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- #256000 - LEIGH SYNDROME, NUCLEAR; NULS
- OMIM
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<span class="h4">#256000</span>
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<div><a href="https://clinicaltrials.gov/search?cond=LEIGH SYNDROME, NUCLEAR" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=532&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 style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1203/" title="Mitochondrial DNA Deletion Syndromes" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Mitochondrial DNA Deletion…</a></div><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/NBK320989/" title="Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Nuclear Gene-Encoded Leigh…</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4157" 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 style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/leigh-syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">Leigh syndrome&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/pdhb" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">PDHB gene&nbsp;</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=506" 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>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/d7b86fbd-8137-4a8e-ae9a-f60d23f1a90a/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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:3652" 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>
<div><a href="http://www.informatics.jax.org/disease/256000" 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>
<div><a href="https://omia.org/results?search_type=advanced&omia_id=002147,002840" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:3652" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:256000" 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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 29570005<br />
<strong>ORPHA:</strong> 506<br />
<strong>DO:</strong> 3652<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
256000
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
LEIGH SYNDROME, NUCLEAR; NULS
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
NECROTIZING ENCEPHALOPATHY, INFANTILE SUBACUTE, OF LEIGH; SNE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/256000" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br /> -
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 />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span><br /> -
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br /> -
Strabismus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22066006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22066006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.40</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038379</a>, <a href="https://bioportal.bioontology.org/search?q=C2020541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2020541</a>, <a href="https://bioportal.bioontology.org/search?q=C1423541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1423541</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span><br /> -
Ptosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11934000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11934000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29696001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29696001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.409</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/374.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005745</a>, <a href="https://bioportal.bioontology.org/search?q=C0033377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Ptosis-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Pigmentary retinopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28835009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28835009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.52</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551715&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551715</a>, <a href="https://bioportal.bioontology.org/search?q=C0035334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035334</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000580" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000580</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000580" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000580</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Abnormal respiratory patterns <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837388&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837388</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002793" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002793</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002793" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002793</a>]</span><br /> -
Respiratory failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409622000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409622000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J96.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J96.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1145670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1145670</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002878</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002878</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertrichosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29966009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29966009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271607001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271607001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L68" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L68</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/L68.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L68.3</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/L68.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L68.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020555&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020555</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000998" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000998</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000998" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000998</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Psychomotor retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398991009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398991009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1144814003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1144814003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424230</a>, <a href="https://bioportal.bioontology.org/search?q=C5441816&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441816</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
Dysarthria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8011004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8011004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.13</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/784.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001260</a>]</span><br /> -
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
Hyperreflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Brainstem abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850601&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850601</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002363" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002363</a>]</span><br /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Lesions in basal ganglia, brainstem, cerebellum, thalamus, spinal cord characterized by demyelination, necrosis, gliosis, spongiosis, and capillary proliferation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673315</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Emotional lability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18963009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18963009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R45.86" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R45.86</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085633&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085633</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</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> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Increased serum lactate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5888306&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5888306</a>, <a href="https://bioportal.bioontology.org/search?q=C1836440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002151</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002151</a>]</span><br /> -
Increased CSF lactate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1167918&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1167918</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002490" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002490</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002490" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002490</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset usually in infancy or early childhood<br /> -
Progressive disorder, usually with rapid, relentless course<br /> -
Clinical heterogeneity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
Genetic heterogeneity (may be caused by mutation in nuclear-encoded or mitochondrial-encoded genes) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br /> -
