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<title>
Entry
- #256810 - MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE); MTDPS6
- OMIM
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<span class="h4">#256810</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/256810"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS603041"> <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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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE)" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19812&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK487393/" title="Mitochondrial DNA Maintenance Defects Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Mitochondrial DNA Maintena…</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK92947/" title="MPV17-Related Hepatocerebral Mitochondrial DNA Maintenance Defect" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">MPV17-Related Hepatocerebr…</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/mpv17-related-hepatocerebral-mitochondrial-dna-depletion-syndrome" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=255229" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/c5556012-c13d-45d6-8d75-7f0a637b3f4e/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0080125" 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/256810" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/OMIA001150/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0080125" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 784346006<br />
<strong>ORPHA:</strong> 255229<br />
<strong>DO:</strong> 0080125<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>
256810
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE); MTDPS6
</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">
NAVAJO NEUROHEPATOPATHY; NNH<br />
NAVAJO NEUROPATHY; NN
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
NAVAJO FAMILIAL NEUROGENIC ARTHROPATHY, INCLUDED
</span>
</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/2/131?start=-3&limit=10&highlight=131">
2p23.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256810"> 256810 </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">
MPV17
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/137960"> 137960 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/256810" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS603041" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&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/256810" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/256810" 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> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Weight </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Poor weight gain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36440009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36440009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231246&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231246</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>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Corneal ulcerations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91514001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91514001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/370.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/370.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010043&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010043</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012804</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012804</a>]</span><br /> -
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br />
</span>
</div>
</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">
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br /> -
Acute hepatic failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197270009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197270009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162557</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006554" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006554</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006554" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006554</a>]</span><br /> -
Reye syndrome-like episodes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850413&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850413</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006582</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006582</a>]</span><br /> -
Biopsy shows multinucleated giant cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850414&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850414</a>]</span><br /> -
Macrovesicular steatosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837256&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837256</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001403" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001403</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001403" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001403</a>]</span><br /> -
Microvesicular steatosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850415&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850415</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001414" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001414</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001414" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001414</a>]</span><br /> -
Pseudo-acini <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850416&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850416</a>]</span><br /> -
Inflammation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/257552002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">257552002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021368&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021368</a>]</span><br /> -
Cholestasis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30144000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30144000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33688009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33688009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197446008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197446008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K83.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K83.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/576.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">576.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008370</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001396" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001396</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001396" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001396</a>]</span><br /> -
Bridging fibrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/31313009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">31313009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0334160&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0334160</a>]</span><br /> -
Cirrhosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19943007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19943007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K74.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K74.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023890&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023890</a>, <a href="https://bioportal.bioontology.org/search?q=C1623038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1623038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001394</a>]</span><br /> -
Mitochondrial DNA depletion in liver tissue <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278608&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278608</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">
- Vomiting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br /> -
Diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011991</a>, <a href="https://bioportal.bioontology.org/search?q=C2169706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2169706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Painless fractures due to injury <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837602&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837602</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002661" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002661</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002661" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002661</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Acral ulceration and osteomyelitis leading to autoamputation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837603</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Acral ulceration and osteomyelitis leading to autoamputation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837603</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> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Neonatal jaundice <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/387712008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">387712008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P59.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P59.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022353&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022353</a>, <a href="https://bioportal.bioontology.org/search?q=C1859236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859236</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006579</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006579</a>]</span><br />
</span>
</div>
</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">
- Progressive white matter lesions in the brain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850408&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850408</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 /> -
Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
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 /> -
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 />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Progressive sensorimotor neuropathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850409&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850409</a>]</span><br /> -
Pain insensitivity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38433004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38433004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0344307&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344307</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007021" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007021</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007021" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007021</a>]</span><br /> -
Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
Areflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37280007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37280007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234146</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span><br /> -
