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<title>
Entry
- #220111 - MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5
- OMIM
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<span class="h4">#220111</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/220111"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS220110"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE) OR (LRPPRC)" class="mim-tip-hint" title="Clinical Trials" 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=10945&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>
<div><a href="https://www.diseaseinfosearch.org/x/4158" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=220111[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70472" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0111180" 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/220111" 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://wormbase.org/resources/disease/DOID:0111180" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
<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;
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</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> 718219002<br />
<strong>ORPHA:</strong> 70472<br />
<strong>DO:</strong> 0111180<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>
220111
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5
</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">
CYTOCHROME c OXIDASE DEFICIENCY, FRENCH CANADIAN TYPE<br />
LEIGH SYNDROME, FRENCH CANADIAN TYPE; LSFC<br />
COX DEFICIENCY, FRENCH CANADIAN TYPE<br />
COX DEFICIENCY, SAGUENAY-LAC-SAINT-JEAN TYPE<br />
LEIGH SYNDROME, SAGUENAY-LAC-SAINT-JEAN TYPE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/220?start=-3&limit=10&highlight=220">
2p21
</a>
</span>
</td>
<td>
<span class="mim-font">
Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian)
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/220111"> 220111 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
LRPPRC
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607544"> 607544 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
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<a href="/clinicalSynopsis/220111" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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&nbsp;
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<a href="/phenotypicSeries/PS220110" class="btn btn-info" role="button"> Phenotypic Series </a>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/220111" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/220111" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> 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> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Microcephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca&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 /> -
Prominent forehead <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837260</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011220</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011220</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=a2091161c29564b62e12b608022a4044" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Forehead,Prominent-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=a2091161c29564b62e12b608022a4044&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dysmorphic features <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253978002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253978002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0432072&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0432072</a>]</span><br /> -
Midface hypoplasia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853242&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853242</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011800" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011800</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011800" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011800</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=f0adae8ae2dc0ad9ed28c3c3e0e8f8a9" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Midface_Retrusion-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=f0adae8ae2dc0ad9ed28c3c3e0e8f8a9&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 /> -
Mask-like facies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103606006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103606006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424448&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424448</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000298</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000298</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertelorism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22006008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22006008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/376.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">376.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020534&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020534</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Eyes,Widely_Spaced-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a&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 /> -
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 /> -
Arched eyebrows <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868571</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002553" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002553</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002553" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002553</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Anteverted nares <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/708670007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">708670007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840077&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840077</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000463" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000463</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000463" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000463</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=656ef0aca7742d97c5769f51f0dd56de" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nares,Anteverted-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=656ef0aca7742d97c5769f51f0dd56de&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 /> -
Wide nasal bridge <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249321001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249321001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849367</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000431</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000431</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=3f6587f50506c9d70db0628b3fa5f2c5" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Bridge,Wide-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=3f6587f50506c9d70db0628b3fa5f2c5&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertrophic cardiomyopathy (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/195020003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">195020003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233873004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233873004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45227007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45227007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/425.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/425.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425.11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551472&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551472</a>, <a href="https://bioportal.bioontology.org/search?q=C0340425&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340425</a>, <a href="https://bioportal.bioontology.org/search?q=C0007194&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007194</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001639</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">
- Transient tachypnea of the newborn <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7550008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7550008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P22.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P22.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/770.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">770.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0158940&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158940</a>]</span><br /> -
Abnormal breathing patterns <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806247&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806247</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Liver biopsy shows increased lipid droplets (microvesicular steatosis) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857356&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857356</a>]</span><br /> -
Decreased cytochrome c oxidase activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857357&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857357</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dysphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br /> -
Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
Tube feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61420007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61420007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0041281&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041281</a>, <a href="https://bioportal.bioontology.org/search?q=C0014327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033454" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033454</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040288</a>]</span><br />
</span>
</div>
</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">
- Low frontal hairline <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1842366&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1842366</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000294" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000294</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000294" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000294</a>]</span><br /> -
