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<title>
Entry
- #203700 - MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE); MTDPS4A
- OMIM
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<span class="h4">#203700</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/203700"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS603041"> <strong>Phenotypic Series</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="#biochemicalFeatures">Biochemical Features</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="#heterogeneity">Heterogeneity</a>
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<div><a href="https://clinicaltrials.gov/search?cond=MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS 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=1730&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/NBK26471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">POLG-Related Disorders</a></div><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>
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<div><a href="https://medlineplus.gov/genetics/condition/alpers-huttenlocher-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=726" 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/7a763204-56c5-43ec-8b70-9d5fa273ce91/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:0080122" 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/203700" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0080122" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:203700" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 20415001<br />
<strong>ICD10CM:</strong> G31.81<br />
<strong>ORPHA:</strong> 726<br />
<strong>DO:</strong> 0080122<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>
203700
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE); MTDPS4A
</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">
ALPERS DIFFUSE DEGENERATION OF CEREBRAL GRAY MATTER WITH HEPATIC CIRRHOSIS<br />
ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY<br />
ALPERS SYNDROME<br />
ALPERS-HUTTENLOCHER SYNDROME<br />
NEURONAL DEGENERATION OF CHILDHOOD WITH LIVER DISEASE, PROGRESSIVE; PNDC
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/498?start=-3&limit=10&highlight=498">
15q26.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Mitochondrial DNA depletion syndrome 4A (Alpers type)
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/203700"> 203700 </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">
POLG
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/174763"> 174763 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/203700" 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/203700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/203700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Visual disturbances <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63102001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63102001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/131182003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">131182003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H53.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H53.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H53" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H53</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">368</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/368.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">368.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0547030&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0547030</a>]</span><br /> -
Loss of vision <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246635007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246635007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H54.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H54.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/369.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">369.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3665346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665346</a>, <a href="https://bioportal.bioontology.org/search?q=C3665386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665386</a>, <a href="https://bioportal.bioontology.org/search?q=C0042798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042798</a>, <a href="https://bioportal.bioontology.org/search?q=C0456909&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0456909</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000618" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000618</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000572" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000572</a>]</span><br /> -
Cortical blindness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413924001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413924001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68574006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68574006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.61</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.75" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.75</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0155320&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0155320</a>, <a href="https://bioportal.bioontology.org/search?q=C4048268&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4048268</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span><br /> -
Abnormal visual evoked potential (VEP) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859869&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859869</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/102968003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">102968003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R94.112" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R94.112</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/794.13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">794.13</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000649" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000649</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">
- Liver failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59927004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59927004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K72.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K72.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001399" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001399</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001399" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001399</a>]</span><br /> -
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 /> -
Biopsy shows microvesicular steatosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859866&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859866</a>]</span><br /> -
Hepatocyte dropout <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859867&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859867</a>]</span><br /> -
Micronodular cirrhosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21861000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21861000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0267812&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0267812</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001413" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001413</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001413" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001413</a>]</span><br /> -
Abnormal bile duct architecture <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859868&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859868</a>]</span><br /> -
Bile duct proliferation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20239009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20239009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0267818&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0267818</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001408" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001408</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001408" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001408</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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Decreased mitochondrial respiratory chain complex activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150112&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150112</a>]</span><br /> -