Subset of patients have cytochrome c oxidase deficiency (see <a href="/entry/220110">220110</a>)<br /> -
See also X-linked Leigh syndrome (<a href="/entry/312170">312170</a>)<br /> -
See also French-Canadian type of Leigh syndrome (<a href="/entry/220111">220111</a>)<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the NADH dehydrogenase, subunit 2 gene (MTND2, <a href="/entry/516001#0006">516001.0006</a>)<br /> -
Caused by mutation in the NADH dehydrogenase, subunit 3 gene (MTND3, <a href="/entry/516002#0003">516002.0003</a>)<br /> -
Caused by mutation in the NADH dehydrogenase, subunit 5 gene (MTND5, <a href="/entry/516005#0003">516005.0003</a>)<br /> -
Caused by mutation in the NADH dehydrogenase, subunit 6 gene (MTND6, <a href="/entry/516006#0002">516006.0002</a>)<br /> -
Caused by mutation in the ATP synthase 6 gene (MTATP6, <a href="/entry/516060#0001">516060.0001</a>)<br /> -
Caused by mutation in the cytochrome c oxidase III gene (MTCO3, <a href="/entry/516050#0005">516050.0005</a>)<br /> -
Caused by mutation in the mitochondrial tRNA (valine) gene (MTTV, <a href="/entry/590105#0002">590105.0002</a>)<br /> -
Caused by mutation in the mitochondrial tRNA (lysine) gene (MTTK, <a href="/entry/590060#0001">590060.0001</a>)<br /> -
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 alpha subcomplex, 2 gene (NDUFA2, <a href="/entry/602137#0001">602137.0001</a>)<br /> -
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 alpha subcomplex, 10 gene (NDUFA10, <a href="/entry/603835#0001">603835.0001</a>)<br /> -
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 alpha subcomplex, 12 gene (NDUFA12, <a href="/entry/614530#0001">614530.0001</a>)<br /> -
Caused by mutation in the NADH dehydrogenase (ubiquinone) complex I, assembly factor 5 gene (NDUFAF5, <a href="/entry/612360#0002">612360.0002</a>)<br /> -
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 3 gene (NDUFV3, <a href="/entry/603846#0001">603846.0001</a>)<br /> -
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 1 gene (NDUFS1, <a href="/entry/157655#0001">157655.0001</a>)<br /> -
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 4 gene (NDUFS4, <a href="/entry/602694#0004">602694.0004</a>)<br /> -
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 7 gene (NDUFS7, <a href="/entry/601825#0001">601825.0001</a>)<br /> -
Caused by mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 8 gene (NDUFS8, <a href="/entry/602141#0001">602141.0001</a>)<br /> -
Caused by mutation in the NADH-ubiquinone oxidoreductase 1 alpha subcomplex 9 gene (NDUFA9, <a href="/entry/603834#0001">603834.0001</a>)<br /> -
Caused by mutation in the succinate dehydrogenase complex, subunit A, flavoprotein gene (SDHA, <a href="/entry/600857#0001">600857.0001</a>)<br /> -
Caused by mutation in the FAD-dependent oxidoreductase domain-containing protein 1 gene (FOXRED1, <a href="/entry/613622#0001">613622.0001</a>)<br /> -
Caused by mutation in the BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone gene (BCS1L, <a href="/entry/603647#0002">603647.0002</a>)<br /> -
Caused by mutation in the surfeit-1 gene (SURF1, <a href="/entry/185620#0001">185620.0001</a>)<br /> -
Caused by mutation in the cytochrome c oxidase, subunit 15 gene (COX15, <a href="/entry/603646#0001">603646.0001</a>)<br /> -
Caused by mutation in the C8ORF38 gene (C8ORF38, <a href="/entry/612392#0001">612392.0001</a>)<br /> -
Caused by mutation in the translational activator of mitochondrially encoded cytochrome c oxidase subunit 1 gene (TACO1, <a href="/entry/612958#0001">612958.0001</a>)<br /> -
Caused by mutation in the mitochondrial methionyl-tRNA formyltransferase gene (MTFMT, <a href="/entry/611766#0001">611766.0001</a>)<br /> -
Caused by mutation in the homolog of the S. cerevisiae PET100 gene (PET100, <a href="/entry/614770#0001">614770.0001</a>).<br />
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<p>A number sign (#) is used with this entry because of evidence that nuclear Leigh syndrome (NULS) can be caused by mutations in several different nuclear-encoded genes, indicating substantial genetic heterogeneity.</p>
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<p>Leigh syndrome is a clinical diagnosis based primarily on characteristic brain imaging findings associated with progressive and severe neurodegenerative features with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by <a href="#16" class="mim-tip-reference" title="Lake, N. J., Compton, A. G., Rahman, S., Thorburn, D. R. &lt;strong&gt;Leigh syndrome: one disorder, more than 75 monogenic causes.&lt;/strong&gt; Ann. Neurol. 79: 190-203, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26506407/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26506407&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.24551&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26506407">Lake et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26506407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Nuclear Leigh Syndrome</em></strong></p><p>
Leigh syndrome is a presentation of numerous genetic disorders resulting from defects in the mitochondrial OXPHOS complex. Accordingly, the genes implicated in Leigh syndrome most commonly encode structural subunits of the OXPHOS complex or proteins required for their assembly, stability, and activity. Mutations in both nuclear and mitochondrial genes have been identified. For a discussion of genetic heterogeneity of mitochondrial Leigh syndrome, see MILS (<a href="/entry/500017">500017</a>).</p><p>Nuclear Leigh syndrome can be caused by mutations in nuclear-encoded genes involved in any of the mitochondrial respiratory chain complexes: complex I deficiency (see <a href="/entry/252010">252010</a>), complex II deficiency (see <a href="/entry/252011">252011</a>), complex III deficiency (see <a href="/entry/124000">124000</a>), complex IV deficiency (cytochrome c oxidase; see <a href="/entry/220110">220110</a>), and complex V deficiency (see <a href="/entry/604273">604273</a>) (summary by <a href="#16" class="mim-tip-reference" title="Lake, N. J., Compton, A. G., Rahman, S., Thorburn, D. R. &lt;strong&gt;Leigh syndrome: one disorder, more than 75 monogenic causes.&lt;/strong&gt; Ann. Neurol. 79: 190-203, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26506407/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26506407&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.24551&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26506407">Lake et al., 2015</a>). Some forms of combined oxidative phosphorylation deficiency (COXPD) can present as Leigh syndrome (see, e.g., <a href="/entry/617664">617664</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26506407" 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>Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, <a href="/entry/238331">238331</a> and PDHA1, <a href="/entry/300502">300502</a>). Deficiency of coenzyme Q10 (<a href="/entry/607426">607426</a>) can present as Leigh syndrome.</p>
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<p>This condition was first described by <a href="#17" class="mim-tip-reference" title="Leigh, D. &lt;strong&gt;Subacute necrotizing encephalomyelopathy in an infant.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 14: 216-221, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14874135/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14874135&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.14.3.216&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14874135">Leigh (1951)</a> in a patient with foci of necrosis and capillary proliferation in the brainstem. <a href="#9" class="mim-tip-reference" title="Feigin, I., Wolf, A. &lt;strong&gt;A disease in infants resembling chronic Wernicke&#x27;s encephalopathy.&lt;/strong&gt; J. Pediat. 45: 243-263, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13202022/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13202022&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(54)80188-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13202022">Feigin and Wolf (1954)</a> observed 2 affected sibs from a consanguineous mating. Because of similarity to Wernicke encephalopathy (<a href="/entry/277730">277730</a>), they suggested that a genetic defect in some way related to thiamine was present (see HISTORY). <a href="#10" class="mim-tip-reference" title="Ford, F. R. &lt;strong&gt;A disease resembling Wernicke&#x27;s encephalopathy (Feigen and Wolf). Diseases of the Nervous System in Infancy, Childhood and Adolescence. (4th ed.)&lt;/strong&gt; Springfield, Ill.: Charles C Thomas (pub.) 1960. Pp. 407-410."None>Ford (1960)</a> referred to 2 affected sibs, and <a href="#1" class="mim-tip-reference" title="Clark, D. B. &lt;strong&gt;Infantile subacute necrotizing encephalopathy. In: Nelson, W. E. (ed.): Textbook of Pediatrics. (8th ed.)&lt;/strong&gt; Philadelphia: W. B. Saunders (pub.) 1964."None>Clark (1964)</a> pictured the histopathology of 1 of them. The main biochemical findings were high pyruvate and lactate in the blood and slightly low glucose levels in blood and cerebrospinal fluid. <a href="#12" class="mim-tip-reference" title="Hommes, F. A., Polman, H. A., Reerink, J. D. &lt;strong&gt;Leigh&#x27;s encephalomyelopathy: an inborn error of gluconeogenesis.&lt;/strong&gt; Arch. Dis. Child. 