Arched eyebrows <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868571</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002553" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002553</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002553" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002553</a>]</span><br /> -
Hirsutism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399939002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399939002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L68.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L68.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/704.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">704.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001007</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">
- Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
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 /> -
Language delay <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023012</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000750" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000750</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000750" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000750</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 /> -
Tremor <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26079004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26079004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</a>]</span><br /> -
Seizures (less common) <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 /> -
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 /> -
Neurologic crises with coma (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278049&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278049</a>]</span><br /> -
Lesions in basal ganglia, brainstem, cerebellum, thalamus, spinal cord <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839886</a>]</span><br /> -
Leigh syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29570005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29570005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G31.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G31.82</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023264&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023264</a>]</span><br /> -
Lesions characterized by demyelination, necrosis, gliosis, spongiosis, and capillary proliferation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839887&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839887</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 /> -
Hypoglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237630007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237630007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271327008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271327008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302866003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302866003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1179458001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1179458001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020615</a>, <a href="https://bioportal.bioontology.org/search?q=C5767385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5767385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span><br /> -
Metabolic crises <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278052&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278052</a>]</span><br /> -
Hyperglycemia during crises <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278053</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 /> -
Decreased cytochrome c oxidase activity in skin fibroblasts, liver, and skeletal muscle <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857359&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857359</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 in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
Death usually occurs by age 2 years<br /> -
Death often occurs during metabolic/acidotic crisis<br /> -
First described in the geographically isolated Saguenay-Lac-Saint-Jean region of Quebec, Canada<br /> -
Incidence of 1 in 2,000 in Saguenay-Lac-Saint-Jean region<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 leucine-rich PPR motif-containing protein gene (LRPPRC, <a href="/entry/607544#0001">607544.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Mitochondrial complex IV deficiency, nuclear-type
- <a href="/phenotypicSeries/PS220110">PS220110</a>
- 23 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1810?start=-3&limit=10&highlight=1810"> 1q42.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616501"> Mitochondrial complex IV deficiency, nuclear type 13 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616501"> 616501 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614772"> COA6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614772"> 614772 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1850?start=-3&limit=10&highlight=1850"> 1q44 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619054"> Mitochondrial complex IV deficiency, nuclear type 11 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619054"> 619054 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614698"> COX20 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614698"> 614698 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/220?start=-3&limit=10&highlight=220"> 2p21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/220111"> Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/220111"> 220111 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607544"> LRPPRC </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607544"> 607544 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/496?start=-3&limit=10&highlight=496"> 2q11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616500"> ?Mitochondrial complex IV, deficiency, nuclear type 9 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616500"> 616500 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613920"> COA5 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613920"> 613920 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/71?start=-3&limit=10&highlight=71"> 7p21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619065"> ?Mitochondrial complex IV deficiency, nuclear type 21 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619065"> 619065 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603833"> COXFA4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603833"> 603833 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/612?start=-3&limit=10&highlight=612"> 9q34.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/220110"> Mitochondrial complex IV deficiency, nuclear type 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/220110"> 220110 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/185620"> SURF1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/185620"> 185620 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/468?start=-3&limit=10&highlight=468"> 10q24.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615119"> Mitochondrial complex IV deficiency, nuclear type 6 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615119"> 615119 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603646"> COX15 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603646"> 603646 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/534?start=-3&limit=10&highlight=534"> 11q13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619059"> ?Mitochondrial complex IV deficiency, nuclear type 15 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619059"> 619059 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123870"> COX8A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123870"> 123870 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/372?start=-3&limit=10&highlight=372"> 12q13.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619053"> ?Mitochondrial complex IV deficiency, nuclear type 10 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619053"> 619053 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614478"> COX14 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614478"> 614478 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/347?start=-3&limit=10&highlight=347"> 14q24.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619355"> Mitochondrial complex IV deficiency, nuclear type 22 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619355"> 619355 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618064"> COX16 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618064"> 618064 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/578?start=-3&limit=10&highlight=578"> 14q32.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619061"> Mitochondrial complex IV deficiency, nuclear type 17 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619061"> 619061 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616003"> APOPT1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616003"> 616003 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/391?start=-3&limit=10&highlight=391"> 15q24.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619064"> Mitochondrial complex IV deficiency, nuclear type 20 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619064"> 619064 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603773"> COX5A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603773"> 603773 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/391?start=-3&limit=10&highlight=391"> 16p11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619062"> Mitochondrial complex IV deficiency, nuclear type 18 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
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<span class="mim-font">
<a href="/entry/619062"> 619062 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602009"> COX6A2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602009"> 602009 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/710?start=-3&limit=10&highlight=710"> 16q24.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619060"> Mitochondrial complex IV deficiency, nuclear type 16 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