Mitochondrial DNA depletion <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237995002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237995002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342782&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342782</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
Psychomotor regression, episodic, often associated with common childhood infections <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859861&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859861</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span><br /> -
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 /> -
Hypertonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56731001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56731001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/41581000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">41581000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026826&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026826</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001276</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001276</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 /> -
Seizures, sudden-onset, drug-resistant <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859862&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859862</a>]</span><br /> -
Status epilepticus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230456007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230456007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038220&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038220</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002133</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002133</a>]</span><br /> -
Epilepsia partialis continua <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/241006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">241006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G40.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G40.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/345.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">345.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085543&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085543</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012847" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012847</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012847" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012847</a>]</span><br /> -
Myoclonus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17450006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17450006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/333.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">333.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027066&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027066</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span><br /> -
Paralysis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44695005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44695005</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/344.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">344.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0522224&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0522224</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003470</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003470</a>]</span><br /> -
Dementia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011265</a>, <a href="https://bioportal.bioontology.org/search?q=C0497327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
Cerebral cortical neurodegeneration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859863&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859863</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006964" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006964</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006964" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006964</a>]</span><br /> -
Cerebellar atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0740279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0740279</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span><br /> -
Neuronal loss <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850496&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850496</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002529" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002529</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002529" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002529</a>]</span><br /> -
Astrocytosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81415000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81415000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887640&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887640</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002446" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002446</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002446" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002446</a>]</span><br /> -
Gliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/359580009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">359580009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81415000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81415000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887640&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887640</a>, <a href="https://bioportal.bioontology.org/search?q=C0017639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017639</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002171</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002446" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002446</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002171</a>]</span><br /> -
Pseudolaminar spongiform changes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859864&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859864</a>]</span><br /> -
EEG shows slow frequency high amplitude waves with high frequency polyspikes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1859865&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1859865</a>]</span><br />
</span>
</div>
</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 function tests <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/863927004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">863927004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0877359&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0877359</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 CSF protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1806780&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1806780</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002922</a>]</span><br /> -
Decreased DNA polymerase-gamma (POLG, <a href="/entry/174763">174763</a>) activity<br /> -
Increased serum lactate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5888306&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5888306</a>, <a href="https://bioportal.bioontology.org/search?q=C1836440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002151</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002151</a>]</span><br /> -
Intermittent 3-methylglutaconic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150113&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150113</a>]</span><br /> -
Intermittent ethylmalonic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150114&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150114</a>]</span><br /> -
Intermittent dicarbonic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150115&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150115</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset in infancy after normal birth and neonatal period<br /> -
Rapidly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838681&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838681</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003678" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003678</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003678" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003678</a>]</span><br /> -