Muscle weakness, distal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249942005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249942005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427065&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427065</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span><br /> -
Delayed motor nerve conduction velocities (NCV) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850411&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850411</a>]</span><br /> -
Loss of large and small myelinated fibers seen on nerve biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278607&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278607</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 />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> IMMUNOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Systemic infections <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91302008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91302008</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/995.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">995.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0243026&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0243026</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">
- Elevated liver enzymes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235996</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span><br /> -
Increased total and conjugated bilirubin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278610&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278610</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">
- Early onset (1 month to 4 years)<br /> -
Frequently occurs in Navajo children, especially in Western reservations<br /> -
Death in the first decade, usually from liver failure<br /> -
Liver disease may be the most predominant finding<br /> -
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
Phenotypic variability <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br />
</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 mitochondrial inner membrane protein MPV17 gene (MPV17, <a href="/entry/137960#0001">137960.0001</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 DNA depletion syndrome
- <a href="/phenotypicSeries/PS603041">PS603041</a>
- 25 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/1/1772?start=-3&limit=10&highlight=1772"> 1q42.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/621071"> Mitochondrial DNA depletion syndrome 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/621071"> 621071 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/139270"> GUK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/139270"> 139270 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/131?start=-3&limit=10&highlight=131"> 2p23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256810"> Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) </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/256810"> 256810 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/137960"> MPV17 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/137960"> 137960 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/371?start=-3&limit=10&highlight=371"> 2p13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/251880"> Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) </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/251880"> 251880 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601465"> DGUOK </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601465"> 601465 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/413?start=-3&limit=10&highlight=413"> 2p11.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/245400"> Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) </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/245400"> 245400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611224"> SUCLG1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611224"> 611224 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/975?start=-3&limit=10&highlight=975"> 3q29 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616896"> ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) </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/616896"> 616896 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605290"> OPA1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605290"> 605290 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/714?start=-3&limit=10&highlight=714"> 4q35.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617184"> Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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/617184"> 617184 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103220"> SLC25A4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103220"> 103220 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/714?start=-3&limit=10&highlight=714"> 4q35.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615418"> Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR </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/615418"> 615418 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103220"> SLC25A4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/103220"> 103220 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/722?start=-3&limit=10&highlight=722"> 6q16.1-q16.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615471"> Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) </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/615471"> 615471 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605654"> FBXL4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605654"> 605654 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/21?start=-3&limit=10&highlight=21"> 7p22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618567"> Mitochondrial DNA depletion syndrome 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/618567"> 618567 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606906"> MRM2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606906"> 606906 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/744?start=-3&limit=10&highlight=744"> 7q34 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/212350"> Sengers syndrome </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/212350"> 212350 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610345"> AGK </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610345"> 610345 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/452?start=-3&limit=10&highlight=452"> 8q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612075"> Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) </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/612075"> 612075 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604712"> RRM2B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604712"> 604712 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/452?start=-3&limit=10&highlight=452"> 8q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612075"> Mitochondrial DNA depletion syndrome 8B (MNGIE type) </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/612075"> 612075 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604712"> RRM2B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604712"> 604712 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/214?start=-3&limit=10&highlight=214"> 10q21.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617156"> ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) </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/617156"> 617156 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600438"> TFAM </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600438"> 600438 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/489?start=-3&limit=10&highlight=489"> 10q24.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/271245"> Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) </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/271245"> 271245 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606075"> TWNK </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606075"> 606075 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/158?start=-3&limit=10&highlight=158"> 13q14.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612073"> Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) </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/612073"> 612073 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603921"> SUCLA2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603921"> 603921 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/182?start=-3&limit=10&highlight=182"> 14q13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618811"> ?Mitochondrial DNA depletion syndrome 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>
<td>
<span class="mim-font">
<a href="/entry/618811"> 618811 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607571"> SLC25A21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607571"> 607571 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/498?start=-3&limit=10&highlight=498"> 15q26.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613662"> Mitochondrial DNA depletion syndrome 4B (MNGIE type) </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/613662"> 613662 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/174763"> POLG </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/174763"> 174763 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/498?start=-3&limit=10&highlight=498"> 15q26.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/203700"> Mitochondrial DNA depletion syndrome 4A (Alpers type) </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/203700"> 203700 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/174763"> POLG </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/174763"> 174763 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/511?start=-3&limit=10&highlight=511"> 16q21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609560"> Mitochondrial DNA depletion syndrome 2 (myopathic type) </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/609560"> 609560 </a>
</span>
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<span class="mim-font">
<a href="/entry/188250"> TK2 </a>
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<span class="mim-font">
<a href="/entry/188250"> 188250 </a>
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<span class="mim-font">
<a href="/geneMap/17/413?start=-3&limit=10&highlight=413"> 17q12 </a>
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<span class="mim-font">
<a href="/entry/619780"> Mitochondrial DNA depletion syndrome 20 (MNGIE type) </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/619780"> 619780 </a>
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<span class="mim-font">
<a href="/entry/600940"> LIG3 </a>
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<span class="mim-font">
<a href="/entry/600940"> 600940 </a>
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<span class="mim-font">
<a href="/geneMap/17/857?start=-3&limit=10&highlight=857"> 17q23.3 </a>
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<span class="mim-font">
<a href="/entry/619425"> ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type) </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/619425"> 619425 </a>