43: 423-426, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4873809/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4873809&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.43.230.423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4873809">Hommes et al. (1968)</a>, who studied a family with 3 affected sibs, found absence of pyruvate carboxylase in the liver and concluded that gluconeogenesis was impaired. <a href="#2" class="mim-tip-reference" title="Clayton, B. E., Dobbs, R. H., Patrick, A. D. &lt;strong&gt;Leigh&#x27;s subacute necrotizing encephalopathy: clinical and biochemical study, with special reference to therapy with lipoate.&lt;/strong&gt; Arch. Dis. Child. 42: 467-478, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4862967/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4862967&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.42.225.467&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4862967">Clayton et al. (1967)</a> demonstrated therapeutic benefit of lipoic acid. <a href="#19" class="mim-tip-reference" title="Montpetit, V. J. A., Andermann, F., Carpenter, S., Fawcett, J. S., Zborowska-Sluis, D., Giberson, H. R. &lt;strong&gt;Subacute necrotizing encephalomyelopathy: a review and a study of two families.&lt;/strong&gt; Brain 94: 1-30, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5552162/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5552162&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/94.1.1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5552162">Montpetit et al. (1971)</a> pointed out similarity in the distribution and histology of the lesions of SNE to those of Wernicke disease. They tabulated instances of affected sibs and consanguineous parents. <a href="#13" class="mim-tip-reference" title="Kohlschutter, A., Kraus-Ruppert, R., Rohrer, T., Herschkowitz, N. N. &lt;strong&gt;Myelin studies in a case of subacute necrotizing encephalomyelopathy (SNE).&lt;/strong&gt; J. Neuropath. Exp. Neurol. 37: 155-164, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/632845/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;632845&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005072-197803000-00004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="632845">Kohlschutter et al. (1978)</a> reported 2 sisters and a brother born of consanguineous parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14874135+4873809+5552162+632845+4862967+13202022" 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="Gordon, N., Marsden, H. B., Lewis, D. M. &lt;strong&gt;Subacute necrotizing encephalomyelopathy in three siblings.&lt;/strong&gt; Dev. Med. Child Neurol. 16: 64-78, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4813493/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4813493&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-8749.1974.tb02713.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4813493">Gordon et al. (1974)</a> noted that since oxidation of pyruvate is dependent on a multienzyme complex (the pyruvate dehydrogenase complex), it is likely that a number of apoenzyme and coenzyme deficiencies could lead to this disorder. Whereas <a href="#15" class="mim-tip-reference" title="Kustermann-Kuhn, B., Harzer, K., Schroder, R., Permanetter, W., Peiffer, J. &lt;strong&gt;Pyruvate dehydrogenase activity is not deficient in the brain of three autopsied cases with Leigh disease (subacute necrotizing encephalomyelopathy, SNE).&lt;/strong&gt; Hum. Genet. 68: 51-53, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6437963/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6437963&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00293871&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6437963">Kustermann-Kuhn et al. (1984)</a> had found that activity of the pyruvate dehydrogenase complex was not deficient in the brain of 3 autopsied cases of Leigh disease, <a href="#14" class="mim-tip-reference" title="Kretzschmar, H. A., DeArmond, S. J., Koch, T. K., Patel, M. S., Newth, C. J. L., Schmidt, K. A., Packman, S. &lt;strong&gt;Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease).&lt;/strong&gt; Pediatrics 79: 370-373, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3103091/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3103091&lt;/a&gt;]" pmid="3103091">Kretzschmar et al. (1987)</a> reported a patient with well-documented clinical and biochemical pyruvate dehydrogenase complex deficiency who at postmortem examination was found to have the specific CNS pathologic changes of Leigh disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6437963+4813493+3103091" 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="#28" class="mim-tip-reference" title="Rutledge, J. C., Haas, J. E., Monnat, R. &lt;strong&gt;Hypertrophic cardiomyopathy is a feature of subacute necrotizing encephalomyelopathy. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 33: 89A only, 1981."None>Rutledge et al. (1981)</a> pointed out that hypertrophic cardiomyopathy (CMH; see <a href="/entry/192600">192600</a>) is a frequent associated finding in Leigh syndrome. Of 12 autopsy cases, 7 (including a pair of sibs) had hypertrophic cardiomyopathy, and 4 of these had asymmetric septal hypertrophy. The authors suggested that this feature may be useful in premortem diagnosis.</p><p><a href="#29" class="mim-tip-reference" title="van Erven, P. M. M., Gabreels, F. J. M., Ruitenbeek, W., Renier, W. O., Lamers, K. J. B., Slooff, J. L. &lt;strong&gt;Familial Leigh&#x27;s syndrome: association with a defect in oxidative metabolism probably restricted to brain.&lt;/strong&gt; J. Neurol. 234: 215-219, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3612192/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3612192&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00618253&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3612192">Van Erven et al. (1987)</a> reported 4 sibs (1 male, 3 female) of unrelated parents with what the authors considered to be an autosomal recessive juvenile form of Leigh syndrome. They detected no abnormalities of pyruvate metabolism in urine and serum, but all patients had marked elevations of CSF pyruvate and lactate concentrations. Although the affected sibs lived to adulthood, they were severely affected and 1 of them died at age 17 years. The mother had the onset of neurologic signs and symptoms at age 56 years. The authors suggested a defect restricted to the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3612192" 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="#7" class="mim-tip-reference" title="DiMauro, S., De Vivo, D. C. &lt;strong&gt;Genetic heterogeneity in Leigh syndrome. (Letter)&lt;/strong&gt; Ann. Neurol. 40: 5-7, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8687192/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8687192&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410400104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8687192">DiMauro and De Vivo (1996)</a> reviewed the genetic heterogeneity of Leigh syndrome and noted that multiple defects had been described in association with Leigh syndrome, including mutations in PDHA1, mutations in the mitochondrial MTATP6 gene, and defects in complex IV. Thus, there are at least 3 major causes of Leigh syndrome, each transmitted by a different mode of inheritance: X-linked recessive, mitochondrial, and autosomal recessive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687192" 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="#26" class="mim-tip-reference" title="Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R. &lt;strong&gt;Leigh syndrome: clinical features and biochemical and DNA abnormalities.&lt;/strong&gt; Ann. Neurol. 39: 343-351, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8602753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8602753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410390311&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8602753">Rahman et al. (1996)</a> investigated Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups: in 80% of the tightly defined group and 41% of the 'Leigh-like' group. Enzyme defects were found in 29 patients: in respiratory chain complex I in 13, in complex IV in 9, and in the pyruvate dehydrogenase complex (PDHC) in 7. Complex I deficiency (see <a href="/entry/252010">252010</a>) was more common than had previously been recognized. Eleven patients had mitochondrial mutations, including point mutations in the MTATP6 gene (e.g., <a href="/entry/516060#0001">516060.0001</a>) a mutation in the gene encoding mitochondrial transfer RNA-lysine (MTTK) (<a href="/entry/590060#0001">590060.0001</a>), which is common in MERRF syndrome (<a href="/entry/545000">545000</a>), and a mitochondrial deletion. In 6 of the 7 PDHC-deficient patients, mutations were identified in the X-linked E1-alpha subunit of PDHC (PDHA1; <a href="/entry/300502">300502</a>). <a href="#26" class="mim-tip-reference" title="Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R. &lt;strong&gt;Leigh syndrome: clinical features and biochemical and DNA abnormalities.&lt;/strong&gt; Ann. Neurol. 39: 343-351, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8602753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8602753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410390311&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8602753">Rahman et al. (1996)</a> found no strong correlation between the clinical features and basic defects. Parental consanguinity suggested autosomal recessive inheritance in 2 complex IV-deficient sibships. An assumption of autosomal recessive inheritance would have been wrong in nearly one-half of those in whom a cause was found: 11 of 28 tightly defined and 18 of 41 total patients. The experience illustrated that a specific defect must be identified if reliable genetic counseling is to be provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8602753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M. &lt;strong&gt;Deficiency of respiratory chain complex I is a common cause of Leigh disease.