Death usually by age 3 years<br /> -
Later onset (late childhood to young adult) has been reported<br /> -
Increased sensitivity to valproic acid toxicity<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 nuclear-encoded mitochondrial DNA polymerase-gamma gene (POLG, <a href="/entry/174763#0008">174763.0008</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>
</td>
<td>
<span class="mim-font">
<a href="/entry/188250"> TK2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/188250"> 188250 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/413?start=-3&limit=10&highlight=413"> 17q12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619780"> Mitochondrial DNA depletion syndrome 20 (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/619780"> 619780 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600940"> LIG3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600940"> 600940 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/857?start=-3&limit=10&highlight=857"> 17q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619425"> ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic 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/619425"> 619425 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604983"> POLG2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604983"> 604983 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/857?start=-3&limit=10&highlight=857"> 17q23.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618528"> ?Mitochondrial DNA depletion syndrome 16 (hepatic 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/618528"> 618528 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604983"> POLG2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604983"> 604983 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/1040?start=-3&limit=10&highlight=1040"> 17q25.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618972"> ?Mitochondrial DNA depletion syndrome 19 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618972"> 618972 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606794"> SLC25A10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606794"> 606794 </a>
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<a href="/geneMap/20/118?start=-3&limit=10&highlight=118"> 20p11.23 </a>
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<a href="/entry/615084"> Mitochondrial DNA depletion syndrome 11 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/615084"> 615084 </a>
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<a href="/entry/615076"> MGME1 </a>
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<a href="/entry/615076"> 615076 </a>
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<a href="/geneMap/22/417?start=-3&limit=10&highlight=417"> 22q13.33 </a>
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<a href="/entry/603041"> Mitochondrial DNA depletion syndrome 1 (MNGIE type) </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/603041"> 603041 </a>
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<a href="/entry/131222"> TYMP </a>
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<a href="/entry/131222"> 131222 </a>
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<p>A number sign (#) is used with this entry because mitochondrial DNA (mtDNA) depletion syndrome-4A (MTDPS4A), which manifests as Alpers syndrome, is caused by homozygous or compound heterozygous mutation in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG; <a href="/entry/174763">174763</a>) on chromosome 15q26.</p>
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<p>Mitochondrial DNA depletion syndrome-4A (MTDPS4A), also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. The disorder is progressive and often leads to death from hepatic failure or status epilepticus before age 3 years (review by <a href="#19" class="mim-tip-reference" title="Milone, M., Massie, R. &lt;strong&gt;Polymerase gamma 1 mutations: clinical correlations.&lt;/strong&gt; Neurologist 16: 84-91, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20220442/&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;20220442&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/NRL.0b013e3181c78a89&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="20220442">Milone and Massie, 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20220442" 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>Some affected individuals may show mild intermittent 3-methylglutaconic aciduria and defects in mitochondrial oxidative phosphorylation (<a href="#29" class="mim-tip-reference" title="Wortmann, S. B., Rodenburg, R. J. T., Jonckheere, A., de Vries, M. C., Huizing, M., Heldt, K., van den Heuvel, L. P., Wendel, U., Kluijtmans, L. A., Engelke, U. F., Wevers, R. A., Smeitink, J. A. M., Morava, E. &lt;strong&gt;Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy.&lt;/strong&gt; Brain 132: 136-146, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19015156/&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;19015156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awn296&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="19015156">Wortmann et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19015156" 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><p>Neuropathologic changes characteristic of Alpers syndrome, namely laminar cortical necrosis, may also be seen in some patients with combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>), caused by mutation in the FARS2 gene (<a href="/entry/611592">611592</a>), and COXPD24 (<a href="/entry/616239">616239</a>), caused by mutation in the NARS2 gene (<a href="/entry/612803">612803</a>).</p>
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<p>Bernard <a href="#2" class="mim-tip-reference" title="Alpers, B. J. &lt;strong&gt;Diffuse progressive degeneration of gray matter of cerebrum.&lt;/strong&gt; Arch. Neurol. Psychiat. 25: 469-505, 1931."None>Alpers (1931)</a> described the neuropathology and clinical features in a 4-month-old girl with a one-month illness characterized by intractable generalized seizures. He termed the disorder 'diffuse progressive degeneration of the gray matter of the cerebrum.' <a href="#20" class="mim-tip-reference" title="Morse, W. I. &lt;strong&gt;Hereditary myoclonus epilepsy: two cases with pathological findings.&lt;/strong&gt; Bull. Johns Hopkins Hosp. 84: 116-134, 1949.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18128978/&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;18128978&lt;/a&gt;]" pmid="18128978">Morse (1949)</a> reported a brother and sister with hereditary myoclonus epilepsy who were later reported by <a href="#9" class="mim-tip-reference" title="Ford, F. R., Livingston, S., Pryles, C. V. &lt;strong&gt;Familial degeneration of the cerebral gray matter in childhood with convulsions, myoclonus, spasticity, cerebral ataxia, choreoathetosis, dementia, and death in status epilepticus. Differentiation of infantile and juvenile types.&lt;/strong&gt; J. Pediat. 39: 33-43, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14851183/&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;14851183&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(51)80278-6&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="14851183">Ford et al. (1951)</a> as having from 'familial degeneration of the cerebral gray matter in childhood,' similar to the cases of <a href="#2" class="mim-tip-reference" title="Alpers, B. J. &lt;strong&gt;Diffuse progressive degeneration of gray matter of cerebrum.&lt;/strong&gt; Arch. Neurol. Psychiat. 25: 469-505, 1931."None>Alpers (1931)</a>. Familial cases were also reported by <a href="#25" class="mim-tip-reference" title="Palinsky, M., Kozinn, P. J., Zahtz, H. &lt;strong&gt;Acute familial infantile heredodegenerative disorder of the central nervous system.&lt;/strong&gt; J. Pediat. 45: 538-545, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13212595/&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;13212595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(54)80116-8&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="13212595">Palinsky et al. (1954)</a> and <a href="#5" class="mim-tip-reference" title="Christensen, E., Hojgaard, K. &lt;strong&gt;Poliodystrophia cerebri progressiva infantilis.&lt;/strong&gt; Acta Neurol. Scand. 40: 21-40, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14108415/&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;14108415&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-0404.1964.tb04263.