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<span class="mim-font">
<a href="/entry/604983"> POLG2 </a>
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<span class="mim-font">
<a href="/entry/604983"> 604983 </a>
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<span class="mim-font">
<a href="/geneMap/17/857?start=-3&limit=10&highlight=857"> 17q23.3 </a>
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<span class="mim-font">
<a href="/entry/618528"> ?Mitochondrial DNA depletion syndrome 16 (hepatic type) </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/618528"> 618528 </a>
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<span class="mim-font">
<a href="/entry/604983"> POLG2 </a>
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<span class="mim-font">
<a href="/entry/604983"> 604983 </a>
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<span class="mim-font">
<a href="/geneMap/17/1040?start=-3&limit=10&highlight=1040"> 17q25.3 </a>
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<span class="mim-font">
<a href="/entry/618972"> ?Mitochondrial DNA depletion syndrome 19 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/618972"> 618972 </a>
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<span class="mim-font">
<a href="/entry/606794"> SLC25A10 </a>
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<span class="mim-font">
<a href="/entry/606794"> 606794 </a>
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<span class="mim-font">
<a href="/geneMap/20/118?start=-3&limit=10&highlight=118"> 20p11.23 </a>
</span>
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<span class="mim-font">
<a href="/entry/615084"> Mitochondrial DNA depletion syndrome 11 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
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<span class="mim-font">
<a href="/entry/615084"> 615084 </a>
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<span class="mim-font">
<a href="/entry/615076"> MGME1 </a>
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<span class="mim-font">
<a href="/entry/615076"> 615076 </a>
</span>
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<span class="mim-font">
<a href="/geneMap/22/417?start=-3&limit=10&highlight=417"> 22q13.33 </a>
</span>
</td>
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<span class="mim-font">
<a href="/entry/603041"> Mitochondrial DNA depletion syndrome 1 (MNGIE type) </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>
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<span class="mim-font">
<a href="/entry/603041"> 603041 </a>
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<span class="mim-font">
<a href="/entry/131222"> TYMP </a>
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</td>
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<span class="mim-font">
<a href="/entry/131222"> 131222 </a>
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</tr>
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</table>
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &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>
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<p>A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-6 (MTDPS6), also known as Navajo neurohepatopathy (NNH), is caused by homozygous or compound heterozygous mutation in the MPV17 gene (<a href="/entry/137960">137960</a>) on chromosome 2p23.</p><p>Biallelic mutations in the MPV17 gene can also caused CMT2EE (<a href="/entry/618400">618400</a>), a much less severe disorder.</p>
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<strong>Description</strong>
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<p>Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, and psychomotor regression (<a href="#10" class="mim-tip-reference" title="Spinazzola, A., Santer, R., Akman, O. H., Tsiakas, K., Schaefer, H., Ding, X., Karadimas, C. L., Shanske, S., Ganesh, J., Di Mauro, S., Zeviani, M. &lt;strong&gt;Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.&lt;/strong&gt; Arch. Neurol. 65: 1108-1113, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18695062/&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;18695062&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.65.8.1108&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="18695062">Spinazzola et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18695062" 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 autosomal recessive mtDNA depletion syndromes, see MTDPS1 (<a href="/entry/603041">603041</a>).</p>
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<strong>Clinical Features</strong>
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<p><a href="#1" class="mim-tip-reference" title="Appenzeller, O., Kornfeld, M., Snyder, R. &lt;strong&gt;Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children.&lt;/strong&gt; Arch. Neurol. 33: 733-738, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/185990/&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;185990&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1976.00500110001001&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="185990">Appenzeller et al. (1976)</a> described 4 Navajo children with a mutilating neuropathy with severe motor involvement. The disorder appeared to be recessively inherited and was present from a very early age. Manifestations included severe anesthesia leading to corneal ulceration, painless fractures, and acral mutilation; muscle weakness; absent or markedly decreased deep tendon reflexes; and normal IQ. Sural nerve biopsy showed nearly complete absence of myelinated fibers without evidence of regeneration, and degenerative unmyelinated fibers with evidence of regeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=185990" 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="Snyder, R. D., Appenzeller, O., Johnson, P. C., Ferry, P. C., Capin, D. M., Singleton, R., Johnsen, S. D., Orrison, W. &lt;strong&gt;Infantile onset and late central white matter lesions in Navajo neuropathy. (Abstract)&lt;/strong&gt; Ann. Neurol. 24: 327 only, 1988."None>Snyder et al. (1988)</a> reported 4 children with Navajo neuropathy, including 1 previously reported by <a href="#1" class="mim-tip-reference" title="Appenzeller, O., Kornfeld, M., Snyder, R. &lt;strong&gt;Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children.&lt;/strong&gt; Arch. Neurol. 33: 733-738, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/185990/&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;185990&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1976.00500110001001&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="185990">Appenzeller et al. (1976)</a>, and extended the clinical spectrum to include progressive central nervous system white matter abnormalities with spinal cord atrophy in older children and onset during early infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=185990" 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="Singleton, R., Helgerson, S. D., Snyder, R. D., O&#x27;Conner, P. J., Nelson, S., Johnsen, S. D., Allanson, J. E. &lt;strong&gt;Neuropathy in Navajo children: clinical and epidemiologic features.&lt;/strong&gt; Neurology 40: 363-367, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2300261/&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;2300261&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.40.2.363&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="2300261">Singleton et al. (1990)</a> performed a major epidemiologic survey of Navajo neuropathy, identifying 20 definite and 4 possible cases from a review of reservation hospital records and a questionnaire directed to all health providers on the Navajo reservation. The 24 cases identified came from 13 families, with 6 families having more than 1 affected child. Clinical features included sensorimotor neuropathy, corneal ulcerations, acral mutilation, poor weight gain, short stature, serious systemic infections, sexual infantilism, and liver disease. The liver disease presented as hepatomegaly, persistent neonatal jaundice, and even a Reye-like syndrome of acute hepatic failure. Brain imaging showed progressive CNS white matter lesions. Diagnosis was usually at the end of the first year of life or in the beginning of the second year, either because of neurologic symptoms or liver disease. The mean age of death was approximately 10 years, frequently due to liver disease. The incidence of this syndrome on the Western Navajo reservation was 5 times higher than on the Eastern reservations (38 compared to 7 cases per 100,000 births). <a href="#8" class="mim-tip-reference" title="Singleton, R., Helgerson, S. D., Snyder, R. D., O&#x27;Conner, P. J., Nelson, S., Johnsen, S. D., Allanson, J. E. &lt;strong&gt;Neuropathy in Navajo children: clinical and epidemiologic features.&lt;/strong&gt; Neurology 40: 363-367, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2300261/&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;2300261&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.40.2.363&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="2300261">Singleton et al. (1990)</a> suggested an inborn error of metabolism, inherited in an autosomal recessive pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2300261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of 20 children with Navajo neuropathy, <a href="#5" class="mim-tip-reference" title="Holve, S., Hu, D., Shub, M., Tyson, R. W., Sokol, R. J. &lt;strong&gt;Liver disease in Navajo neuropathy.&lt;/strong&gt; J. Pediat. 135: 482-493, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10518083/&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;10518083&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(99)70172-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10518083">Holve et al. (1999)</a> found that all had liver disease. Three phenotypes were observed, based on age at presentation and disease course: 5 patients had onset before 6 months of age with jaundice and failure to thrive followed by progression to liver failure before 2 years of age; 6 children had onset between 1 and 5 years of age with liver dysfunction progressing to liver failure and death within 6 months; and 9 children had variable onset of liver disease, but progressive neurologic deterioration. Liver histologic findings included multinucleated giant cells, macrovesicular and microvesicular steatosis, pseudo-acini, inflammation, cholestasis, and bridging fibrosis and cirrhosis. Cases of all 3 phenotypes occurred within the same kindred. <a href="#5" class="mim-tip-reference" title="Holve, S., Hu, D., Shub, M., Tyson, R. W., Sokol, R. J. &lt;strong&gt;Liver disease in Navajo neuropathy.&lt;/strong&gt; J. Pediat. 135: 482-493, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10518083/&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;10518083&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(99)70172-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10518083">Holve et al. (1999)</a> emphasized that liver disease is an important component of Navajo neuropathy and may be the predominant feature in infants and young children. They proposed changing the name of the disorder to Navajo neurohepatopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Erickson, R. P. &lt;strong&gt;Southwestern Athabaskan (Navajo and Apache) genetic diseases.