&lt;/strong&gt; Ann. Neurol. 40: 25-30, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8687187/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8687187&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410400107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8687187">Morris et al. (1996)</a> reviewed the clinical features and biochemical cause of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of the pedigrees, and in 74% of the 19 pedigrees with pathologically confirmed Leigh disease. Mutation in the MTATP6 gene (<a href="/entry/516060#0001">516060.0001</a>) was found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M. &lt;strong&gt;Deficiency of respiratory chain complex I is a common cause of Leigh disease.&lt;/strong&gt; Ann. Neurol. 40: 25-30, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8687187/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8687187&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410400107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8687187">Morris et al. (1996)</a> described complex I deficiency (see <a href="/entry/252010">252010</a>) as an important cause of Leigh syndrome. Identified in 7 of 25 patients, it was the second most common biochemical abnormality after complex IV deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8687187" 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="Dahl, H.-H. &lt;strong&gt;Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. (Editorial)&lt;/strong&gt; Am. J. Hum. Genet. 63: 1594-1597, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9837811/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9837811&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302169&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9837811">Dahl (1998)</a> reviewed mutations of respiratory chain-enzyme genes that cause Leigh syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9837811" 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 review of the mechanisms of mitochondrial respiratory chain diseases, <a href="#8" class="mim-tip-reference" title="DiMauro, S., Schon, E. A. &lt;strong&gt;Mitochondrial respiratory-chain diseases.&lt;/strong&gt; New Eng. J. Med. 348: 2656-2668, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12826641/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12826641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMra022567&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12826641">DiMauro and Schon (2003)</a> diagrammed the defects resulting from mutations in complexes I, II, III, IV, and V, all of which had Leigh syndrome as one of their pathologic consequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12826641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between a neurodegenerative disorder with clinical features of Leigh syndrome and variation in the GYG2 gene, see <a href="/entry/300198#0001">300198.0001</a>.</p><p>For discussion of a possible association between Leigh syndrome and variation in the IARS2 gene, see <a href="/entry/612801#0002">612801.0002</a>.</p>
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<p>Denis Leigh was a registrar in the Department of Neuropathology, Institute of Psychiatry, Maudsley Hospital, London, at the time he described this condition and named it subacute necrotizing encephalomyelopathy, or SNE (<a href="#17" class="mim-tip-reference" title="Leigh, D. &lt;strong&gt;Subacute necrotizing encephalomyelopathy in an infant.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 14: 216-221, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14874135/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14874135&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.14.3.216&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14874135">Leigh, 1951</a>). He pronounced his name 'Lee,' not 'Lay'(<a href="#18" class="mim-tip-reference" title="McHugh, P. R. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Baltimore, Md. 12/1/1993."None>McHugh, 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14874135" 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>It was originally suggested that the biochemical defect in Leigh syndrome was a block in thiamine metabolism. Cooper et al. (<a href="#3" class="mim-tip-reference" title="Cooper, J. R., Itokawa, Y., Pincus, J. H. &lt;strong&gt;Thiamine triphosphate deficiency in subacute necrotizing encephalomyelopathy.&lt;/strong&gt; Science 164: 74-75, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5773712/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5773712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.164.3875.74&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5773712">1969</a>, <a href="#4" class="mim-tip-reference" title="Cooper, J. R., Pincus, J. H., Itokawa, Y., Piros, K. &lt;strong&gt;Experience with phosphoryl transferase inhibition in subacute necrotizing encephalomyelopathy.&lt;/strong&gt; New Eng. J. Med. 283: 793-795, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5456237/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5456237&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197010082831506&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5456237">1970</a>) found that patients with SNE elaborate a factor, found in the blood and urine, that inhibits the synthesis of thiamine triphosphate (TTP) in brain tissue. The enzyme responsible for TTP synthesis is called thiamine pyrophosphate-adenosine triphosphate phosphoryl transferase. TTP was completely absent in postmortem brain. They suggested that an assay for the inhibitor of TTP synthesis could be performed on urine or blood for diagnostic purposes. In the urine of obligatory or presumptive heterozygotes, <a href="#22" class="mim-tip-reference" title="Murphy, J. V. &lt;strong&gt;Subacute necrotizing encephalomyelopathy (Leigh&#x27;s disease): detection of the heterozygous carrier state.&lt;/strong&gt; Pediatrics 51: 710-715, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4697519/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4697519&lt;/a&gt;]" pmid="4697519">Murphy (1973)</a> found an inhibitor of thiamine triphosphate synthesis in vitro. <a href="#24" class="mim-tip-reference" title="Pincus, J. H., Itokawa, Y., Cooper, J. R. &lt;strong&gt;Enzyme-inhibiting factor in subacute necrotizing encephalomyelopathy.&lt;/strong&gt; Neurology 19: 841-845, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5816876/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5816876&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.19.9.841&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5816876">Pincus et al. (1969)</a> had described the inhibitor in untreated patients. Thiamine derivatives in therapy were studied by <a href="#23" class="mim-tip-reference" title="Pincus, J. H., Cooper, J. R., Murphy, J. V., Rabe, E. F., Lonsdale, D., Dunn, H. G. &lt;strong&gt;Thiamine derivatives in subacute necrotizing encephalomyelopathy.&lt;/strong&gt; Pediatrics 51: 716-721, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4697520/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4697520&lt;/a&gt;]" pmid="4697520">Pincus et al. (1973)</a>. By direct examination of amniotic fluid for the inhibitor of TTP synthesis, <a href="#21" class="mim-tip-reference" title="Murphy, J. V., Craig, L. J., Diven, W. F. &lt;strong&gt;Prenatal detection of Leigh&#x27;s disease: current status. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 27: 68A only, 1975."None>Murphy et al. (1975)</a> suggested that Leigh syndrome could probably be diagnosed antenatally. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5816876+4697520+5456237+4697519+5773712" 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="#25" class="mim-tip-reference" title="Plaitakis, A., Whetsell, W. O., Jr., Cooper, J. R., Yahr, M. D. &lt;strong&gt;Chronic Leigh disease: a genetic and biochemical study.&lt;/strong&gt; Ann. Neurol. 7: 304-310, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6246834/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6246834&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410070404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6246834">Plaitakis et al. (1980)</a> studied the family of a patient who died at age 21 years. The patient came from an isolated Greek island with a population of 1,200. Studies of the family showed inhibitor of adenosine triphosphate-thiamine diphosphate phosphoryltransferase in several members of the family and many of these had a chronic neurologic illness compatible with Leigh disease. Several sibships had more than 1 affected member and the parents were demonstrably consanguineous in several instances. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6246834" 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="#David1970" class="mim-tip-reference" title="David, R. B., Gomez, M. R., Okazaki, H. &lt;strong&gt;Necrotizing encephalomyelopathy (Leigh).&lt;/strong&gt; Dev. Med. Child Neurol. 12: 436-445, 1970.">David et al. (1970)</a>; <a href="#Richter1957" class="mim-tip-reference" title="Richter, R. B. &lt;strong&gt;Infantile subacute necrotizing encephalopathy with predilection for the brain stem.&lt;/strong&gt; J. Neuropath. Exp. Neurol. 16: 281-307, 1957.">Richter (1957)</a>
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Clark, D. B.