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14108415">Christensen and Hojgaard (1964)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14108415+18128978+14851183+13212595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Alberca-Serrano, R., Fabiani, F., Deneve, V., Macken, J. &lt;strong&gt;Familial spastic diplegia due to anoxic encephalopathy (Alpers). A contribution to the study of vascular fragilities of the nervous system of genetic type.&lt;/strong&gt; J. Neurol. Sci. 2: 419-433, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5878525/&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;5878525&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(65)90118-8&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="5878525">Alberca-Serrano et al. (1965)</a> reported a family in which 4 of 6 sibs were affected with spastic diplegia due to anoxic encephalopathy, which they termed 'Alpers' syndrome. The parents were unrelated. Several relatives of the father may have had the same disorder. All affected members had reacted to infections with violent convulsions. The authors suggested that this represented a familial susceptibility and that the cerebral damage was secondary to anoxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5878525" 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="Blackwood, W., Buxton, P. H., Cumings, J. N., Robertson, D. J., Tucker, S. M. &lt;strong&gt;Diffuse cerebral degeneration in infancy (Alpers&#x27; disease).&lt;/strong&gt; Arch. Dis. Child. 38: 193-204, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13971413/&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;13971413&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.38.199.193&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="13971413">Blackwood et al. (1963)</a> described 2 sibs in whom diffuse cerebral degeneration (Alpers disease) was associated with cirrhosis of the liver. <a href="#27" class="mim-tip-reference" title="Wefring, K. W., Lamvik, J. O. &lt;strong&gt;Familial progressive poliodystrophy with cirrhosis of the liver.&lt;/strong&gt; Acta Paediat. Scand. 56: 295-300, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6033104/&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;6033104&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1651-2227.1967.tb15380.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6033104">Wefring and Lamvik (1967)</a> described brother and sister who developed convulsions at ages 11 and 14 months, followed by progressive hypotonia, dementia, and jaundice 4 and 2 weeks before death at the ages of 15 and 20 months. In addition to the typical findings of Alpers disease, the liver showed extensive atrophy with fibrosis, inflammation and bile duct proliferation. The diagnosis was made at autopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13971413+6033104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Sandbank, U., Lerman, P. &lt;strong&gt;Progressive cerebral poliodystrophy--Alpers&#x27; disease: disorganized giant neuronal mitochondria on electron microscopy.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 35: 749-755, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4647849/&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;4647849&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.35.6.749&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="4647849">Sandbank and Lerman (1972)</a> reported 3 sibs with Alpers disease, characterized by progressive mental retardation, seizures, rigidity, and degeneration of the cerebral cortex. Neuropathologic examination showed disorganization of the cerebral cortex with neuronal loss and astroglial proliferation. There were abnormal mitochondria of variable sizes, some with electron dense inclusions. The authors suggested autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4647849" 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="#16" class="mim-tip-reference" title="Huttenlocher, P. R., Solitare, G. B., Adams, G. &lt;strong&gt;Infantile diffuse cerebral degeneration with hepatic cirrhosis.&lt;/strong&gt; Arch. Neurol. 33: 186-192, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1252162/&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;1252162&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1976.00500030042009&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="1252162">Huttenlocher et al. (1976)</a> reported 2 sibships with 2 affected children in each. Clinical features included early onset (average 2 years) of delayed motor development, vomiting, multifocal seizures, status epilepticus, stupor, hypotonia, paralysis, increased CSF protein, and later onset of hepatic disease. Intermittent unexplained fever occurred frequently. None of the children survived beyond age 3 years. Pathologic examination showed degeneration of the cerebral gray matter with loss of neurons and reactive astrocytosis in the brain and fatty accumulation and cirrhosis in the liver. The authors rejected the idea of anoxic encephalopathy and suggested that the syndrome was a familial disorder with autosomal recessive inheritance. <a href="#16" class="mim-tip-reference" title="Huttenlocher, P. R., Solitare, G. B., Adams, G. &lt;strong&gt;Infantile diffuse cerebral degeneration with hepatic cirrhosis.&lt;/strong&gt; Arch. Neurol. 33: 186-192, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1252162/&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;1252162&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1976.00500030042009&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="1252162">Huttenlocher et al. (1976)</a> noted that hepatic involvement was absent in some cases reported earlier, including the case reported by <a href="#2" class="mim-tip-reference" title="Alpers, B. J. &lt;strong&gt;Diffuse progressive degeneration of gray matter of cerebrum.&lt;/strong&gt; Arch. Neurol. Psychiat. 25: 469-505, 1931."None>Alpers (1931)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1252162" 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="#15" class="mim-tip-reference" title="Harding, B. N. &lt;strong&gt;Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review.&lt;/strong&gt; J. Child Neurol. 5: 273-287, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2246481/&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;2246481&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389000500402&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="2246481">Harding (1990)</a> reviewed the clinical, neurologic, electrophysiologic, and histopathologic features of Alpers syndrome in 32 patients. Birth was usually normal, with some developmental delay in infancy, often with hypotonia and bouts of vomiting. The seizure disorder usually had an abrupt onset and although clinical signs of liver disease often appeared later, biochemical evidence of liver disease was sometimes present before the onset of seizures. EEG and visual evoked potentials were abnormal. Most patients died before the age of 3 years. Less frequently, late presentation occurred, even up to 25 years of age. Some patients also had visual disturbances. Liver pathologic findings, including fatty changes, abnormal bile duct architecture, and fibrosis, were unrelated to anticonvulsant therapy. Neuropathology showed severe cortical neurodegeneration and astrocytosis. In 12 of the 26 families in their series, 2 or 3 sibs were affected, including one pair of twins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246481" 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="Frydman, M., Jager-Roman, E., de Vries, L., Stoltenburg-Didinger, G., Nussinovitch, M., Sirota, L. &lt;strong&gt;Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome.&lt;/strong&gt; Am. J. Med. Genet. 