&lt;/strong&gt; Genet. Med. 1: 151-157, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11258351/&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;11258351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00125817-199905000-00007&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="11258351">Erickson (1999)</a> reviewed genetic diseases among the Navajo population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D&#x27;Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M. &lt;strong&gt;MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.&lt;/strong&gt; Nature Genet. 38: 570-575, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16582910/&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;16582910&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1765&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="16582910">Spinazzola et al. (2006)</a> studied 3 families with the hepatocerebral form of mtDNA depletion syndrome caused by MPV17 mutations. In a multigeneration family originating from southern Italy, 2 children died of liver failure during the first year of life, but liver transplantation at 1 year of age in another child and dietary control of hypoglycemia in a fourth were effective in maintaining relative metabolic compensation and long-term survival. However, growth in the surviving children, who were 4 and 9 years old at the time of report, remained below the fifth percentile and the older child had developed neurologic symptoms and multiple brain lesions documented by MRI. The probands of the other 2 families died of liver failure in the first months after birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16582910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Spinazzola, A., Santer, R., Akman, O. H., Tsiakas, K., Schaefer, H., Ding, X., Karadimas, C. L., Shanske, S., Ganesh, J., Di Mauro, S., Zeviani, M. &lt;strong&gt;Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.&lt;/strong&gt; Arch. Neurol. 65: 1108-1113, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18695062/&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;18695062&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.65.8.1108&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="18695062">Spinazzola et al. (2008)</a> reported 2 sisters, born of Iraqi consanguineous parents, with a hepatocerebral form of MTDPS confirmed by genetic analysis (<a href="/entry/137960#0005">137960.0005</a>). The family history was positive for 2 miscarriages. At age 2 months, the older sister developed jaundice and hepatomegaly associated with clinical liver failure that progressed rapidly over the next few months. Initial MRI at age 3 months was normal but later showed edema of the white matter. She developed dystonic movements and deteriorating neurologic status and died from liver failure at age 11 months. The younger sister showed hypotonia and died of rapidly progressive liver failure at age 5 months. A third unrelated girl, conceived by artificial insemination because of a history of endometriosis in the mother, cried immediately after birth, fed poorly, and was jittery. At age 2 weeks, she was lethargic and had abnormal liver function tests. Brain MRI showed bilateral subdural hemorrhages with an area of periventricular leukomalacia in the right parietal region. Physical examination at age 5 months showed poor growth, hypotonia, roving eye movements, and nystagmus. She died of liver failure at 9 months of age. Genetic analysis showed compound heterozygosity for 2 mutations in the MPV17 gene (<a href="/entry/137960#0006">137960.0006</a>; <a href="/entry/137960#0007">137960.0007</a>). <a href="#10" class="mim-tip-reference" title="Spinazzola, A., Santer, R., Akman, O. H., Tsiakas, K., Schaefer, H., Ding, X., Karadimas, C. L., Shanske, S., Ganesh, J., Di Mauro, S., Zeviani, M. &lt;strong&gt;Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.&lt;/strong&gt; Arch. Neurol. 65: 1108-1113, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18695062/&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;18695062&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.65.8.1108&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="18695062">Spinazzola et al. (2008)</a> concluded that MPV17 mutations are associated with rapidly progressive infantile hepatic failure with subsequent neurologic involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18695062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="El-Hattab, A. W., Wang, J., Dai, H., Almannai, M., Staufner, C., Alfadhel, M., Gambello, M. J., Prasun, P., Raza, S., Lyons, H. J., Afqi, M., Saleh, M. A. M., and 11 others. &lt;strong&gt;MPV17-related mitochondrial DNA maintenance defect: new cases and review of clinical, biochemical, and molecular aspects.&lt;/strong&gt; Hum. Mutat. 39: 461-40, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29282788/&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;29282788&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.23387&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="29282788">El-Hattab et al. (2018)</a> reviewed 75 individuals with biallelic MPV17 mutations and added 25 newly described patients. The vast majority of patients presented with an early-onset encephalohepatic disease consistent with MTDPS6. Patients had failure to thrive, lactic acidemia, and mtDNA depletion, mainly in liver tissue. Hepatic abnormalities included elevated liver enzymes, jaundice, hyperbilirubinemia, cholestasis, steatosis, hepatomegaly, and frank liver failure. Neurologic abnormalities included hypotonia, developmental delay, and neurologic deterioration later in childhood. Common, but not universal, features included feeding difficulties, seizures, microcephaly, and sensorimotor peripheral neuropathy. Less common features (in less than 10% of patients) included dystonia, ataxia, retinopathy, corneal ulcerations, nystagmus, renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Brain imaging showed diffuse white matter abnormalities consistent with leukodystrophy or hypomyelination, but many had normal scans. The prognosis was very poor: most patients (about 75%) died in the first decade of liver or multiorgan failure. Four of the 100 patients presented with later onset of a neuromyopathic disease with little or no liver involvement (see CMT2EE; <a href="/entry/618400">618400</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29282788" 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>Navajo Familial Neurogenic Arthropathy</em></strong></p><p>
<a href="#6" class="mim-tip-reference" title="Johnsen, S. D., Johnson, P. C., Stein, S. R. &lt;strong&gt;Familial sensory autonomic neuropathy with arthropathy in Navajo children.&lt;/strong&gt; Neurology 43: 1120-1125, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8170555/&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;8170555&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.43.6.1120&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="8170555">Johnsen et al. (1993)</a> reported 8 Navajo children with a disorder that they termed 'Navajo familial neurogenic arthropathy,' which was characterized by Charcot joints (neurogenic arthropathy) and unrecognized fractures, but with intact reflexes and normal strength. The sensory examination was variable: many had no discernible sensory deficit, whereas others had subtle deficiency in deep pain sensation, temperature discrimination, and corneal sensitivity. Nerve conduction velocities were normal, but sural nerve biopsy showed a marked reduction in small myelinated and unmyelinated nerve fibers. The 8 patients were distributed in 3 families in a pattern consistent with autosomal recessive inheritance. <a href="#6" class="mim-tip-reference" title="Johnsen, S. D., Johnson, P. C., Stein, S. R. &lt;strong&gt;Familial sensory autonomic neuropathy with arthropathy in Navajo children.&lt;/strong&gt; Neurology 43: 1120-1125, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8170555/&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;8170555&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.43.6.1120&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="8170555">Johnsen et al. (1993)</a> concluded that the disorder was distinct from that described by <a href="#1" class="mim-tip-reference" title="Appenzeller, O., Kornfeld, M., Snyder, R. &lt;strong&gt;Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children.&lt;/strong&gt; Arch. Neurol. 33: 733-738, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/185990/&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;185990&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1976.00500110001001&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="185990">Appenzeller et al. (1976)</a> as an acromutilating sensory neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=185990+8170555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Confounding Phenotypes</em></strong></p><p>
<a href="#2" class="mim-tip-reference" title="Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J. &lt;strong&gt;Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.&lt;/strong&gt; Neurology 70: 2343-2344, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18541889/&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;18541889&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000314731.65875.5c&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="18541889">Ebermann et al. (2008)</a> reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy, including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene, <a href="#2" class="mim-tip-reference" title="Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J. &lt;strong&gt;Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.&lt;/strong&gt; Neurology 70: 2343-2344, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18541889/&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;18541889&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000314731.65875.5c&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="18541889">Ebermann et al. (2008)</a> postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (<a href="/entry/610860">610860</a>), consistent with glycogen storage disease III (GSD3; <a href="/entry/232400">232400</a>), and a homozygous mutation in the SCN9A gene (<a href="/entry/603415">603415</a>), consistent with congenital insensitivity to pain (CIPA; <a href="/entry/243000">243000</a>). His sister had the AGL mutation and GSD3 only. <a href="#2" class="mim-tip-reference" title="Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J. &lt;strong&gt;Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.&lt;/strong&gt; Neurology 70: 2343-2344, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18541889/&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;18541889&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000314731.65875.5c&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="18541889">Ebermann et al. (2008)</a> emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18541889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The clinical, pathologic, and biochemical features seen in patients with NNH resembles those in patients with mtDNA depletion syndrome, suggesting that abnormal regulation of mtDNA copy number may be the primary defect in NNH (<a href="#13" class="mim-tip-reference" title="Vu, T. H., Tanji, K., Holve, S. A., Bonilla, E., Sokol, R. J., Snyder, R. D., Fiore, S., Deutsch, G. H., DiMauro, S., De Vivo, D. &lt;strong&gt;Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?