<strong>Infantile subacute necrotizing encephalopathy. In: Nelson, W. E. (ed.): Textbook of Pediatrics. (8th ed.)</strong>
Philadelphia: W. B. Saunders (pub.) 1964.
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Clayton, B. E., Dobbs, R. H., Patrick, A. D.
<strong>Leigh's subacute necrotizing encephalopathy: clinical and biochemical study, with special reference to therapy with lipoate.</strong>
Arch. Dis. Child. 42: 467-478, 1967.
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[<a href="https://doi.org/10.1136/adc.42.225.467" target="_blank">Full Text</a>]
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<strong>Thiamine triphosphate deficiency in subacute necrotizing encephalomyelopathy.</strong>
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[<a href="https://doi.org/10.1126/science.164.3875.74" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197010082831506" target="_blank">Full Text</a>]
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<strong>Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. (Editorial)</strong>
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[<a href="https://doi.org/10.1086/302169" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-8749.1970.tb01937.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410400104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMra022567" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(54)80188-0" target="_blank">Full Text</a>]
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<strong>A disease resembling Wernicke's encephalopathy (Feigen and Wolf). Diseases of the Nervous System in Infancy, Childhood and Adolescence. (4th ed.)</strong>
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<strong>Subacute necrotizing encephalomyelopathy in three siblings.</strong>
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[<a href="https://doi.org/10.1111/j.1469-8749.1974.tb02713.x" target="_blank">Full Text</a>]
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Hommes, F. A., Polman, H. A., Reerink, J. D.
<strong>Leigh's encephalomyelopathy: an inborn error of gluconeogenesis.</strong>
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[<a href="https://doi.org/10.1136/adc.43.230.423" target="_blank">Full Text</a>]
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<strong>Myelin studies in a case of subacute necrotizing encephalomyelopathy (SNE).</strong>
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[<a href="https://doi.org/10.1097/00005072-197803000-00004" target="_blank">Full Text</a>]
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Kretzschmar, H. A., DeArmond, S. J., Koch, T. K., Patel, M. S., Newth, C. J. L., Schmidt, K. A., Packman, S.
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<strong>Pyruvate dehydrogenase activity is not deficient in the brain of three autopsied cases with Leigh disease (subacute necrotizing encephalomyelopathy, SNE).</strong>
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[<a href="https://doi.org/10.1007/BF00293871" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.24551" target="_blank">Full Text</a>]
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<strong>Subacute necrotizing encephalomyelopathy in an infant.</strong>
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[<a href="https://doi.org/10.1136/jnnp.14.3.216" target="_blank">Full Text</a>]
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Montpetit, V. J. A., Andermann, F., Carpenter, S., Fawcett, J. S., Zborowska-Sluis, D., Giberson, H. R.
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[<a href="https://doi.org/10.1093/brain/94.1.1" target="_blank">Full Text</a>]
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Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M.
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[<a href="https://doi.org/10.1002/ana.410400107" target="_blank">Full Text</a>]
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Murphy, J. V., Craig, L. J., Diven, W. F.
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<strong>Subacute necrotizing encephalomyelopathy (Leigh's disease): detection of the heterozygous carrier state.</strong>
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Pincus, J. H., Cooper, J. R., Murphy, J. V., Rabe, E. F., Lonsdale, D., Dunn, H. G.
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Pincus, J. H., Itokawa, Y., Cooper, J. R.
<strong>Enzyme-inhibiting factor in subacute necrotizing encephalomyelopathy.</strong>
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[<a href="https://doi.org/10.1212/wnl.19.9.841" target="_blank">Full Text</a>]
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Plaitakis, A., Whetsell, W. O., Jr., Cooper, J. R., Yahr, M. D.
<strong>Chronic Leigh disease: a genetic and biochemical study.</strong>
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[<a href="https://doi.org/10.1002/ana.410070404" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1002/ana.410390311" target="_blank">Full Text</a>]
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<strong>Infantile subacute necrotizing encephalopathy with predilection for the brain stem.</strong>
J. Neuropath. Exp. Neurol. 16: 281-307, 1957.
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[<a href="https://doi.org/10.1097/00005072-195707000-00001" target="_blank">Full Text</a>]
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Am. J. Hum. Genet. 33: 89A only, 1981.
</p>
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van Erven, P. M. M., Gabreels, F. J. M., Ruitenbeek, W., Renier, W. O., Lamers, K. J. B., Slooff, J. L.
<strong>Familial Leigh's syndrome: association with a defect in oxidative metabolism probably restricted to brain.</strong>
J. Neurol. 234: 215-219, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3612192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3612192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3612192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00618253" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 12/06/2018
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Ada Hamosh - updated : 1/20/2016<br>Cassandra L. Kniffin - updated : 3/27/2014<br>Marla J. F. O'Neill - updated : 3/13/2013<br>Cassandra L. Kniffin - updated : 3/7/2013<br>Cassandra L. Kniffin - updated : 11/29/2012<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 2/16/2012<br>Ada Hamosh - updated : 1/6/2012<br>Marla J. F. O'Neill - updated : 11/9/2010<br>Cassandra L. Kniffin - updated : 8/21/2009<br>Cassandra L. Kniffin - updated : 9/10/2008<br>Cassandra L. Kniffin - updated : 12/12/2006<br>Victor A. McKusick - updated : 11/28/2006<br>Cassandra L. Kniffin - updated : 3/10/2006<br>Cassandra L. Kniffin - updated : 7/26/2004<br>Marla J. F. O'Neill - updated : 7/20/2004<br>Natalie E. Krasikov - updated : 3/29/2004<br>Cassandra L. Kniffin - updated : 1/7/2004<br>Victor A. McKusick - updated : 8/13/2003<br>Cassandra L. Kniffin - reorganized : 7/10/2003<br>Cassandra L. Kniffin - updated : 7/9/2003<br>Cassandra L. Kniffin - updated : 1/23/2003<br>Michael B. Petersen - updated : 10/22/2002<br>Jane Kelly - updated : 11/3/2000<br>Michael J. Wright - updated : 5/5/2000<br>Victor A. McKusick - updated : 2/24/1999<br>Victor A. McKusick - updated : 2/23/1999<br>Victor A. McKusick - updated : 11/24/1998<br>Victor A. McKusick - updated : 3/23/1998<br>Victor A. McKusick - updated : 3/10/1998
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Creation Date:
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Victor A. McKusick : 6/4/1986
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carol : 05/14/2024
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<strong>#</strong> 256000
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LEIGH SYNDROME, NUCLEAR; NULS
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<em>Alternative titles; symbols</em>
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NECROTIZING ENCEPHALOPATHY, INFANTILE SUBACUTE, OF LEIGH; SNE
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<strong>SNOMEDCT:</strong> 29570005; &nbsp;
<strong>ORPHA:</strong> 506; &nbsp;
<strong>DO:</strong> 3652; &nbsp;
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that nuclear Leigh syndrome (NULS) can be caused by mutations in several different nuclear-encoded genes, indicating substantial genetic heterogeneity.</p>
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<strong>Description</strong>
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<p>Leigh syndrome is a clinical diagnosis based primarily on characteristic brain imaging findings associated with progressive and severe neurodegenerative features with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by Lake et al., 2015). </p><p><strong><em>Genetic Heterogeneity of Nuclear Leigh Syndrome</em></strong></p><p>