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<span class="mim-font">
<a href="/entry/619060"> 619060 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123864"> COX4I1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/123864"> 123864 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/228?start=-3&limit=10&highlight=228"> 17p13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619048"> Mitochondrial complex IV deficiency, nuclear type 4 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619048"> 619048 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603644"> SCO1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603644"> 603644 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/242?start=-3&limit=10&highlight=242"> 17p12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619046"> Mitochondrial complex IV deficiency, nuclear type 3 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619046"> 619046 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602125"> COX10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602125"> 602125 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/593?start=-3&limit=10&highlight=593"> 17q21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619058"> ?Mitochondrial complex IV deficiency, nuclear type 14 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619058"> 619058 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614775"> COA3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614775"> 614775 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/761?start=-3&limit=10&highlight=761"> 17q22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620275"> Mitochondrial complex IV deficiency, nuclear type 23 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620275"> 620275 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603648"> COX11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603648"> 603648 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/837?start=-3&limit=10&highlight=837"> 17q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619052"> Mitochondrial complex IV deficiency, nuclear type 8 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619052"> 619052 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612958"> TACO1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612958"> 612958 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/210?start=-3&limit=10&highlight=210"> 19p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619055"> Mitochondrial complex IV deficiency, nuclear type 12 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619055"> 619055 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614770"> PET100 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614770"> 614770 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/592?start=-3&limit=10&highlight=592"> 19q13.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619051"> Mitochondrial complex IV deficiency, nuclear type 7 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619051"> 619051 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/124089"> COX6B1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/124089"> 124089 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/121?start=-3&limit=10&highlight=121"> 20p11.23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619063"> ?Mitochondrial complex IV deficiency, nuclear type 19 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619063"> 619063 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614771"> PET117 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614771"> 614771 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/416?start=-3&limit=10&highlight=416"> 22q13.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604377"> Mitochondrial complex IV deficiency, nuclear type 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604377"> 604377 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604272"> SCO2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604272"> 604272 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
</span>
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</h4>
<div id="mimTextFold" class="collapse in ">
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that mitochondrial complex IV deficiency nuclear type 5 (MC4DN5), also known as the French Canadian type of Leigh syndrome, is caused by homozygous or compound heterozygous mutation in the LRPPRC gene (<a href="/entry/607544">607544</a>) on chromosome 2p21.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="description" class="mim-anchor"></a>
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Description</strong>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
<span class="mim-text-font">
<p>Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see <a href="/entry/256000">256000</a>). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by <a href="#2" class="mim-tip-reference" title="Debray, F. G., Morin, C., Janvier, A., Villeneuve, J., Maranda, B., Laframboise, R., Lacroix, J., Decarie, J.-C., Robitaille, Y., Lambert, M., Robinson, B. H., Mitchell, G. A. &lt;strong&gt;LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.&lt;/strong&gt; J. Med. Genet. 48: 183-189, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21266382/&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;21266382&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2010.081976&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="21266382">Debray et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see <a href="/entry/220110">220110</a>.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="clinicalFeatures" class="mim-anchor"></a>
<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Clinical Features</strong>
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</h4>
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<p>In the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec province in Canada, <a href="#6" class="mim-tip-reference" title="Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H. &lt;strong&gt;A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec.&lt;/strong&gt; Am. J. Hum. Genet. 53: 481-487, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8392290/&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;8392290&lt;/a&gt;]" pmid="8392290">Merante et al. (1993)</a> described a biochemically distinct form of COX deficiency presenting as Leigh syndrome. Thirty-four children were observed to have a similar phenotype consisting of developmental delay, hypotonia, mild facial dysmorphism, chronic well-compensated metabolic acidosis, and high mortality due to episodes of severe acidosis and coma. Enzyme activity was close to normal in kidney and heart, 50% of normal in fibroblasts and skeletal muscle, and nearly absent in brain and liver. The deficiency of enzyme activity appeared to result from a failure to assemble an active enzyme complex. The cDNA sequences of cytochrome oxidase subunits VIa and VIIa were normal. <a href="#6" class="mim-tip-reference" title="Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H. &lt;strong&gt;A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec.&lt;/strong&gt; Am. J. Hum. Genet. 53: 481-487, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8392290/&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;8392290&lt;/a&gt;]" pmid="8392290">Merante et al. (1993)</a> demonstrated that the underlying defect was deficiency of COX, which was particularly severe in the liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Morin, C., Mitchell, G., Larochelle, J., Lambert, M., Ogier, H., Robinson, B. H., De Braekeleer, M. &lt;strong&gt;Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean.&lt;/strong&gt; Am. J. Hum. Genet. 53: 488-496, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8392291/&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;8392291&lt;/a&gt;]" pmid="8392291">Morin et al. (1993)</a> described the clinical findings of 15 of the 34 patients referred to by <a href="#6" class="mim-tip-reference" title="Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H. &lt;strong&gt;A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec.&lt;/strong&gt; Am. J. Hum. Genet. 53: 481-487, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8392290/&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;8392290&lt;/a&gt;]" pmid="8392290">Merante et al. (1993)</a> who had biochemical evidence of COX deficiency. Fifteen patients in whom clinical findings were reported in detail were 6 months to 11 years of age; 11 children died in episodes of fulminant metabolic acidosis. These patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Characteristic changes of Leigh disease were found in the central nervous system and microvesicular steatosis was found in the liver in all affected patients in whom postmortem examination was performed. <a href="#6" class="mim-tip-reference" title="Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H. &lt;strong&gt;A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec.&lt;/strong&gt; Am. J. Hum. Genet. 53: 481-487, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8392290/&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;8392290&lt;/a&gt;]" pmid="8392290">Merante et al. (1993)</a> found that the severity of the biochemical defect varied greatly in different tissues. The activity of COX in skin fibroblasts, amniocytes, and skeletal muscle was 50% of normal, while in kidney and heart it was close to normal. Brain and liver, on the other hand, had very low activities. The deficiency of activity appeared to result from a failure of assembly of the cytochrome oxidase complex in liver, but levels of mRNA for both mitochondrially encoded and nuclear-encoded subunits in liver and skin fibroblasts were found to be the same as those in controls. The cDNA sequence of the liver-specific cytochrome oxidase subunits VIa and VIIa were determined in samples from patient liver and skin fibroblasts and showed normal coding sequence. Segregation analysis was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8392290+8392291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Debray, F. G., Morin, C., Janvier, A., Villeneuve, J., Maranda, B., Laframboise, R., Lacroix, J., Decarie, J.-C., Robitaille, Y., Lambert, M., Robinson, B. H., Mitchell, G. A. &lt;strong&gt;LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.&lt;/strong&gt; J. Med. Genet. 