&lt;/strong&gt; Hepatology 34: 116-120, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11431741/&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;11431741&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1053/jhep.2001.25921&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="11431741">Vu et al., 2001</a>). Homozygosity mapping of 2 families with NNH suggested linkage to chromosome 2p24 (<a href="#7" class="mim-tip-reference" title="Karadimas, C. L., Vu, T. H., Holve, S. A., Chronopoulou, P., Quinzii, C., Johnsen, S. D., Kurth, J., Eggers, E., Palenzuela, L., Tanji, K., Bonilla, E., De Vivo, D. C., DiMauro, S., Hitano, M. &lt;strong&gt;Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.&lt;/strong&gt; Am. J. Hum. Genet. 79: 544-548, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16909392/&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;16909392&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/506913&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="16909392">Karadimas et al., 2006</a>). This locus includes the MPV17 gene, which, when mutated, was known to cause hepatocerebral mtDNA depletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431741+16909392" 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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<div class="mim-changed mim-change"><p>The transmission pattern of MTDPS6 in the families reported by <a href="#11" class="mim-tip-reference" title="Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D&#x27;Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M. &lt;strong&gt;MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.&lt;/strong&gt; Nature Genet. 38: 570-575, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16582910/&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;16582910&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1765&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="16582910">Spinazzola et al. (2006)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16582910" 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></div>
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<p>In affected members of an Italian and Moroccan family with the hepatocerebral form of mtDNA depletion syndrome, <a href="#11" class="mim-tip-reference" title="Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D&#x27;Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M. &lt;strong&gt;MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.&lt;/strong&gt; Nature Genet. 38: 570-575, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16582910/&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;16582910&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1765&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="16582910">Spinazzola et al. (2006)</a> identified homozygous mutations in the MPV17 gene (<a href="/entry/137960#0001">137960.0001</a>-<a href="/entry/137960#0002">137960.0002</a>). An affected proband from a Canadian family was found to be compound heterozygous for 2 MPV17 mutations (<a href="/entry/137960#0003">137960.0003</a> and <a href="/entry/137960#0004">137960.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16582910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Karadimas, C. L., Vu, T. H., Holve, S. A., Chronopoulou, P., Quinzii, C., Johnsen, S. D., Kurth, J., Eggers, E., Palenzuela, L., Tanji, K., Bonilla, E., De Vivo, D. C., DiMauro, S., Hitano, M. &lt;strong&gt;Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.&lt;/strong&gt; Am. J. Hum. Genet. 79: 544-548, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16909392/&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;16909392&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/506913&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="16909392">Karadimas et al. (2006)</a> sequenced the MPV17 gene in 6 patients with Navajo neurohepatopathy from 5 families and found the homozygous arg50-to-gln mutation previously described in a southern Italian family (<a href="/entry/137960#0001">137960.0001</a>) with hepatocerebral mtDNA depletion syndrome (<a href="#11" class="mim-tip-reference" title="Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D&#x27;Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M. &lt;strong&gt;MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.&lt;/strong&gt; Nature Genet. 38: 570-575, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16582910/&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;16582910&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1765&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="16582910">Spinazzola et al., 2006</a>). Identification of a single missense mutation in patients with NNH confirmed that the disease is probably due to a founder effect, and extended the phenotypic spectrum associated with MPV17 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16582910+16909392" 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="mimGenotypePhenotypeCorrelationsToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<p>In a large review of 100 patients, <a href="#3" class="mim-tip-reference" title="El-Hattab, A. W., Wang, J., Dai, H., Almannai, M., Staufner, C., Alfadhel, M., Gambello, M. J., Prasun, P., Raza, S., Lyons, H. J., Afqi, M., Saleh, M. A. M., and 11 others. &lt;strong&gt;MPV17-related mitochondrial DNA maintenance defect: new cases and review of clinical, biochemical, and molecular aspects.&lt;/strong&gt; Hum. Mutat. 39: 461-40, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29282788/&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;29282788&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.23387&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="29282788">El-Hattab et al. (2018)</a> found that about half of the pathogenic MPV17 variants were missense, but other types of mutations (nonsense, frameshift, in-frame deletions, splice site) occurred throughout the gene. In general, those with biallelic missense mutations tended to have a less severe phenotype, in particular those with homozygous R50Q (<a href="/entry/137960#0001">137960.0001</a>), P98L (<a href="/entry/137960#0008">137960.0008</a>), or R41Q (<a href="/entry/137960#0009">137960.0009</a>) mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29282788" 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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<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>In an Mpv17-knockout mouse model, <a href="#12" class="mim-tip-reference" title="Viscomi, C., Spinazzola, A., Maggioni, M., Fernandez-Vizarra, E., Massa, V., Pagano, C., Vettor, R., Mora, M., Zeviani, M. &lt;strong&gt;Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.&lt;/strong&gt; Hum. Molec. Genet. 18: 12-26, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18818194/&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;18818194&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18818194[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/hmg/ddn309&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="18818194">Viscomi et al. (2009)</a> found severe mtDNA depletion in liver and skeletal muscle, whereas hardly any depletion was detected in brain and kidney. Mouse embryonic fibroblasts only showed mtDNA depletion after several culturing passages or in serum-free medium. In spite of severe mtDNA depletion, only moderate decreases in respiratory chain enzymatic activities and mild cytoarchitectural alterations were observed in Mpv17 -/- livers, but neither cirrhosis nor failure ever occurred. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensation for the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf (<a href="/entry/602318">602318</a>), a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear, and kidney. The coat of the Mpv17 -/- mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter life span. Coincidental with the onset of FSGS, minimal mtDNA was measurable in glomerular tufts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18818194" 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="references"class="mim-anchor"></a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Appenzeller1976" class="mim-anchor"></a>
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Appenzeller, O., Kornfeld, M., Snyder, R.
<strong>Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children.</strong>
Arch. Neurol. 33: 733-738, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/185990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">185990</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=185990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.1976.00500110001001" target="_blank">Full Text</a>]
</p>
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<a id="2" class="mim-anchor"></a>
<a id="Ebermann2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J.
<strong>Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.</strong>
Neurology 70: 2343-2344, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541889</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18541889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000314731.65875.5c" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="El-Hattab2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
El-Hattab, A. W., Wang, J., Dai, H., Almannai, M., Staufner, C., Alfadhel, M., Gambello, M. J., Prasun, P., Raza, S., Lyons, H. J., Afqi, M., Saleh, M. A. M., and 11 others.
<strong>MPV17-related mitochondrial DNA maintenance defect: new cases and review of clinical, biochemical, and molecular aspects.</strong>
Hum. Mutat. 39: 461-40, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29282788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29282788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29282788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.23387" target="_blank">Full Text</a>]
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<a id="Erickson1999" class="mim-anchor"></a>
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Erickson, R. P.
<strong>Southwestern Athabaskan (Navajo and Apache) genetic diseases.</strong>
Genet. Med. 1: 151-157, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11258351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11258351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/00125817-199905000-00007" target="_blank">Full Text</a>]
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<a id="Holve1999" class="mim-anchor"></a>
<div class="">
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Holve, S., Hu, D., Shub, M., Tyson, R. W., Sokol, R. J.
<strong>Liver disease in Navajo neuropathy.</strong>
J. Pediat. 135: 482-493, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518083</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518083" 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/s0022-3476(99)70172-1" target="_blank">Full Text</a>]
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<a id="Johnsen1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Johnsen, S. D., Johnson, P. C., Stein, S. R.