47: 31-36, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8368248/&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;8368248&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470107&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="8368248">Frydman et al. (1993)</a> reported the cases of 8 patients from 2 families. Onset in the first family was prenatal; in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity, were found. The second family presented with an early infantile form. All of the affected offspring had micrognathia and 1 had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all of the infants died before age 20 months. Comprehensive biochemical and metabolic studies in both families yielded normal results, and the diagnosis was supported by demonstration of extensive progressive brain atrophy on computerized tomography and typical histologic findings; for example, the parietal cortex showed spongy state with focally accentuated severe loss of neurons. The cerebellar cortex showed severe loss of almost all granular cells and persistent Purkinje cells. Anomalies of dendritic arborization were also seen. Both families were of Israeli Arab ethnicity and the parents were first cousins in both cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8368248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Harding, B. N., Alsanjari, N., Smith, S. J. M., Wiles, C. M., Thrush, D., Miller, D. H., Scaravilli, F., Harding, A. E. &lt;strong&gt;Progressive neuronal degeneration of childhood with liver disease (Alpers&#x27; disease) presenting in young adults.&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 58: 320-325, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7897414/&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;7897414&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.58.3.320&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="7897414">Harding et al. (1995)</a> reported the unusual cases of 2 unrelated girls, aged 17 and 18, with a progressive encephalopathy, visual signs and symptoms, multiple types of drug-resistant seizures, and liver failure. Brain imaging showed lesions in the occipital lobe, and EEG showed slow waves with polyspikes. Both patients had a rapid degenerative course and died within 8 months of onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7897414" 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="De Vries, M. C, Rodenburg, R. J., Morava, E., van Kaauwen, E. P. M., ter Laak, H., Mullaart, R. A., Snoeck I. N., van Hasselt, P. M., Harding, P., van den Heuvel, L. P. W., Smeitink, J. A. M. &lt;strong&gt;Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.&lt;/strong&gt; Europ. J. Pediat. 166: 229-234, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16957900/&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;16957900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00431-006-0234-9&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="16957900">De Vries et al. (2007)</a> reported 3 unrelated patients with Alpers syndrome due to POLG mutations. Age at onset was 4 to 8 months, and all died by 17 months of age. All showed severe failure to thrive, developmental retardation, hypotonia, seizures, and liver insufficiency. Two had delayed cerebral myelination and 1 had cerebral atrophy. Urinary amino acids showed different patterns, including intermediates of the tricarboxylic acid cycle, 3-methylglutaconic aciduria, ethylmalonic aciduria, dicarbonic aciduria and high lactate levels. All 3 patients also had significant decreases in ATP production, consistent with a defect in mitochondrial oxidative phosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16957900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Wiltshire, E., Davidzon, G., DiMauro, S., Akman, H. O., Sadleir, L., Haas, L., Zuccollo, J., McEwen, A., Thorburn, D. R. &lt;strong&gt;Juvenile Alpers disease.&lt;/strong&gt; Arch. Neurol. 65: 121-124, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18195149/&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;18195149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2007.14&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="18195149">Wiltshire et al. (2008)</a> reported a 17-year-old girl who presented with intractable epilepsy and recent onset of mild clumsiness. Developmental milestones, intelligence, vision, and hearing were otherwise normal. During the next 2 months, she had repeated admissions for status epilepticus or encephalopathy, and showed stepwise neurologic deterioration with memory impairment, slurred speech, and hemiparesis. Treatment with a variety of anticonvulsant agents coincided with progressive liver deterioration. MRI findings were initially normal but showed progressive abnormality with increased signal on T2-weighted images in the cortical and subcortical white matter and basal ganglia. She died at age 17 years, 9 months, of respiratory failure secondary to her neurologic condition. Genetic analysis identified compound heterozygous mutations in the POLG gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18195149" 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>Among 136 children with a variety of severe neurologic defects, <a href="#17" class="mim-tip-reference" title="Isohanni, P., Hakonen, A. H., Euro, L., Paetau, I., Linnankivi, T., Liukkonen, E., Wallden, T., Luostarinen, L., Valanne, L., Paetau, A., Uusimaa, J., Lonnqvist, T., Suomalainen, A., Pihko, H. &lt;strong&gt;POLG1 manifestations in childhood.&lt;/strong&gt; Neurology 76: 811-815, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21357833/&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;21357833&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31820e7b25&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="21357833">Isohanni et al. (2011)</a> identified 7 patients from 6 families with compound heterozygous POLG mutations. Disease onset was acute or subacute, often with preceding infection. All had a severe encephalopathic phenotype with intractable epilepsy and liver involvement, except 1 patient who did not have liver involvement. All those exposed to valproate developed fatal liver toxicity. <a href="#17" class="mim-tip-reference" title="Isohanni, P., Hakonen, A. H., Euro, L., Paetau, I., Linnankivi, T., Liukkonen, E., Wallden, T., Luostarinen, L., Valanne, L., Paetau, A., Uusimaa, J., Lonnqvist, T., Suomalainen, A., Pihko, H. &lt;strong&gt;POLG1 manifestations in childhood.&lt;/strong&gt; Neurology 76: 811-815, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21357833/&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;21357833&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0b013e31820e7b25&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="21357833">Isohanni et al. (2011)</a> concluded that although POLG mutations are not a common cause of isolated epilepsy or ataxia in childhood, the POLG gene should be studied in children with a progressive epileptic encephalopathy with liver involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21357833" 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>Clinical Variability</em></strong></p><p>
<a href="#18" class="mim-tip-reference" title="Kurt, B., Jaeken, J., Van Hove, J., Lagae, L., Lofgren, A., Everman, D. B., Jayakar, P., Naini, A., Wierenga, K. J., Van Goethem, G., Copeland, W. C., DiMauro, S. &lt;strong&gt;A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes.&lt;/strong&gt; Arch. Neurol. 67: 239-244, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142534/&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;20142534&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20142534[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/10.1001/archneurol.2009.332&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="20142534">Kurt et al. (2010)</a> reported 4 patients with a POLG-related hepatocerebral disorder with psychomotor delay, seizures, and liver disease, most consistent with Alpers syndrome. An unrelated girl and boy were compound heterozygous for the P1073L (<a href="/entry/174763#0022">174763.0022</a>) and A467T (<a href="/entry/174763#0002">174763.0002</a>) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; <a href="/entry/613662">613662</a>). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for P1073L and W748S (<a href="/entry/174763#0013">174763.0013</a>) and G848S (<a href="/entry/174763#0006">174763.0006</a>), respectively. One child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. <a href="#18" class="mim-tip-reference" title="Kurt, B., Jaeken, J., Van Hove, J., Lagae, L., Lofgren, A., Everman, D. B., Jayakar, P., Naini, A., Wierenga, K. J., Van Goethem, G., Copeland, W. C., DiMauro, S. &lt;strong&gt;A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes.&lt;/strong&gt; Arch. Neurol. 