48: 183-189, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21266382/&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;21266382&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2010.081976&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="21266382">Debray et al. (2011)</a> retrospectively reviewed the clinical course of 56 patients with genetically confirmed French Canadian Leigh syndrome. The median age at onset was 5 months, and patients presented with neonatal distress, psychomotor delay, failure to thrive, ataxia, and acute metabolic acidosis. Other features during the neonatal period included hypotonia (58%), transient tachypnea of the newborn (47%), poor sucking (44%), tremor (28%), and hypoglycemia (17%). There were mild craniofacial features such as prominent forehead, midfacial hypoplasia, broad nasal bridge, hypertelorism, hirsutism, and arched eyebrows. All had developmental and language delay. Older ambulatory patients had truncal ataxia with wide-based gait and mild intention tremor. Most (90%) had 1 or more episodes of acute metabolic and/or neurologic decompensation, most of which (82%) resulted in death at a median age of 1.6 years. Metabolic crises were often associated with an infectious illness and were characterized by increased serum lactate, hyperglycemia, hypotonia, coma, liver dysfunction, shock, respiratory distress, and multiorgan failure. Neurologic crises were characterized by hypotonia, ataxia, coma, abnormal breathing patterns, seizures, and stroke-like episodes. There was a higher incidence of these acute episodes in patients with LRPPC mutations compared to patients with COX deficiency and Leigh syndrome due to SURF1 (<a href="/entry/185620">185620</a>) mutations (see <a href="/entry/220110">220110</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others. &lt;strong&gt;LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.&lt;/strong&gt; Brain 138: 3503-3519, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26510951/&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;26510951&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26510951[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awv291&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="26510951">Olahova et al. (2015)</a> reported 10 patients from 7 unrelated families that were not of French Canadian origin who had a severe neurodevelopmental disorder associated with biallelic LRPPRC mutations. Most presented at birth with lactic acidosis, hypotonia, and severely delayed psychomotor development with absent speech, although a few patients had normal early development with episodic decompensation and developmental regression associated with infection. A few patients had mild nonspecific dysmorphic features. Six patients died in infancy or early childhood. Those who survived showed variable neurologic features, including dystonia, ataxia, dysphagia, strabismus, and seizures. Neuroimaging in 2 patients showed features consistent with Leigh syndrome, but lesions were absent in other patients. Three had a striking leukoencephalopathy and 4 had cerebral malformations, such as cerebellar hypoplasia, gyral abnormalities, and hippocampal abnormalities. Other features included hypertrophic cardiomyopathy (in 2 patients), hypospadias (2 patients), anteriorly placed anus (1 patient), polysyndactyly (1 patient), and complex congenital heart disease (1 patient). All patients tested had variably decreased complex IV activity in fibroblasts and/or muscle tissue (range 3 to 70% residual activity). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26510951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p>The transmission pattern of MC4DN5 in the families reported by <a href="#9" class="mim-tip-reference" title="Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others. &lt;strong&gt;LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.&lt;/strong&gt; Brain 138: 3503-3519, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26510951/&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;26510951&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26510951[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awv291&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="26510951">Olahova et al. (2015)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26510951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<p>To identify the gene involved in COX deficiency in the Saguenay-Lac-Saint-Jean region, <a href="#4" class="mim-tip-reference" title="Lee, H. R. N., Rioux, J. D., Daly, M. J., Lander, E. S., Hudson, T. J., Morin, C. C., Robinson, B. H. &lt;strong&gt;Genetic mapping of Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 63: A296 only, 1998."None>Lee et al. (1998)</a> performed linkage disequilibrium mapping with a 318-marker genomewide scan using DNA from 14 affected individuals and their parents. One marker on chromosome 2 showed significant linkage disequilibrium. Further testing with additional affected individuals and additional markers spanning approximately 8 to 10 cM and observation of recombination events narrowed the SLSJ cytochrome oxidase deficiency critical region to approximately 1 to 2 cM.</p><p><a href="#5" class="mim-tip-reference" title="Lee, N., Daly, M. J., Delmonte, T., Lander, E. S., Xu, F., Hudson, T. J., Mitchell, G. A., Morin, C. C., Robinson, B. H., Rioux, J. D. &lt;strong&gt;A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16.&lt;/strong&gt; Am. J. Hum. Genet. 68: 397-409, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11156535/&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;11156535&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11156535[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318197&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="11156535">Lee et al. (2001)</a> performed a genomewide linkage disequilibrium scan and localized the Saguenay-Lac-Saint-Jean COX deficiency locus to 2p16. By identifying a common ancestral haplotype, they limited the critical region to approximately 2 cM between D2S119 and D2S2174. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p>In 21 of 22 patients with LSFC, <a href="#7" class="mim-tip-reference" title="Mootha, V. K., Lepage, P., Miller, K., Bunkenborg, J., Reich, M., Hjerrild, M., Delmonte, T., Villeneuve, A., Sladek, R., Xu, F., Mitchell, G. A., Morin, C., Mann, M., Hudson, T. J., Robinson, B., Rioux, J. D., Lander, E. S. &lt;strong&gt;Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 605-610, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12529507/&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;12529507&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12529507[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.242716699&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="12529507">Mootha et al. (2003)</a> identified a homozygous mutation in the LRPPRC gene (<a href="/entry/607544#0001">607544.0001</a>). The remaining patient was a compound heterozygote; see <a href="/entry/607544#0001">607544.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529507" 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 10 patients from 7 unrelated families with LSFC who were not of French Canadian origin, <a href="#9" class="mim-tip-reference" title="Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others. &lt;strong&gt;LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.&lt;/strong&gt; Brain 138: 3503-3519, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26510951/&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;26510951&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26510951[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awv291&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="26510951">Olahova et al. (2015)</a> identified 5 different biallelic mutations in the LRPPRC gene (<a href="/entry/607544#0003">607544.0003</a>-<a href="/entry/607544#0007">607544.0007</a>). Patients from 4 unrelated families of Indian or Pakistani origin were homozygous for the same mutation (<a href="/entry/607544#0003">607544.0003</a>). The mutations were found by whole-exome sequencing or candidate gene sequencing and segregated with the disorder in the families. Studies of fibroblast and muscle tissue from 3 patients showed decreased levels of the LRPPRC protein compared to controls, as well as a significant decrease in the basal oxygen consumption rate. There was almost complete loss of complex IV subunits as well as variable loss of other mitochondrial respiratory subunits, particularly complex I, and decreased levels of steady-state mitochondrial mRNA in patient fibroblasts and muscle tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26510951" 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>Exclusion Studies</em></strong></p><p>
<a href="#5" class="mim-tip-reference" title="Lee, N., Daly, M. J., Delmonte, T., Lander, E. S., Xu, F., Hudson, T. J., Mitchell, G. A., Morin, C. C., Robinson, B. H., Rioux, J. D. &lt;strong&gt;A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16.&lt;/strong&gt; Am. J. Hum. Genet. 68: 397-409, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11156535/&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;11156535&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11156535[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/318197&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="11156535">Lee et al. (2001)</a> performed mutation screening of the COX7A2L gene (<a href="/entry/605771">605771</a>), which maps to chromosome 2, in patients with MC4DN5 and in controls and found no functional mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<p><a href="#10" class="mim-tip-reference" title="Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E. A., LSFC Consortium. &lt;strong&gt;LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.&lt;/strong&gt; Molec. Biol. Cell 21: 1315-1323, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20200222/&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;20200222&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20200222[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1091/mbc.e10-01-0047&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="20200222">Sasarman et al. (2010)</a> found that mutant LRPPRC was targeted normally to the mitochondrial compartment in immortalized LSFC patient fibroblasts, but that LRPPRC protein content was reduced. In vitro assays revealed that COX activity was reduced in LSFC patient fibroblasts compared with controls. Patient fibroblasts also showed reduced amounts of mitochondrial-encoded COX subunits I (MTCO1; <a href="/entry/516030">516030</a>) and II (MTCO2; <a href="/entry/516040">516040</a>), with a smaller decrease in the level of nuclear-encoded complex IV. LSFC patient fibroblasts showed reduced steady-state levels of mitochondrial mRNAs and had a defect in mitochondrial protein synthesis. Mitochondrial rRNAs and tRNAs were normal in LSFC fibroblasts. Knockdown of LRPPRC in control fibroblasts via siRNA replicated the generalized assembly defect in oxidative phosphorylation complexes. <a href="#10" class="mim-tip-reference" title="Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E. A., LSFC Consortium. &lt;strong&gt;LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.&lt;/strong&gt; Molec. Biol. Cell 21: 1315-1323, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20200222/&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;20200222&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20200222[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1091/mbc.e10-01-0047&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="20200222">Sasarman et al. (2010)</a> observed that COX mRNAs appeared to be more sensitive than other mRNAs to reduced LRPPRC content in LSFC fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20200222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="populationGenetics" class="mim-anchor"></a>