<strong>Familial sensory autonomic neuropathy with arthropathy in Navajo children.</strong>
Neurology 43: 1120-1125, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8170555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8170555</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8170555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.43.6.1120" target="_blank">Full Text</a>]
</p>
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<a id="7" class="mim-anchor"></a>
<a id="Karadimas2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Karadimas, C. L., Vu, T. H., Holve, S. A., Chronopoulou, P., Quinzii, C., Johnsen, S. D., Kurth, J., Eggers, E., Palenzuela, L., Tanji, K., Bonilla, E., De Vivo, D. C., DiMauro, S., Hitano, M.
<strong>Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.</strong>
Am. J. Hum. Genet. 79: 544-548, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909392</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16909392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/506913" target="_blank">Full Text</a>]
</p>
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<a id="Singleton1990" class="mim-anchor"></a>
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Singleton, R., Helgerson, S. D., Snyder, R. D., O'Conner, P. J., Nelson, S., Johnsen, S. D., Allanson, J. E.
<strong>Neuropathy in Navajo children: clinical and epidemiologic features.</strong>
Neurology 40: 363-367, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2300261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2300261</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2300261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.40.2.363" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Snyder1988" class="mim-anchor"></a>
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<p class="mim-text-font">
Snyder, R. D., Appenzeller, O., Johnson, P. C., Ferry, P. C., Capin, D. M., Singleton, R., Johnsen, S. D., Orrison, W.
<strong>Infantile onset and late central white matter lesions in Navajo neuropathy. (Abstract)</strong>
Ann. Neurol. 24: 327 only, 1988.
</p>
</div>
</li>
<li>
<a id="10" class="mim-anchor"></a>
<a id="Spinazzola2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Spinazzola, A., Santer, R., Akman, O. H., Tsiakas, K., Schaefer, H., Ding, X., Karadimas, C. L., Shanske, S., Ganesh, J., Di Mauro, S., Zeviani, M.
<strong>Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.</strong>
Arch. Neurol. 65: 1108-1113, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18695062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18695062</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18695062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archneur.65.8.1108" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Spinazzola2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D'Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M.
<strong>MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.</strong>
Nature Genet. 38: 570-575, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16582910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16582910</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16582910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1765" target="_blank">Full Text</a>]
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<a id="Viscomi2009" class="mim-anchor"></a>
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<p class="mim-text-font">
Viscomi, C., Spinazzola, A., Maggioni, M., Fernandez-Vizarra, E., Massa, V., Pagano, C., Vettor, R., Mora, M., Zeviani, M.
<strong>Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.</strong>
Hum. Molec. Genet. 18: 12-26, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18818194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18818194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18818194[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=18818194" 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/hmg/ddn309" target="_blank">Full Text</a>]
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<a id="Vu2001" class="mim-anchor"></a>
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Vu, T. H., Tanji, K., Holve, S. A., Bonilla, E., Sokol, R. J., Snyder, R. D., Fiore, S., Deutsch, G. H., DiMauro, S., De Vivo, D.
<strong>Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?</strong>
Hepatology 34: 116-120, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431741</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1053/jhep.2001.25921" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 04/24/2019
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Cassandra L. Kniffin - updated : 12/9/2010<br>Cassandra L. Kniffin - updated : 10/8/2008<br>Victor A. McKusick - updated : 8/23/2006<br>Cassandra L. Kniffin - reorganized : 5/24/2004<br>Cassandra L. Kniffin - updated : 5/17/2004<br>Victor A. McKusick - updated : 9/15/1999
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Victor A. McKusick : 8/28/1987
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carol : 12/10/2024
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carol : 05/14/2019<br>alopez : 04/25/2019<br>ckniffin : 04/24/2019<br>carol : 06/10/2016<br>carol : 6/8/2016<br>carol : 10/16/2012<br>carol : 12/21/2010<br>carol : 12/20/2010<br>ckniffin : 12/9/2010<br>wwang : 10/15/2008<br>ckniffin : 10/8/2008<br>alopez : 8/25/2006<br>terry : 8/23/2006<br>carol : 5/24/2004<br>ckniffin : 5/17/2004<br>joanna : 3/19/2004<br>carol : 9/20/1999<br>mgross : 9/20/1999<br>terry : 9/15/1999<br>mimadm : 3/11/1994<br>carol : 9/8/1993<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988
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<strong>#</strong> 256810
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<span class="mim-font">
MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE); MTDPS6
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<em>Alternative titles; symbols</em>
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NAVAJO NEUROHEPATOPATHY; NNH<br />
NAVAJO NEUROPATHY; NN
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Other entities represented in this entry:
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NAVAJO FAMILIAL NEUROGENIC ARTHROPATHY, INCLUDED
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<strong>SNOMEDCT:</strong> 784346006; &nbsp;
<strong>ORPHA:</strong> 255229; &nbsp;
<strong>DO:</strong> 0080125; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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2p23.3
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Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
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256810
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Autosomal recessive
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3
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MPV17
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137960
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-6 (MTDPS6), also known as Navajo neurohepatopathy (NNH), is caused by homozygous or compound heterozygous mutation in the MPV17 gene (137960) on chromosome 2p23.</p><p>Biallelic mutations in the MPV17 gene can also caused CMT2EE (618400), a much less severe disorder.</p>
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<strong>Description</strong>
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<p>Mitochondrial DNA depletion syndrome-6 is an autosomal recessive disorder characterized by infantile onset of progressive liver failure, often leading to death in the first year of life. Those that survive develop progressive neurologic involvement, including ataxia, hypotonia, dystonia, and psychomotor regression (Spinazzola et al., 2008). </p><p>For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).</p>
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<strong>Clinical Features</strong>
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<p>Appenzeller et al. (1976) described 4 Navajo children with a mutilating neuropathy with severe motor involvement. The disorder appeared to be recessively inherited and was present from a very early age. Manifestations included severe anesthesia leading to corneal ulceration, painless fractures, and acral mutilation; muscle weakness; absent or markedly decreased deep tendon reflexes; and normal IQ. Sural nerve biopsy showed nearly complete absence of myelinated fibers without evidence of regeneration, and degenerative unmyelinated fibers with evidence of regeneration. </p><p>Snyder et al. (1988) reported 4 children with Navajo neuropathy, including 1 previously reported by Appenzeller et al. (1976), and extended the clinical spectrum to include progressive central nervous system white matter abnormalities with spinal cord atrophy in older children and onset during early infancy. </p><p>Singleton et al. (1990) performed a major epidemiologic survey of Navajo neuropathy, identifying 20 definite and 4 possible cases from a review of reservation hospital records and a questionnaire directed to all health providers on the Navajo reservation. The 24 cases identified came from 13 families, with 6 families having more than 1 affected child. Clinical features included sensorimotor neuropathy, corneal ulcerations, acral mutilation, poor weight gain, short stature, serious systemic infections, sexual infantilism, and liver disease. The liver disease presented as hepatomegaly, persistent neonatal jaundice, and even a Reye-like syndrome of acute hepatic failure. Brain imaging showed progressive CNS white matter lesions. Diagnosis was usually at the end of the first year of life or in the beginning of the second year, either because of neurologic symptoms or liver disease. The mean age of death was approximately 10 years, frequently due to liver disease. The incidence of this syndrome on