67: 239-244, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142534/&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;20142534&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20142534[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/10.1001/archneurol.2009.332&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="20142534">Kurt et al. (2010)</a> emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the 4 children had gastrointestinal dysmotility, suggesting that the P1073L mutation may be associated with that particular feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142534" 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>Cases with a disturbance in pyruvate metabolism and NADH oxidation (Gabreels et al. (<a href="#11" class="mim-tip-reference" title="Gabreels, F. J. M., Prick, M. J. J., Renier, W. O., Willems, J. L., Trijbels, J. M. F., Ter Laak, H. J., Jaspar, H. H. J., Slooff, J. L., Van Haelst, U. J. G. M., Sengers, R. C. A. &lt;strong&gt;Progressive infantile poliodystrophy (Alpers&#x27; disease) associated with disturbed NADH oxidation, lipid myopathy and abnormal muscle mitochondria. In: Busch, H. F. M.; Jennekens, F. G. I.; Scholte, H. R.: Mitochondria and Muscular Diseases.&lt;/strong&gt; Beetsterzwaag, The Netherlands: Mefar (pub.) 1981. Pp. 165-171."None>1981</a>, <a href="#12" class="mim-tip-reference" title="Gabreels, F. J., Prick, M. J., Trijbels, J. M., Renier, W. O., Jaspar, H. H., Janssen, A. J., Slooff, J. L. &lt;strong&gt;Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy.&lt;/strong&gt; Acta Neurol. Scand. 70: 145-154, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6439001/&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;6439001&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-0404.1984.tb00813.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6439001">1984</a>)) have been described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6439001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with mtDNA depletion and Alpers syndrome, <a href="#23" class="mim-tip-reference" title="Naviaux, R. K., Nyhan, W. L., Barshop, B. A., Poulton, J., Markusic, D., Karpinski, N. C., Haas, R. H. &lt;strong&gt;Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers&#x27; syndrome.&lt;/strong&gt; Ann. Neurol. 45: 54-58, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9894877/&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;9894877&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1531-8249(199901)45:1&lt;54::aid-art10&gt;3.0.co;2-b&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="9894877">Naviaux et al. (1999)</a> found global reduction in respiratory chain complex I, II/III, and IV activity and deficiency of mitochondrial DNA polymerase gamma activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9894877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Gauthier-Villars, M., Landrieu, P., Cormier-Daire, V., Jacquemin, E., Chretien, D., Rotig, A., Rustin, P., Munnich, A., de Lonlay, P. &lt;strong&gt;Respiratory chain deficiency in Alpers syndrome.&lt;/strong&gt; Neuropediatrics 32: 150-152, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11521212/&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;11521212&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2001-16614&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="11521212">Gauthier-Villars et al. (2001)</a> confirmed the mitochondrial respiratory chain abnormalities in the liver of 4 unrelated patients with Alpers syndrome. One patient had a complex I deficiency, another a complex IV deficiency, and 2 had a combined deficiency of complexes I and IV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11521212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#21" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. &lt;strong&gt;POLG mutations associated with Alpers&#x27; syndrome and mitochondrial DNA depletion.&lt;/strong&gt; Ann. Neurol. 55: 706-712, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15122711/&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;15122711&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20079&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="15122711">Naviaux and Nguyen (2004)</a> demonstrated autosomal recessive inheritance of mitochondrial DNA depletion syndrome-4A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><a href="#21" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. &lt;strong&gt;POLG mutations associated with Alpers&#x27; syndrome and mitochondrial DNA depletion.&lt;/strong&gt; Ann. Neurol. 55: 706-712, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15122711/&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;15122711&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20079&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="15122711">Naviaux and Nguyen (2004)</a> reported 3 patients with Alpers syndrome who were homozygous for a mutation (E873X; <a href="/entry/174763#0008">174763.0008</a>) in the POLG gene. They later published a correction (<a href="#22" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. &lt;strong&gt;POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter)&lt;/strong&gt; Ann. Neurol. 58: 491 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16130100/&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;16130100&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20544&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="16130100">Naviaux and Nguyen, 2005</a>) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (<a href="/entry/174763#0002">174763.0002</a>). <a href="#22" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. &lt;strong&gt;POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter)&lt;/strong&gt; Ann. Neurol. 58: 491 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16130100/&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;16130100&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20544&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="16130100">Naviaux and Nguyen (2005)</a> stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. The clinical features of the family had been described by <a href="#23" class="mim-tip-reference" title="Naviaux, R. K., Nyhan, W. L., Barshop, B. A., Poulton, J., Markusic, D., Karpinski, N. C., Haas, R. H. &lt;strong&gt;Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers&#x27; syndrome.&lt;/strong&gt; Ann. Neurol. 45: 54-58, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9894877/&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;9894877&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1531-8249(199901)45:1&lt;54::aid-art10&gt;3.0.co;2-b&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="9894877">Naviaux et al. (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15122711+16130100+9894877" 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 4 patients with Alpers syndrome, <a href="#6" class="mim-tip-reference" title="Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H. L., Kirby, D., Thorburn, D. R., DiMauro, S. &lt;strong&gt;POLG mutations and Alpers syndrome.&lt;/strong&gt; Ann. Neurol. 57: 921-924, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15929042/&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;15929042&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.20498&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="15929042">Davidzon et al. (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene (<a href="/entry/174763#0006">174763.0006</a> and <a href="/entry/174763#0013">174763.0013</a>). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929042" 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="Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R., Zeviani, M. &lt;strong&gt;Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gamma A.&lt;/strong&gt; Brain 128: 723-731, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15689359/&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;15689359&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awh410&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="15689359">Ferrari et al. (2005)</a> identified mutations in the POLG gene in 8 patients with Alpers syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689359" 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="genotypePhenotypeCorrelations" class="mim-anchor"></a>
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<strong>Genotype/Phenotype Correlations</strong>