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<strong>Population Genetics</strong>
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<p>In the French Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec province, <a href="#1" class="mim-tip-reference" title="De Braekeleer, M. &lt;strong&gt;Hereditary disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada).&lt;/strong&gt; Hum. Hered. 41: 141-146, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1937486/&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;1937486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000153992&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="1937486">De Braekeleer (1991)</a> estimated the prevalence at birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a carrier frequency of 1 in 28. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1937486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Morin, C., Mitchell, G., Larochelle, J., Lambert, M., Ogier, H., Robinson, B. H., De Braekeleer, M. &lt;strong&gt;Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean.&lt;/strong&gt; Am. J. Hum. Genet. 53: 488-496, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8392291/&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;8392291&lt;/a&gt;]" pmid="8392291">Morin et al. (1993)</a> estimated the incidence of cytochrome c oxidase deficiency at 1 in 2,063 live births between 1979 and 1990, giving a carrier rate of 1 in 23 among inhabitants of the SLSJ region. The genealogic reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Of these, 22 were 17th-century Europeans, suggesting that the COX-deficient gene was introduced into the French Canadian population by early settlers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="history" class="mim-anchor"></a>
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<strong>History</strong>
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<p>Two clinical forms of cytochrome c oxidase deficiency are recognized (<a href="#3" class="mim-tip-reference" title="DiMauro, S., Lombes, A., Nakase, H., Mita, S., Fabrizi, G. M., Tritschler, H.-J., Bonilla, E., Miranda, A. F., DeVivo, D. C., Schon, E. A. &lt;strong&gt;Cytochrome c oxidase deficiency.&lt;/strong&gt; Pediat. Res. 28: 536-541, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2175026/&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;2175026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-199011000-00025&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="2175026">DiMauro et al., 1990</a>): a 'muscular' form in which marked weakness predominates, and a 'nonmuscular' form presenting with Leigh disease, a neurodegenerative condition of the brainstem, cerebellum, and basal ganglia, with symmetric, well-demarcated regions of necrosis, gliosis, and vascular proliferation (<a href="#11" class="mim-tip-reference" title="van Erven, P. M. M., Cillessen, J. P. M., Eekhoff, E. M. W., Gabreels, F. J. M., Doesburg, W. H., Lemmens, W. A. J. G., Slooff, J. L., Renier, W. O., Ruitenbeek, W. &lt;strong&gt;Leigh syndrome, a mitochondrial encephalo(myo)pathy: a review of the literature.&lt;/strong&gt; Clin. Neurol. Neurosurg. 89: 217-230, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3319345/&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;3319345&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0303-8467(87)80020-3&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="3319345">van Erven et al., 1987</a>). Leigh disease can also result from other inborn errors of energy metabolism, such as pyruvate dehydrogenase deficiency (<a href="/entry/266150">266150</a>), complex I deficiency (<a href="/entry/252010">252010</a>), and mutation in a mitochondrial DNA gene for complex V (<a href="/entry/516060">516060</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2175026+3319345" 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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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="1" class="mim-anchor"></a>
<a id="De Braekeleer1991" class="mim-anchor"></a>
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<p class="mim-text-font">
De Braekeleer, M.
<strong>Hereditary disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada).</strong>
Hum. Hered. 41: 141-146, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937486</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1937486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000153992" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Debray2011" class="mim-anchor"></a>
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<p class="mim-text-font">
Debray, F. G., Morin, C., Janvier, A., Villeneuve, J., Maranda, B., Laframboise, R., Lacroix, J., Decarie, J.-C., Robitaille, Y., Lambert, M., Robinson, B. H., Mitchell, G. A.
<strong>LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.</strong>
J. Med. Genet. 48: 183-189, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21266382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21266382</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2010.081976" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="DiMauro1990" class="mim-anchor"></a>
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<p class="mim-text-font">
DiMauro, S., Lombes, A., Nakase, H., Mita, S., Fabrizi, G. M., Tritschler, H.-J., Bonilla, E., Miranda, A. F., DeVivo, D. C., Schon, E. A.
<strong>Cytochrome c oxidase deficiency.</strong>
Pediat. Res. 28: 536-541, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2175026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2175026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2175026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1203/00006450-199011000-00025" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="Lee1998" class="mim-anchor"></a>
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Lee, H. R. N., Rioux, J. D., Daly, M. J., Lander, E. S., Hudson, T. J., Morin, C. C., Robinson, B. H.
<strong>Genetic mapping of Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency. (Abstract)</strong>
Am. J. Hum. Genet. 63: A296 only, 1998.
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<a id="5" class="mim-anchor"></a>
<a id="Lee2001" class="mim-anchor"></a>
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<p class="mim-text-font">
Lee, N., Daly, M. J., Delmonte, T., Lander, E. S., Xu, F., Hudson, T. J., Mitchell, G. A., Morin, C. C., Robinson, B. H., Rioux, J. D.
<strong>A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16.</strong>
Am. J. Hum. Genet. 68: 397-409, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11156535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/318197" target="_blank">Full Text</a>]
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<a id="Merante1993" class="mim-anchor"></a>
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<p class="mim-text-font">
Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H.
<strong>A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec.</strong>
Am. J. Hum. Genet. 53: 481-487, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="Mootha2003" class="mim-anchor"></a>
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Mootha, V. K., Lepage, P., Miller, K., Bunkenborg, J., Reich, M., Hjerrild, M., Delmonte, T., Villeneuve, A., Sladek, R., Xu, F., Mitchell, G. A., Morin, C., Mann, M., Hudson, T. J., Robinson, B., Rioux, J. D., Lander, E. S.
<strong>Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics.</strong>
Proc. Nat. Acad. Sci. 100: 605-610, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529507</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12529507[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.242716699" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Morin1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Morin, C., Mitchell, G., Larochelle, J., Lambert, M., Ogier, H., Robinson, B. H., De Braekeleer, M.
<strong>Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean.</strong>
Am. J. Hum. Genet. 53: 488-496, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8392291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8392291</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8392291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Olahova2015" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others.
<strong>LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.</strong>
Brain 138: 3503-3519, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26510951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26510951</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26510951[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26510951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/awv291" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
<a id="Sasarman2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E. A., LSFC Consortium.