the Western Navajo reservation was 5 times higher than on the Eastern reservations (38 compared to 7 cases per 100,000 births). Singleton et al. (1990) suggested an inborn error of metabolism, inherited in an autosomal recessive pattern. </p><p>In a review of 20 children with Navajo neuropathy, Holve et al. (1999) found that all had liver disease. Three phenotypes were observed, based on age at presentation and disease course: 5 patients had onset before 6 months of age with jaundice and failure to thrive followed by progression to liver failure before 2 years of age; 6 children had onset between 1 and 5 years of age with liver dysfunction progressing to liver failure and death within 6 months; and 9 children had variable onset of liver disease, but progressive neurologic deterioration. Liver histologic findings included multinucleated giant cells, macrovesicular and microvesicular steatosis, pseudo-acini, inflammation, cholestasis, and bridging fibrosis and cirrhosis. Cases of all 3 phenotypes occurred within the same kindred. Holve et al. (1999) emphasized that liver disease is an important component of Navajo neuropathy and may be the predominant feature in infants and young children. They proposed changing the name of the disorder to Navajo neurohepatopathy. </p><p>Erickson (1999) reviewed genetic diseases among the Navajo population. </p><p>Spinazzola et al. (2006) studied 3 families with the hepatocerebral form of mtDNA depletion syndrome caused by MPV17 mutations. In a multigeneration family originating from southern Italy, 2 children died of liver failure during the first year of life, but liver transplantation at 1 year of age in another child and dietary control of hypoglycemia in a fourth were effective in maintaining relative metabolic compensation and long-term survival. However, growth in the surviving children, who were 4 and 9 years old at the time of report, remained below the fifth percentile and the older child had developed neurologic symptoms and multiple brain lesions documented by MRI. The probands of the other 2 families died of liver failure in the first months after birth. </p><p>Spinazzola et al. (2008) reported 2 sisters, born of Iraqi consanguineous parents, with a hepatocerebral form of MTDPS confirmed by genetic analysis (137960.0005). The family history was positive for 2 miscarriages. At age 2 months, the older sister developed jaundice and hepatomegaly associated with clinical liver failure that progressed rapidly over the next few months. Initial MRI at age 3 months was normal but later showed edema of the white matter. She developed dystonic movements and deteriorating neurologic status and died from liver failure at age 11 months. The younger sister showed hypotonia and died of rapidly progressive liver failure at age 5 months. A third unrelated girl, conceived by artificial insemination because of a history of endometriosis in the mother, cried immediately after birth, fed poorly, and was jittery. At age 2 weeks, she was lethargic and had abnormal liver function tests. Brain MRI showed bilateral subdural hemorrhages with an area of periventricular leukomalacia in the right parietal region. Physical examination at age 5 months showed poor growth, hypotonia, roving eye movements, and nystagmus. She died of liver failure at 9 months of age. Genetic analysis showed compound heterozygosity for 2 mutations in the MPV17 gene (137960.0006; 137960.0007). Spinazzola et al. (2008) concluded that MPV17 mutations are associated with rapidly progressive infantile hepatic failure with subsequent neurologic involvement. </p><p>El-Hattab et al. (2018) reviewed 75 individuals with biallelic MPV17 mutations and added 25 newly described patients. The vast majority of patients presented with an early-onset encephalohepatic disease consistent with MTDPS6. Patients had failure to thrive, lactic acidemia, and mtDNA depletion, mainly in liver tissue. Hepatic abnormalities included elevated liver enzymes, jaundice, hyperbilirubinemia, cholestasis, steatosis, hepatomegaly, and frank liver failure. Neurologic abnormalities included hypotonia, developmental delay, and neurologic deterioration later in childhood. Common, but not universal, features included feeding difficulties, seizures, microcephaly, and sensorimotor peripheral neuropathy. Less common features (in less than 10% of patients) included dystonia, ataxia, retinopathy, corneal ulcerations, nystagmus, renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Brain imaging showed diffuse white matter abnormalities consistent with leukodystrophy or hypomyelination, but many had normal scans. The prognosis was very poor: most patients (about 75%) died in the first decade of liver or multiorgan failure. Four of the 100 patients presented with later onset of a neuromyopathic disease with little or no liver involvement (see CMT2EE; 618400). </p><p><strong><em>Navajo Familial Neurogenic Arthropathy</em></strong></p><p>
Johnsen et al. (1993) reported 8 Navajo children with a disorder that they termed 'Navajo familial neurogenic arthropathy,' which was characterized by Charcot joints (neurogenic arthropathy) and unrecognized fractures, but with intact reflexes and normal strength. The sensory examination was variable: many had no discernible sensory deficit, whereas others had subtle deficiency in deep pain sensation, temperature discrimination, and corneal sensitivity. Nerve conduction velocities were normal, but sural nerve biopsy showed a marked reduction in small myelinated and unmyelinated nerve fibers. The 8 patients were distributed in 3 families in a pattern consistent with autosomal recessive inheritance. Johnsen et al. (1993) concluded that the disorder was distinct from that described by Appenzeller et al. (1976) as an acromutilating sensory neuropathy. </p>
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<strong>Diagnosis</strong>
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<p><strong><em>Confounding Phenotypes</em></strong></p><p>
Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy, including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene, Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (610860), consistent with glycogen storage disease III (GSD3; 232400), and a homozygous mutation in the SCN9A gene (603415), consistent with congenital insensitivity to pain (CIPA; 243000). His sister had the AGL mutation and GSD3 only. Ebermann et al. (2008) emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling. </p>
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<strong>Mapping</strong>
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<p>The clinical, pathologic, and biochemical features seen in patients with NNH resembles those in patients with mtDNA depletion syndrome, suggesting that abnormal regulation of mtDNA copy number may be the primary defect in NNH (Vu et al., 2001). Homozygosity mapping of 2 families with NNH suggested linkage to chromosome 2p24 (Karadimas et al., 2006). This locus includes the MPV17 gene, which, when mutated, was known to cause hepatocerebral mtDNA depletion syndrome. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of MTDPS6 in the families reported by Spinazzola et al. (2006) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>In affected members of an Italian and Moroccan family with the hepatocerebral form of mtDNA depletion syndrome, Spinazzola et al. (2006) identified homozygous mutations in the MPV17 gene (137960.0001-137960.0002). An affected proband from a Canadian family was found to be compound heterozygous for 2 MPV17 mutations (137960.0003 and 137960.0004). </p><p>Karadimas et al. (2006) sequenced the MPV17 gene in 6 patients with Navajo neurohepatopathy from 5 families and found the homozygous arg50-to-gln mutation previously described in a southern Italian family (137960.0001) with hepatocerebral mtDNA depletion syndrome (Spinazzola et al., 2006). Identification of a single missense mutation in patients with NNH confirmed that the disease is probably due to a founder effect, and extended the phenotypic spectrum associated with MPV17 mutations. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>In a large review of 100 patients, El-Hattab et al. (2018) found that about half of the pathogenic MPV17 variants were missense, but other types of mutations (nonsense, frameshift, in-frame deletions, splice site) occurred throughout the gene. In general, those with biallelic missense mutations tended to have a less severe phenotype, in particular those with homozygous R50Q (137960.0001), P98L (137960.0008), or R41Q (137960.0009) mutations. </p>
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<strong>Animal Model</strong>
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<p>In an Mpv17-knockout mouse model, Viscomi et al. (2009) found severe mtDNA depletion in liver and skeletal muscle, whereas hardly any depletion was detected in brain and kidney. Mouse embryonic fibroblasts only showed mtDNA depletion after several culturing passages or in serum-free medium. In spite of severe mtDNA depletion, only moderate decreases in respiratory chain enzymatic activities and mild cytoarchitectural alterations were observed in Mpv17 -/- livers, but neither cirrhosis nor failure ever occurred. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensation for the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf (602318), a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear, and kidney. The coat of the Mpv17 -/- mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter life span. Coincidental with the onset of FSGS, minimal mtDNA was measurable in glomerular tufts. </p>
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<strong>REFERENCES</strong>
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<p class="mim-text-font">
Appenzeller, O., Kornfeld, M., Snyder, R.