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<p><a href="#24" class="mim-tip-reference" title="Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K. &lt;strong&gt;POLG mutations in Alpers syndrome.&lt;/strong&gt; Neurology 65: 1493-1495, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16177225/&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;16177225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000182814.55361.70&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="16177225">Nguyen et al. (2005)</a> reported a child with Alpers syndrome who was homozygous for the A467T mutation in the POLG gene (<a href="/entry/174763#0002">174763.0002</a>). Unlike other children with the disorder, he showed late onset at age 8.5 years and death by age 9 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177225" 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 study of the cellular phenotype derived from 24 children with biallelic POLG mutations, 21 of whom had a clinical diagnosis of Alpers syndrome, <a href="#3" class="mim-tip-reference" title="Ashley, N., O&#x27;Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G. K., Fratter, C., Poulton, J. &lt;strong&gt;Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.&lt;/strong&gt; Hum. Molec. Genet. 17: 2496-2506, 2008. Note: Erratum: Hum. Molec. Genet. 18: 4905-4906, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18487244/&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;18487244&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18487244[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/ddn150&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="18487244">Ashley et al. (2008)</a> found that the cellular mtDNA content reflected the genotype. Those with mtDNA depletion in the liver and/or muscle had at least 1 missense or nonsense mutation in a catalytic domain, either the polymerase or exonuclease region. Four of 10 patients analyzed in detail showed a progressive, mosaic pattern of mtDNA depletion in fibroblasts, and all had biallelic mutations in POLG catalytic domains. These patients had a severe clinical phenotype with early onset before 1 year of age, hepatic involvement, and death by 16 months of age. Their cells showed respiratory chain defects. Patients with 2 mutations in the linker region of the gene did not show mtDNA depletion and had the mildest phenotype with onset in childhood or adolescence and little liver involvement. The study also found that the average mtDNA content declined with serial passage in cell culture in patients with mtDNA depletion, which <a href="#3" class="mim-tip-reference" title="Ashley, N., O&#x27;Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G. K., Fratter, C., Poulton, J. &lt;strong&gt;Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.&lt;/strong&gt; Hum. Molec. Genet. 17: 2496-2506, 2008. Note: Erratum: Hum. Molec. Genet. 18: 4905-4906, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18487244/&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;18487244&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18487244[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/ddn150&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="18487244">Ashley et al. (2008)</a> postulated was a result of mtDNA replication stalling, indicating the requirement for both catalytic actions of POLG in mitochondrial replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18487244" 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="heterogeneity" class="mim-anchor"></a>
<h4 href="#mimHeterogeneityFold" id="mimHeterogeneityToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Heterogeneity</strong>
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<p><strong><em>Genetic Heterogeneity</em></strong></p><p>
<a href="#29" class="mim-tip-reference" title="Wortmann, S. B., Rodenburg, R. J. T., Jonckheere, A., de Vries, M. C., Huizing, M., Heldt, K., van den Heuvel, L. P., Wendel, U., Kluijtmans, L. A., Engelke, U. F., Wevers, R. A., Smeitink, J. A. M., Morava, E. &lt;strong&gt;Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy.&lt;/strong&gt; Brain 132: 136-146, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19015156/&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;19015156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awn296&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="19015156">Wortmann et al. (2009)</a> reported 3 unrelated patients, 2 of Dutch and 1 of German origin, with mild intermittent 3-methylglutaconic aciduria associated with a hepatocerebral syndrome. The first patient had subepidermal hemorrhage and bilateral mild periventricular leukomalacia at birth. At age 3.5 months, she had epilepsy, hypertonia, and delayed psychomotor development. From age 2 years, she had unexplained encephalopathic periods with atonia, apneas, and stupor. Brain MRI showed mild periventricular leukomalacia, irregularly widened ventricles, gracile corpus callosum, and partial pachygyria. She also had transient elevation of liver enzymes, indicating hepatic involvement. She died of cardiorespiratory failure in an encephalopathic state at age 3 years. The second patient was born at 26 weeks' gestation with intrauterine growth retardation. He had an infantile encephalopathy with epilepsy, delayed psychomotor development, hypo- and hyperthermia, resistance to pain, and severe failure to thrive. At age 9 years he had a stroke-like episode with hemiplegia after valproic acid administration. He also had multiorgan failure with liver dysfunction, but recovered. The third patient had severe microcephaly, dysmorphic features, psychomotor retardation, no development, hypotonia, epilepsy, and failure to thrive. She suffered from recurrent episodes of hyperthermia, liver dysfunction, and intractable seizures, and died at the age of 2.5 years. Biochemical studies of all these patients suggested a defect in mitochondrial oxidative phosphorylation. Although a molecular basis for the disorder was not established, <a href="#29" class="mim-tip-reference" title="Wortmann, S. B., Rodenburg, R. J. T., Jonckheere, A., de Vries, M. C., Huizing, M., Heldt, K., van den Heuvel, L. P., Wendel, U., Kluijtmans, L. A., Engelke, U. F., Wevers, R. A., Smeitink, J. A. M., Morava, E. &lt;strong&gt;Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy.&lt;/strong&gt; Brain 132: 136-146, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19015156/&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;19015156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awn296&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="19015156">Wortmann et al. (2009)</a> noted that the patients had a similar phenotype to those reported by <a href="#7" class="mim-tip-reference" title="De Vries, M. C, Rodenburg, R. J., Morava, E., van Kaauwen, E. P. M., ter Laak, H., Mullaart, R. A., Snoeck I. N., van Hasselt, P. M., Harding, P., van den Heuvel, L. P. W., Smeitink, J. A. M. &lt;strong&gt;Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.&lt;/strong&gt; Europ. J. Pediat. 166: 229-234, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16957900/&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;16957900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00431-006-0234-9&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="16957900">De Vries et al. (2007)</a>, who had Alpers syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16957900+19015156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="history" class="mim-anchor"></a>
<h4 href="#mimHistoryFold" id="mimHistoryToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>History</strong>
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<p>As noted by <a href="#15" class="mim-tip-reference" title="Harding, B. N. &lt;strong&gt;Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review.&lt;/strong&gt; J. Child Neurol. 5: 273-287, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2246481/&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;2246481&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389000500402&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="2246481">Harding (1990)</a> in a review of Alpers syndrome, there was much confusion in the past regarding the nosology, pathogenesis, and diagnosis of the disease. Some reported cases seemed to be caused by anoxia at birth or illness, whereas others were familial with normal births. Cerebral damage was also thought to be a result of intractable seizures or hepatic toxicity, and hepatic damage was believed in some cases to be caused by anticonvulsive drugs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1016/0022-510x(65)90118-8" target="_blank">Full Text</a>]
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Alpers, B. J.