<strong>LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.</strong>
Molec. Biol. Cell 21: 1315-1323, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20200222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20200222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20200222[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20200222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1091/mbc.e10-01-0047" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="van Erven1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van Erven, P. M. M., Cillessen, J. P. M., Eekhoff, E. M. W., Gabreels, F. J. M., Doesburg, W. H., Lemmens, W. A. J. G., Slooff, J. L., Renier, W. O., Ruitenbeek, W.
<strong>Leigh syndrome, a mitochondrial encephalo(myo)pathy: a review of the literature.</strong>
Clin. Neurol. Neurosurg. 89: 217-230, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3319345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3319345</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3319345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0303-8467(87)80020-3" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Cassandra L. Kniffin - updated : 10/23/2020
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Cassandra L. Kniffin - updated : 12/2/2015<br>Patricia A. Hartz - updated : 5/11/2015<br>Cassandra L. Kniffin - updated : 12/1/2011<br>Cassandra L. Kniffin - reorganized : 7/10/2003<br>Victor A. McKusick - updated : 2/12/2003<br>Victor A. McKusick - updated : 2/24/1999<br>Victor A. McKusick - updated : 11/30/1998
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Creation Date:
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Victor A. McKusick : 8/30/1993
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carol : 11/02/2020
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ckniffin : 10/29/2020<br>carol : 10/23/2020<br>carol : 10/15/2020<br>carol : 08/03/2020<br>carol : 03/15/2018<br>alopez : 12/03/2015<br>ckniffin : 12/2/2015<br>mgross : 5/11/2015<br>carol : 12/5/2011<br>ckniffin : 12/1/2011<br>ckniffin : 12/1/2011<br>terry : 10/26/2011<br>terry : 2/22/2005<br>carol : 7/10/2003<br>ckniffin : 7/10/2003<br>ckniffin : 7/10/2003<br>mgross : 2/14/2003<br>mgross : 2/14/2003<br>terry : 2/12/2003<br>carol : 3/26/2001<br>mcapotos : 3/12/2001<br>carol : 10/24/2000<br>carol : 9/29/1999<br>carol : 3/22/1999<br>terry : 2/24/1999<br>alopez : 12/8/1998<br>alopez : 11/30/1998<br>carol : 7/13/1996<br>davew : 6/1/1994<br>mimadm : 3/11/1994<br>carol : 10/18/1993<br>carol : 9/8/1993<br>carol : 8/30/1993
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<strong>#</strong> 220111
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MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5
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<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
CYTOCHROME c OXIDASE DEFICIENCY, FRENCH CANADIAN TYPE<br />
LEIGH SYNDROME, FRENCH CANADIAN TYPE; LSFC<br />
COX DEFICIENCY, FRENCH CANADIAN TYPE<br />
COX DEFICIENCY, SAGUENAY-LAC-SAINT-JEAN TYPE<br />
LEIGH SYNDROME, SAGUENAY-LAC-SAINT-JEAN TYPE
</span>
</h4>
</div>
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<div>
<br />
</div>
</div>
<div>
<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 718219002; &nbsp;
<strong>ORPHA:</strong> 70472; &nbsp;
<strong>DO:</strong> 0111180; &nbsp;
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
2p21
</span>
</td>
<td>
<span class="mim-font">
Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian)
</span>
</td>
<td>
<span class="mim-font">
220111
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
LRPPRC
</span>
</td>
<td>
<span class="mim-font">
607544
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that mitochondrial complex IV deficiency nuclear type 5 (MC4DN5), also known as the French Canadian type of Leigh syndrome, is caused by homozygous or compound heterozygous mutation in the LRPPRC gene (607544) on chromosome 2p21.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). </p><p>For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.</p>
</span>
<div>
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<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
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</h4>
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<span class="mim-text-font">
<p>In the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec province in Canada, Merante et al. (1993) described a biochemically distinct form of COX deficiency presenting as Leigh syndrome. Thirty-four children were observed to have a similar phenotype consisting of developmental delay, hypotonia, mild facial dysmorphism, chronic well-compensated metabolic acidosis, and high mortality due to episodes of severe acidosis and coma. Enzyme activity was close to normal in kidney and heart, 50% of normal in fibroblasts and skeletal muscle, and nearly absent in brain and liver. The deficiency of enzyme activity appeared to result from a failure to assemble an active enzyme complex. The cDNA sequences of cytochrome oxidase subunits VIa and VIIa were normal. Merante et al. (1993) demonstrated that the underlying defect was deficiency of COX, which was particularly severe in the liver. </p><p>Morin et al. (1993) described the clinical findings of 15 of the 34 patients referred to by Merante et al. (1993) who had biochemical evidence of COX deficiency. Fifteen patients in whom clinical findings were reported in detail were 6 months to 11 years of age; 11 children died in episodes of fulminant metabolic acidosis. These patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Characteristic changes of Leigh disease were found in the central nervous system and microvesicular steatosis was found in the liver in all affected patients in whom postmortem examination was performed. Merante et al. (1993) found that the severity of the biochemical defect varied greatly in different tissues. The activity of COX in skin fibroblasts, amniocytes, and skeletal muscle was 50% of normal, while in kidney and heart it was close to normal. Brain and liver, on the other hand, had very low activities. The deficiency of activity appeared to result from a failure of assembly of the cytochrome oxidase complex in liver, but levels of mRNA for both mitochondrially encoded and nuclear-encoded subunits in liver and skin fibroblasts were found to be the same as those in controls. The cDNA sequence of the liver-specific cytochrome oxidase subunits VIa and VIIa were determined in samples from patient liver and skin fibroblasts and showed normal coding sequence. Segregation analysis was consistent with autosomal recessive inheritance. </p><p>Debray et al. (2011) retrospectively reviewed the clinical course of 56 patients with genetically confirmed French Canadian Leigh syndrome. The median age at onset was 5 months, and patients presented with neonatal distress, psychomotor delay, failure to thrive, ataxia, and acute metabolic acidosis. Other features during the neonatal period included hypotonia (58%), transient tachypnea of the newborn (47%), poor sucking (44%), tremor (28%), and hypoglycemia (17%). There were mild