation predisposed the patient to the detrimental effects of valproate on oxidative phosphorylation. The findings of Lam et al. (1997) supported the suggestion that valproate should not be given to patients suspected of having mitochondrial diseases. In addition, for patients whose seizures worsen with valproate therapy, an inborn error of mitochondrial metabolism should be suspected. </p><p>In a patient with MELAS due to the 3243A-G mutation (590050.0001), Costello and Sims (2009) reported safe and effective treatment of symptomatic myoclonus with lamotrigine. </p><p>Ma et al. (2015) generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A-G (590050.0001), causing MELAS, and 8993T-G (516060.0001) and 13513G-A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wildtype or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T-G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wildtype mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wildtype mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. Ma et al. (2015) concluded that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wildtype mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Ciafaloni et al. (1992); Danks et al. (1988); Enter et al. (1991);
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Goto et al. (1990); Goto et al. (1991); Kobayashi et al. (1990);
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Kobayashi et al. (1991); Lertrit et al. (1992); Moraes et al. (1992);
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Mosewich et al. (1993); Yoneda et al. (1992)
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</span>
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<div>
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<br />
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<div>
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<h4>
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<strong>An mtDNA mutation, 14453G-A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.</strong>
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Europ. J. Hum. Genet. 9: 805-809, 2001.
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[PubMed: 11781695]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200712]
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Testai, F. D., Gorelick, P. B.
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<strong>Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes.</strong>
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Arch. Neurol. 67: 19-24, 2010.
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[PubMed: 20065125]
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[Full Text: https://doi.org/10.1001/archneurol.2009.309]
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Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O., Attardi, G.
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<strong>Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy.</strong>
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Proc. Nat. Acad. Sci. 89: 11164-11168, 1992.
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[PubMed: 1454794]
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[Full Text: https://doi.org/10.1073/pnas.89.23.11164]
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Zeviani, M., Muntoni, F., Savarese, N., Serra, G., Tiranti, V., Carrara, F., Mariotti, C., DiDonato, S.
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<strong>A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA-lys gene.</strong>
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Europ. J. Hum. Genet. 1: 80-87, 1993. Note: Erratum: Europ. J. Hum. Genet. 1: 124 only, 1993.
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[PubMed: 8069654]
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[Full Text: https://doi.org/10.1159/000472390]
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Ada Hamosh - updated : 01/20/2016<br>Cassandra L. Kniffin - updated : 12/29/2014<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Cassandra L. Kniffin - updated : 4/7/2010<br>Cassandra L. Kniffin - updated : 11/11/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 11/8/2006<br>Victor A. McKusick - updated : 2/24/2005<br>Jane Kelly - updated : 1/12/2005<br>Cassandra L. Kniffin - updated : 6/2/2004<br>Cassandra L. Kniffin - updated : 8/15/2002<br>Michael B. Petersen - updated : 7/8/2002
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Victor A. McKusick : 9/24/1992
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