Leigh syndrome is a presentation of numerous genetic disorders resulting from defects in the mitochondrial OXPHOS complex. Accordingly, the genes implicated in Leigh syndrome most commonly encode structural subunits of the OXPHOS complex or proteins required for their assembly, stability, and activity. Mutations in both nuclear and mitochondrial genes have been identified. For a discussion of genetic heterogeneity of mitochondrial Leigh syndrome, see MILS (500017).</p><p>Nuclear Leigh syndrome can be caused by mutations in nuclear-encoded genes involved in any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), and complex V deficiency (see 604273) (summary by Lake et al., 2015). Some forms of combined oxidative phosphorylation deficiency (COXPD) can present as Leigh syndrome (see, e.g., 617664). </p><p>Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome.</p>
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<strong>Clinical Features</strong>
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<p>This condition was first described by Leigh (1951) in a patient with foci of necrosis and capillary proliferation in the brainstem. Feigin and Wolf (1954) observed 2 affected sibs from a consanguineous mating. Because of similarity to Wernicke encephalopathy (277730), they suggested that a genetic defect in some way related to thiamine was present (see HISTORY). Ford (1960) referred to 2 affected sibs, and Clark (1964) pictured the histopathology of 1 of them. The main biochemical findings were high pyruvate and lactate in the blood and slightly low glucose levels in blood and cerebrospinal fluid. Hommes et al. (1968), who studied a family with 3 affected sibs, found absence of pyruvate carboxylase in the liver and concluded that gluconeogenesis was impaired. Clayton et al. (1967) demonstrated therapeutic benefit of lipoic acid. Montpetit et al. (1971) pointed out similarity in the distribution and histology of the lesions of SNE to those of Wernicke disease. They tabulated instances of affected sibs and consanguineous parents. Kohlschutter et al. (1978) reported 2 sisters and a brother born of consanguineous parents. </p><p>Gordon et al. (1974) noted that since oxidation of pyruvate is dependent on a multienzyme complex (the pyruvate dehydrogenase complex), it is likely that a number of apoenzyme and coenzyme deficiencies could lead to this disorder. Whereas Kustermann-Kuhn et al. (1984) had found that activity of the pyruvate dehydrogenase complex was not deficient in the brain of 3 autopsied cases of Leigh disease, Kretzschmar et al. (1987) reported a patient with well-documented clinical and biochemical pyruvate dehydrogenase complex deficiency who at postmortem examination was found to have the specific CNS pathologic changes of Leigh disease. </p><p>Rutledge et al. (1981) pointed out that hypertrophic cardiomyopathy (CMH; see 192600) is a frequent associated finding in Leigh syndrome. Of 12 autopsy cases, 7 (including a pair of sibs) had hypertrophic cardiomyopathy, and 4 of these had asymmetric septal hypertrophy. The authors suggested that this feature may be useful in premortem diagnosis.</p><p>Van Erven et al. (1987) reported 4 sibs (1 male, 3 female) of unrelated parents with what the authors considered to be an autosomal recessive juvenile form of Leigh syndrome. They detected no abnormalities of pyruvate metabolism in urine and serum, but all patients had marked elevations of CSF pyruvate and lactate concentrations. Although the affected sibs lived to adulthood, they were severely affected and 1 of them died at age 17 years. The mother had the onset of neurologic signs and symptoms at age 56 years. The authors suggested a defect restricted to the brain. </p>
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<strong>Molecular Genetics</strong>
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<p>DiMauro and De Vivo (1996) reviewed the genetic heterogeneity of Leigh syndrome and noted that multiple defects had been described in association with Leigh syndrome, including mutations in PDHA1, mutations in the mitochondrial MTATP6 gene, and defects in complex IV. Thus, there are at least 3 major causes of Leigh syndrome, each transmitted by a different mode of inheritance: X-linked recessive, mitochondrial, and autosomal recessive. </p><p>Rahman et al. (1996) investigated Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups: in 80% of the tightly defined group and 41% of the 'Leigh-like' group. Enzyme defects were found in 29 patients: in respiratory chain complex I in 13, in complex IV in 9, and in the pyruvate dehydrogenase complex (PDHC) in 7. Complex I deficiency (see 252010) was more common than had previously been recognized. Eleven patients had mitochondrial mutations, including point mutations in the MTATP6 gene (e.g., 516060.0001) a mutation in the gene encoding mitochondrial transfer RNA-lysine (MTTK) (590060.0001), which is common in MERRF syndrome (545000), and a mitochondrial deletion. In 6 of the 7 PDHC-deficient patients, mutations were identified in the X-linked E1-alpha subunit of PDHC (PDHA1; 300502). Rahman et al. (1996) found no strong correlation between the clinical features and basic defects. Parental consanguinity suggested autosomal recessive inheritance in 2 complex IV-deficient sibships. An assumption of autosomal recessive inheritance would have been wrong in nearly one-half of those in whom a cause was found: 11 of 28 tightly defined and 18 of 41 total patients. The experience illustrated that a specific defect must be identified if reliable genetic counseling is to be provided. </p><p>Morris et al. (1996) reviewed the clinical features and biochemical cause of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of the pedigrees, and in 74% of the 19 pedigrees with pathologically confirmed Leigh disease. Mutation in the MTATP6 gene (516060.0001) was found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid. </p><p>Morris et al. (1996) described complex I deficiency (see 252010) as an important cause of Leigh syndrome. Identified in 7 of 25 patients, it was the second most common biochemical abnormality after complex IV deficiency. </p><p>Dahl (1998) reviewed mutations of respiratory chain-enzyme genes that cause Leigh syndrome. </p><p>In a review of the mechanisms of mitochondrial respiratory chain diseases, DiMauro and Schon (2003) diagrammed the defects resulting from mutations in complexes I, II, III, IV, and V, all of which had Leigh syndrome as one of their pathologic consequences. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between a neurodegenerative disorder with clinical features of Leigh syndrome and variation in the GYG2 gene, see 300198.0001.</p><p>For discussion of a possible association between Leigh syndrome and variation in the IARS2 gene, see 612801.0002.</p>
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<strong>History</strong>
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<p>Denis Leigh was a registrar in the Department of Neuropathology, Institute of Psychiatry, Maudsley Hospital, London, at the time he described this condition and named it subacute necrotizing encephalomyelopathy, or SNE (Leigh, 1951). He pronounced his name 'Lee,' not 'Lay'(McHugh, 1993). </p><p>It was originally suggested that the biochemical defect in Leigh syndrome was a block in thiamine metabolism. Cooper et al. (1969, 1970) found that patients with SNE elaborate a factor, found in the blood and urine, that inhibits the synthesis of thiamine triphosphate (TTP) in brain tissue. The enzyme responsible for TTP synthesis is called thiamine pyrophosphate-adenosine triphosphate phosphoryl transferase. TTP was completely absent in postmortem brain. They suggested that an assay for the inhibitor of TTP synthesis could be performed on urine or blood for diagnostic purposes. In the urine of obligatory or presumptive heterozygotes, Murphy (1973) found an inhibitor of thiamine triphosphate synthesis in vitro. Pincus et al. (1969) had described the inhibitor in untreated patients. Thiamine derivatives in therapy were studied by Pincus et al. (1973). By direct examination of amniotic fluid for the inhibitor of TTP synthesis, Murphy et al. (1975) suggested that Leigh syndrome could probably be diagnosed antenatally. </p><p>Plaitakis et al. (1980) studied the family of a patient who died at age 21 years. The patient came from an isolated Greek island with a population of 1,200. Studies of the family showed inhibitor of adenosine triphosphate-thiamine diphosphate phosphoryltransferase in several members of the family and many of these had a chronic neurologic illness compatible with Leigh disease. Several sibships had more than 1 affected member and the parents were demonstrably consanguineous in several instances. </p>
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<strong>See Also:</strong>
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David et al. (1970); Richter (1957)
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<strong>REFERENCES</strong>
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Clark, D. B.