craniofacial features such as prominent forehead, midfacial hypoplasia, broad nasal bridge, hypertelorism, hirsutism, and arched eyebrows. All had developmental and language delay. Older ambulatory patients had truncal ataxia with wide-based gait and mild intention tremor. Most (90%) had 1 or more episodes of acute metabolic and/or neurologic decompensation, most of which (82%) resulted in death at a median age of 1.6 years. Metabolic crises were often associated with an infectious illness and were characterized by increased serum lactate, hyperglycemia, hypotonia, coma, liver dysfunction, shock, respiratory distress, and multiorgan failure. Neurologic crises were characterized by hypotonia, ataxia, coma, abnormal breathing patterns, seizures, and stroke-like episodes. There was a higher incidence of these acute episodes in patients with LRPPC mutations compared to patients with COX deficiency and Leigh syndrome due to SURF1 (185620) mutations (see 220110). </p><p>Olahova et al. (2015) reported 10 patients from 7 unrelated families that were not of French Canadian origin who had a severe neurodevelopmental disorder associated with biallelic LRPPRC mutations. Most presented at birth with lactic acidosis, hypotonia, and severely delayed psychomotor development with absent speech, although a few patients had normal early development with episodic decompensation and developmental regression associated with infection. A few patients had mild nonspecific dysmorphic features. Six patients died in infancy or early childhood. Those who survived showed variable neurologic features, including dystonia, ataxia, dysphagia, strabismus, and seizures. Neuroimaging in 2 patients showed features consistent with Leigh syndrome, but lesions were absent in other patients. Three had a striking leukoencephalopathy and 4 had cerebral malformations, such as cerebellar hypoplasia, gyral abnormalities, and hippocampal abnormalities. Other features included hypertrophic cardiomyopathy (in 2 patients), hypospadias (2 patients), anteriorly placed anus (1 patient), polysyndactyly (1 patient), and complex congenital heart disease (1 patient). All patients tested had variably decreased complex IV activity in fibroblasts and/or muscle tissue (range 3 to 70% residual activity). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The transmission pattern of MC4DN5 in the families reported by Olahova et al. (2015) was consistent with autosomal recessive inheritance. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>To identify the gene involved in COX deficiency in the Saguenay-Lac-Saint-Jean region, Lee et al. (1998) performed linkage disequilibrium mapping with a 318-marker genomewide scan using DNA from 14 affected individuals and their parents. One marker on chromosome 2 showed significant linkage disequilibrium. Further testing with additional affected individuals and additional markers spanning approximately 8 to 10 cM and observation of recombination events narrowed the SLSJ cytochrome oxidase deficiency critical region to approximately 1 to 2 cM.</p><p>Lee et al. (2001) performed a genomewide linkage disequilibrium scan and localized the Saguenay-Lac-Saint-Jean COX deficiency locus to 2p16. By identifying a common ancestral haplotype, they limited the critical region to approximately 2 cM between D2S119 and D2S2174. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In 21 of 22 patients with LSFC, Mootha et al. (2003) identified a homozygous mutation in the LRPPRC gene (607544.0001). The remaining patient was a compound heterozygote; see 607544.0001. </p><p>In 10 patients from 7 unrelated families with LSFC who were not of French Canadian origin, Olahova et al. (2015) identified 5 different biallelic mutations in the LRPPRC gene (607544.0003-607544.0007). Patients from 4 unrelated families of Indian or Pakistani origin were homozygous for the same mutation (607544.0003). The mutations were found by whole-exome sequencing or candidate gene sequencing and segregated with the disorder in the families. Studies of fibroblast and muscle tissue from 3 patients showed decreased levels of the LRPPRC protein compared to controls, as well as a significant decrease in the basal oxygen consumption rate. There was almost complete loss of complex IV subunits as well as variable loss of other mitochondrial respiratory subunits, particularly complex I, and decreased levels of steady-state mitochondrial mRNA in patient fibroblasts and muscle tissue. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
Lee et al. (2001) performed mutation screening of the COX7A2L gene (605771), which maps to chromosome 2, in patients with MC4DN5 and in controls and found no functional mutations. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Sasarman et al. (2010) found that mutant LRPPRC was targeted normally to the mitochondrial compartment in immortalized LSFC patient fibroblasts, but that LRPPRC protein content was reduced. In vitro assays revealed that COX activity was reduced in LSFC patient fibroblasts compared with controls. Patient fibroblasts also showed reduced amounts of mitochondrial-encoded COX subunits I (MTCO1; 516030) and II (MTCO2; 516040), with a smaller decrease in the level of nuclear-encoded complex IV. LSFC patient fibroblasts showed reduced steady-state levels of mitochondrial mRNAs and had a defect in mitochondrial protein synthesis. Mitochondrial rRNAs and tRNAs were normal in LSFC fibroblasts. Knockdown of LRPPRC in control fibroblasts via siRNA replicated the generalized assembly defect in oxidative phosphorylation complexes. Sasarman et al. (2010) observed that COX mRNAs appeared to be more sensitive than other mRNAs to reduced LRPPRC content in LSFC fibroblasts. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In the French Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec province, De Braekeleer (1991) estimated the prevalence at birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a carrier frequency of 1 in 28. </p><p>Morin et al. (1993) estimated the incidence of cytochrome c oxidase deficiency at 1 in 2,063 live births between 1979 and 1990, giving a carrier rate of 1 in 23 among inhabitants of the SLSJ region. The genealogic reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Of these, 22 were 17th-century Europeans, suggesting that the COX-deficient gene was introduced into the French Canadian population by early settlers. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Two clinical forms of cytochrome c oxidase deficiency are recognized (DiMauro et al., 1990): a 'muscular' form in which marked weakness predominates, and a 'nonmuscular' form presenting with Leigh disease, a neurodegenerative condition of the brainstem, cerebellum, and basal ganglia, with symmetric, well-demarcated regions of necrosis, gliosis, and vascular proliferation (van Erven et al., 1987). Leigh disease can also result from other inborn errors of energy metabolism, such as pyruvate dehydrogenase deficiency (266150), complex I deficiency (252010), and mutation in a mitochondrial DNA gene for complex V (516060). </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
De Braekeleer, M.