<strong>Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children.</strong>
Arch. Neurol. 33: 733-738, 1976.
[PubMed: 185990]
[Full Text: https://doi.org/10.1001/archneur.1976.00500110001001]
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Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J.
<strong>Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.</strong>
Neurology 70: 2343-2344, 2008.
[PubMed: 18541889]
[Full Text: https://doi.org/10.1212/01.wnl.0000314731.65875.5c]
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El-Hattab, A. W., Wang, J., Dai, H., Almannai, M., Staufner, C., Alfadhel, M., Gambello, M. J., Prasun, P., Raza, S., Lyons, H. J., Afqi, M., Saleh, M. A. M., and 11 others.
<strong>MPV17-related mitochondrial DNA maintenance defect: new cases and review of clinical, biochemical, and molecular aspects.</strong>
Hum. Mutat. 39: 461-40, 2018.
[PubMed: 29282788]
[Full Text: https://doi.org/10.1002/humu.23387]
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Erickson, R. P.
<strong>Southwestern Athabaskan (Navajo and Apache) genetic diseases.</strong>
Genet. Med. 1: 151-157, 1999.
[PubMed: 11258351]
[Full Text: https://doi.org/10.1097/00125817-199905000-00007]
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<p class="mim-text-font">
Holve, S., Hu, D., Shub, M., Tyson, R. W., Sokol, R. J.
<strong>Liver disease in Navajo neuropathy.</strong>
J. Pediat. 135: 482-493, 1999.
[PubMed: 10518083]
[Full Text: https://doi.org/10.1016/s0022-3476(99)70172-1]
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Johnsen, S. D., Johnson, P. C., Stein, S. R.
<strong>Familial sensory autonomic neuropathy with arthropathy in Navajo children.</strong>
Neurology 43: 1120-1125, 1993.
[PubMed: 8170555]
[Full Text: https://doi.org/10.1212/wnl.43.6.1120]
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Karadimas, C. L., Vu, T. H., Holve, S. A., Chronopoulou, P., Quinzii, C., Johnsen, S. D., Kurth, J., Eggers, E., Palenzuela, L., Tanji, K., Bonilla, E., De Vivo, D. C., DiMauro, S., Hitano, M.
<strong>Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.</strong>
Am. J. Hum. Genet. 79: 544-548, 2006.
[PubMed: 16909392]
[Full Text: https://doi.org/10.1086/506913]
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<p class="mim-text-font">
Singleton, R., Helgerson, S. D., Snyder, R. D., O'Conner, P. J., Nelson, S., Johnsen, S. D., Allanson, J. E.
<strong>Neuropathy in Navajo children: clinical and epidemiologic features.</strong>
Neurology 40: 363-367, 1990.
[PubMed: 2300261]
[Full Text: https://doi.org/10.1212/wnl.40.2.363]
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<p class="mim-text-font">
Snyder, R. D., Appenzeller, O., Johnson, P. C., Ferry, P. C., Capin, D. M., Singleton, R., Johnsen, S. D., Orrison, W.
<strong>Infantile onset and late central white matter lesions in Navajo neuropathy. (Abstract)</strong>
Ann. Neurol. 24: 327 only, 1988.
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Spinazzola, A., Santer, R., Akman, O. H., Tsiakas, K., Schaefer, H., Ding, X., Karadimas, C. L., Shanske, S., Ganesh, J., Di Mauro, S., Zeviani, M.
<strong>Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations.</strong>
Arch. Neurol. 65: 1108-1113, 2008.
[PubMed: 18695062]
[Full Text: https://doi.org/10.1001/archneur.65.8.1108]
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<li>
<p class="mim-text-font">
Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D'Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., Zeviani, M.
<strong>MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.</strong>
Nature Genet. 38: 570-575, 2006.
[PubMed: 16582910]
[Full Text: https://doi.org/10.1038/ng1765]
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Viscomi, C., Spinazzola, A., Maggioni, M., Fernandez-Vizarra, E., Massa, V., Pagano, C., Vettor, R., Mora, M., Zeviani, M.
<strong>Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice.</strong>
Hum. Molec. Genet. 18: 12-26, 2009.
[PubMed: 18818194]
[Full Text: https://doi.org/10.1093/hmg/ddn309]
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Vu, T. H., Tanji, K., Holve, S. A., Bonilla, E., Sokol, R. J., Snyder, R. D., Fiore, S., Deutsch, G. H., DiMauro, S., De Vivo, D.
<strong>Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?</strong>
Hepatology 34: 116-120, 2001.
[PubMed: 11431741]
[Full Text: https://doi.org/10.1053/jhep.2001.25921]
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Cassandra L. Kniffin - updated : 04/24/2019<br>Cassandra L. Kniffin - updated : 12/9/2010<br>Cassandra L. Kniffin - updated : 10/8/2008<br>Victor A. McKusick - updated : 8/23/2006<br>Cassandra L. Kniffin - reorganized : 5/24/2004<br>Cassandra L. Kniffin - updated : 5/17/2004<br>Victor A. McKusick - updated : 9/15/1999
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