<strong>Infantile subacute necrotizing encephalopathy. In: Nelson, W. E. (ed.): Textbook of Pediatrics. (8th ed.)</strong>
Philadelphia: W. B. Saunders (pub.) 1964.
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Clayton, B. E., Dobbs, R. H., Patrick, A. D.
<strong>Leigh&#x27;s subacute necrotizing encephalopathy: clinical and biochemical study, with special reference to therapy with lipoate.</strong>
Arch. Dis. Child. 42: 467-478, 1967.
[PubMed: 4862967]
[Full Text: https://doi.org/10.1136/adc.42.225.467]
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Cooper, J. R., Itokawa, Y., Pincus, J. H.
<strong>Thiamine triphosphate deficiency in subacute necrotizing encephalomyelopathy.</strong>
Science 164: 74-75, 1969.
[PubMed: 5773712]
[Full Text: https://doi.org/10.1126/science.164.3875.74]
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Cooper, J. R., Pincus, J. H., Itokawa, Y., Piros, K.
<strong>Experience with phosphoryl transferase inhibition in subacute necrotizing encephalomyelopathy.</strong>
New Eng. J. Med. 283: 793-795, 1970.
[PubMed: 5456237]
[Full Text: https://doi.org/10.1056/NEJM197010082831506]
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Dahl, H.-H.
<strong>Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. (Editorial)</strong>
Am. J. Hum. Genet. 63: 1594-1597, 1998.
[PubMed: 9837811]
[Full Text: https://doi.org/10.1086/302169]
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David, R. B., Gomez, M. R., Okazaki, H.
<strong>Necrotizing encephalomyelopathy (Leigh).</strong>
Dev. Med. Child Neurol. 12: 436-445, 1970.
[PubMed: 5457539]
[Full Text: https://doi.org/10.1111/j.1469-8749.1970.tb01937.x]
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DiMauro, S., De Vivo, D. C.
<strong>Genetic heterogeneity in Leigh syndrome. (Letter)</strong>
Ann. Neurol. 40: 5-7, 1996.
[PubMed: 8687192]
[Full Text: https://doi.org/10.1002/ana.410400104]
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DiMauro, S., Schon, E. A.
<strong>Mitochondrial respiratory-chain diseases.</strong>
New Eng. J. Med. 348: 2656-2668, 2003.
[PubMed: 12826641]
[Full Text: https://doi.org/10.1056/NEJMra022567]
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Feigin, I., Wolf, A.
<strong>A disease in infants resembling chronic Wernicke&#x27;s encephalopathy.</strong>
J. Pediat. 45: 243-263, 1954.
[PubMed: 13202022]
[Full Text: https://doi.org/10.1016/s0022-3476(54)80188-0]
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Ford, F. R.
<strong>A disease resembling Wernicke&#x27;s encephalopathy (Feigen and Wolf). Diseases of the Nervous System in Infancy, Childhood and Adolescence. (4th ed.)</strong>
Springfield, Ill.: Charles C Thomas (pub.) 1960. Pp. 407-410.
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Gordon, N., Marsden, H. B., Lewis, D. M.
<strong>Subacute necrotizing encephalomyelopathy in three siblings.</strong>
Dev. Med. Child Neurol. 16: 64-78, 1974.
[PubMed: 4813493]
[Full Text: https://doi.org/10.1111/j.1469-8749.1974.tb02713.x]
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Hommes, F. A., Polman, H. A., Reerink, J. D.
<strong>Leigh&#x27;s encephalomyelopathy: an inborn error of gluconeogenesis.</strong>
Arch. Dis. Child. 43: 423-426, 1968.
[PubMed: 4873809]
[Full Text: https://doi.org/10.1136/adc.43.230.423]
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Kohlschutter, A., Kraus-Ruppert, R., Rohrer, T., Herschkowitz, N. N.
<strong>Myelin studies in a case of subacute necrotizing encephalomyelopathy (SNE).</strong>
J. Neuropath. Exp. Neurol. 37: 155-164, 1978.
[PubMed: 632845]
[Full Text: https://doi.org/10.1097/00005072-197803000-00004]
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Kretzschmar, H. A., DeArmond, S. J., Koch, T. K., Patel, M. S., Newth, C. J. L., Schmidt, K. A., Packman, S.
<strong>Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease).</strong>
Pediatrics 79: 370-373, 1987.
[PubMed: 3103091]
</p>
</li>
<li>
<p class="mim-text-font">
Kustermann-Kuhn, B., Harzer, K., Schroder, R., Permanetter, W., Peiffer, J.
<strong>Pyruvate dehydrogenase activity is not deficient in the brain of three autopsied cases with Leigh disease (subacute necrotizing encephalomyelopathy, SNE).</strong>
Hum. Genet. 68: 51-53, 1984.