<strong>Hereditary disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada).</strong>
Hum. Hered. 41: 141-146, 1991.
[PubMed: 1937486]
[Full Text: https://doi.org/10.1159/000153992]
</p>
</li>
<li>
<p class="mim-text-font">
Debray, F. G., Morin, C., Janvier, A., Villeneuve, J., Maranda, B., Laframboise, R., Lacroix, J., Decarie, J.-C., Robitaille, Y., Lambert, M., Robinson, B. H., Mitchell, G. A.
<strong>LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.</strong>
J. Med. Genet. 48: 183-189, 2011.
[PubMed: 21266382]
[Full Text: https://doi.org/10.1136/jmg.2010.081976]
</p>
</li>
<li>
<p class="mim-text-font">
DiMauro, S., Lombes, A., Nakase, H., Mita, S., Fabrizi, G. M., Tritschler, H.-J., Bonilla, E., Miranda, A. F., DeVivo, D. C., Schon, E. A.
<strong>Cytochrome c oxidase deficiency.</strong>
Pediat. Res. 28: 536-541, 1990.
[PubMed: 2175026]
[Full Text: https://doi.org/10.1203/00006450-199011000-00025]
</p>
</li>
<li>
<p class="mim-text-font">
Lee, H. R. N., Rioux, J. D., Daly, M. J., Lander, E. S., Hudson, T. J., Morin, C. C., Robinson, B. H.
<strong>Genetic mapping of Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency. (Abstract)</strong>
Am. J. Hum. Genet. 63: A296 only, 1998.
</p>
</li>
<li>
<p class="mim-text-font">
Lee, N., Daly, M. J., Delmonte, T., Lander, E. S., Xu, F., Hudson, T. J., Mitchell, G. A., Morin, C. C., Robinson, B. H., Rioux, J. D.
<strong>A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16.</strong>
Am. J. Hum. Genet. 68: 397-409, 2001.
[PubMed: 11156535]
[Full Text: https://doi.org/10.1086/318197]
</p>
</li>
<li>
<p class="mim-text-font">
Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H.
<strong>A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec.</strong>
Am. J. Hum. Genet. 53: 481-487, 1993.
[PubMed: 8392290]
</p>
</li>
<li>
<p class="mim-text-font">
Mootha, V. K., Lepage, P., Miller, K., Bunkenborg, J., Reich, M., Hjerrild, M., Delmonte, T., Villeneuve, A., Sladek, R., Xu, F., Mitchell, G. A., Morin, C., Mann, M., Hudson, T. J., Robinson, B., Rioux, J. D., Lander, E. S.
<strong>Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics.</strong>
Proc. Nat. Acad. Sci. 100: 605-610, 2003.
[PubMed: 12529507]
[Full Text: https://doi.org/10.1073/pnas.242716699]
</p>
</li>
<li>
<p class="mim-text-font">
Morin, C., Mitchell, G., Larochelle, J., Lambert, M., Ogier, H., Robinson, B. H., De Braekeleer, M.
<strong>Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean.</strong>
Am. J. Hum. Genet. 53: 488-496, 1993.
[PubMed: 8392291]
</p>
</li>
<li>
<p class="mim-text-font">
Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others.
<strong>LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.</strong>
Brain 138: 3503-3519, 2015.
[PubMed: 26510951]
[Full Text: https://doi.org/10.1093/brain/awv291]
</p>
</li>
<li>
<p class="mim-text-font">
Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E. A., LSFC Consortium.
<strong>LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria.</strong>
Molec. Biol. Cell 21: 1315-1323, 2010.
[PubMed: 20200222]
[Full Text: https://doi.org/10.1091/mbc.e10-01-0047]
</p>
</li>
<li>
<p class="mim-text-font">
van Erven, P. M. M., Cillessen, J. P. M., Eekhoff, E. M. W., Gabreels, F. J. M., Doesburg, W. H., Lemmens, W. A. J. G., Slooff, J. L., Renier, W. O., Ruitenbeek, W.
<strong>Leigh syndrome, a mitochondrial encephalo(myo)pathy: a review of the literature.</strong>
Clin. Neurol. Neurosurg. 89: 217-230, 1987.
[PubMed: 3319345]
[Full Text: https://doi.org/10.1016/s0303-8467(87)80020-3]
</p>
</li>
</ol>
<div>
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<span class="mim-text-font">
Cassandra L. Kniffin - updated : 10/23/2020<br>Cassandra L. Kniffin - updated : 12/2/2015<br>Patricia A. Hartz - updated : 5/11/2015<br>Cassandra L. Kniffin - updated : 12/1/2011<br>Cassandra L. Kniffin - reorganized : 7/10/2003<br>Victor A. McKusick - updated : 2/12/2003<br>Victor A. McKusick - updated : 2/24/1999<br>Victor A. McKusick - updated : 11/30/1998
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 8/30/1993
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carol : 11/02/2020<br>ckniffin : 10/29/2020<br>carol : 10/23/2020<br>carol : 10/15/2020<br>carol : 08/03/2020<br>carol : 03/15/2018<br>alopez : 12/03/2015<br>ckniffin : 12/2/2015<br>mgross : 5/11/2015<br>carol : 12/5/2011<br>ckniffin : 12/1/2011<br>ckniffin : 12/1/2011<br>terry : 10/26/2011<br>terry : 2/22/2005<br>carol : 7/10/2003<br>ckniffin : 7/10/2003<br>ckniffin : 7/10/2003<br>mgross : 2/14/2003<br>mgross : 2/14/2003<br>terry : 2/12/2003<br>carol : 3/26/2001<br>mcapotos : 3/12/2001<br>carol : 10/24/2000<br>carol : 9/29/1999<br>carol : 3/22/1999<br>terry : 2/24/1999<br>alopez : 12/8/1998<br>alopez : 11/30/1998<br>carol : 7/13/1996<br>davew : 6/1/1994<br>mimadm : 3/11/1994<br>carol : 10/18/1993<br>carol : 9/8/1993<br>carol : 8/30/1993
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