[PubMed: 6437963]
[Full Text: https://doi.org/10.1007/BF00293871]
</p>
</li>
<li>
<p class="mim-text-font">
Lake, N. J., Compton, A. G., Rahman, S., Thorburn, D. R.
<strong>Leigh syndrome: one disorder, more than 75 monogenic causes.</strong>
Ann. Neurol. 79: 190-203, 2015.
[PubMed: 26506407]
[Full Text: https://doi.org/10.1002/ana.24551]
</p>
</li>
<li>
<p class="mim-text-font">
Leigh, D.
<strong>Subacute necrotizing encephalomyelopathy in an infant.</strong>
J. Neurol. Neurosurg. Psychiat. 14: 216-221, 1951.
[PubMed: 14874135]
[Full Text: https://doi.org/10.1136/jnnp.14.3.216]
</p>
</li>
<li>
<p class="mim-text-font">
McHugh, P. R.
<strong>Personal Communication.</strong>
Baltimore, Md. 12/1/1993.
</p>
</li>
<li>
<p class="mim-text-font">
Montpetit, V. J. A., Andermann, F., Carpenter, S., Fawcett, J. S., Zborowska-Sluis, D., Giberson, H. R.
<strong>Subacute necrotizing encephalomyelopathy: a review and a study of two families.</strong>
Brain 94: 1-30, 1971.
[PubMed: 5552162]
[Full Text: https://doi.org/10.1093/brain/94.1.1]
</p>
</li>
<li>
<p class="mim-text-font">
Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M.
<strong>Deficiency of respiratory chain complex I is a common cause of Leigh disease.</strong>
Ann. Neurol. 40: 25-30, 1996.
[PubMed: 8687187]
[Full Text: https://doi.org/10.1002/ana.410400107]
</p>
</li>
<li>
<p class="mim-text-font">
Murphy, J. V., Craig, L. J., Diven, W. F.
<strong>Prenatal detection of Leigh&#x27;s disease: current status. (Abstract)</strong>
Am. J. Hum. Genet. 27: 68A only, 1975.
</p>
</li>
<li>
<p class="mim-text-font">
Murphy, J. V.
<strong>Subacute necrotizing encephalomyelopathy (Leigh&#x27;s disease): detection of the heterozygous carrier state.</strong>
Pediatrics 51: 710-715, 1973.
[PubMed: 4697519]
</p>
</li>
<li>
<p class="mim-text-font">
Pincus, J. H., Cooper, J. R., Murphy, J. V., Rabe, E. F., Lonsdale, D., Dunn, H. G.
<strong>Thiamine derivatives in subacute necrotizing encephalomyelopathy.</strong>
Pediatrics 51: 716-721, 1973.
[PubMed: 4697520]
</p>
</li>
<li>
<p class="mim-text-font">
Pincus, J. H., Itokawa, Y., Cooper, J. R.
<strong>Enzyme-inhibiting factor in subacute necrotizing encephalomyelopathy.</strong>
Neurology 19: 841-845, 1969.
[PubMed: 5816876]
[Full Text: https://doi.org/10.1212/wnl.19.9.841]
</p>
</li>
<li>
<p class="mim-text-font">
Plaitakis, A., Whetsell, W. O., Jr., Cooper, J. R., Yahr, M. D.
<strong>Chronic Leigh disease: a genetic and biochemical study.</strong>
Ann. Neurol. 7: 304-310, 1980.
[PubMed: 6246834]
[Full Text: https://doi.org/10.1002/ana.410070404]
</p>
</li>
<li>
<p class="mim-text-font">
Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R.
<strong>Leigh syndrome: clinical features and biochemical and DNA abnormalities.</strong>
Ann. Neurol. 39: 343-351, 1996.
[PubMed: 8602753]
[Full Text: https://doi.org/10.1002/ana.410390311]
</p>
</li>
<li>
<p class="mim-text-font">
Richter, R. B.
<strong>Infantile subacute necrotizing encephalopathy with predilection for the brain stem.</strong>
J. Neuropath. Exp. Neurol. 16: 281-307, 1957.
[PubMed: 13439393]
[Full Text: https://doi.org/10.1097/00005072-195707000-00001]
</p>
</li>
<li>
<p class="mim-text-font">
Rutledge, J. C., Haas, J. E., Monnat, R.
<strong>Hypertrophic cardiomyopathy is a feature of subacute necrotizing encephalomyelopathy. (Abstract)</strong>
Am. J. Hum. Genet. 33: 89A only, 1981.
</p>
</li>
<li>
<p class="mim-text-font">
van Erven, P. M. M., Gabreels, F. J. M., Ruitenbeek, W., Renier, W. O., Lamers, K. J. B., Slooff, J. L.
<strong>Familial Leigh&#x27;s syndrome: association with a defect in oxidative metabolism probably restricted to brain.</strong>
J. Neurol. 234: 215-219, 1987.
[PubMed: 3612192]
[Full Text: https://doi.org/10.1007/BF00618253]
</p>
</li>
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Contributors:
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Cassandra L. Kniffin - updated : 12/06/2018<br>Ada Hamosh - updated : 1/20/2016<br>Cassandra L. Kniffin - updated : 3/27/2014<br>Marla J. F. O&#x27;Neill - updated : 3/13/2013<br>Cassandra L. Kniffin - updated : 3/7/2013<br>Cassandra L. Kniffin - updated : 11/29/2012<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 2/16/2012<br>Ada Hamosh - updated : 1/6/2012<br>Marla J. F. O&#x27;Neill - updated : 11/9/2010<br>Cassandra L. Kniffin - updated : 8/21/2009<br>Cassandra L. Kniffin - updated : 9/10/2008<br>Cassandra L. Kniffin - updated : 12/12/2006<br>Victor A. McKusick - updated : 11/28/2006<br>Cassandra L. Kniffin - updated : 3/10/2006<br>Cassandra L. Kniffin - updated : 7/26/2004<br>Marla J. F. O&#x27;Neill - updated : 7/20/2004<br>Natalie E. Krasikov - updated : 3/29/2004<br>Cassandra L. Kniffin - updated : 1/7/2004<br>Victor A. McKusick - updated : 8/13/2003<br>Cassandra L. Kniffin - reorganized : 7/10/2003<br>Cassandra L. Kniffin - updated : 7/9/2003<br>Cassandra L. Kniffin - updated : 1/23/2003<br>Michael B. Petersen - updated : 10/22/2002<br>Jane Kelly - updated : 11/3/2000<br>Michael J. Wright - updated : 5/5/2000<br>Victor A. McKusick - updated : 2/24/1999<br>Victor A. McKusick - updated : 2/23/1999<br>Victor A. McKusick - updated : 11/24/1998<br>Victor A. McKusick - updated : 3/23/1998<br>Victor A. McKusick - updated : 3/10/1998
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Victor A. McKusick : 6/4/1986
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