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Ashley, N., O'Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G. K., Fratter, C., Poulton, J.
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Blackwood, W., Buxton, P. H., Cumings, J. N., Robertson, D. J., Tucker, S. M.
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[<a href="https://doi.org/10.1136/adc.38.199.193" target="_blank">Full Text</a>]
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Christensen, E., Hojgaard, K.
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[<a href="https://doi.org/10.1111/j.1600-0404.1964.tb04263.x" target="_blank">Full Text</a>]
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<a id="Davidzon2005" class="mim-anchor"></a>
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Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H. L., Kirby, D., Thorburn, D. R., DiMauro, S.
<strong>POLG mutations and Alpers syndrome.</strong>
Ann. Neurol. 57: 921-924, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929042</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929042" 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/ana.20498" target="_blank">Full Text</a>]
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<a id="De Vries2007" class="mim-anchor"></a>
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De Vries, M. C, Rodenburg, R. J., Morava, E., van Kaauwen, E. P. M., ter Laak, H., Mullaart, R. A., Snoeck I. N., van Hasselt, P. M., Harding, P., van den Heuvel, L. P. W., Smeitink, J. A. M.
<strong>Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.</strong>
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[<a href="https://doi.org/10.1007/s00431-006-0234-9" target="_blank">Full Text</a>]
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<a id="Ferrari2005" class="mim-anchor"></a>
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Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R., Zeviani, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689359</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/awh410" target="_blank">Full Text</a>]
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<a id="Ford1951" class="mim-anchor"></a>
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Ford, F. R., Livingston, S., Pryles, C. V.
<strong>Familial degeneration of the cerebral gray matter in childhood with convulsions, myoclonus, spasticity, cerebral ataxia, choreoathetosis, dementia, and death in status epilepticus. Differentiation of infantile and juvenile types.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(51)80278-6" target="_blank">Full Text</a>]
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<a id="Frydman1993" class="mim-anchor"></a>
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Frydman, M., Jager-Roman, E., de Vries, L., Stoltenburg-Didinger, G., Nussinovitch, M., Sirota, L.
<strong>Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320470107" target="_blank">Full Text</a>]
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<a id="Gabreels1981" class="mim-anchor"></a>
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Gabreels, F. J. M., Prick, M. J. J., Renier, W. O., Willems, J. L., Trijbels, J. M. F., Ter Laak, H. J., Jaspar, H. H. J., Slooff, J. L., Van Haelst, U. J. G. M., Sengers, R. C. A.
<strong>Progressive infantile poliodystrophy (Alpers' disease) associated with disturbed NADH oxidation, lipid myopathy and abnormal muscle mitochondria. In: Busch, H. F. M.; Jennekens, F. G. I.; Scholte, H. R.: Mitochondria and Muscular Diseases.</strong>
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<a id="Gabreels1984" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gabreels, F. J., Prick, M. J., Trijbels, J. M., Renier, W. O., Jaspar, H. H., Janssen, A. J., Slooff, J. L.
<strong>Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy.</strong>
Acta Neurol. Scand. 70: 145-154, 1984.
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[<a href="https://doi.org/10.1111/j.1600-0404.1984.tb00813.x" target="_blank">Full Text</a>]
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<a id="Gauthier-Villars2001" class="mim-anchor"></a>
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Gauthier-Villars, M., Landrieu, P., Cormier-Daire, V., Jacquemin, E., Chretien, D., Rotig, A., Rustin, P., Munnich, A., de Lonlay, P.
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[<a href="https://doi.org/10.1055/s-2001-16614" target="_blank">Full Text</a>]
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<a id="Harding1995" class="mim-anchor"></a>
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Harding, B. N., Alsanjari, N., Smith, S. J. M., Wiles, C. M., Thrush, D., Miller, D. H., Scaravilli, F., Harding, A. E.
<strong>Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults.</strong>
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[<a href="https://doi.org/10.1136/jnnp.58.3.320" target="_blank">Full Text</a>]
</p>
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<a id="Harding1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Harding, B. N.
<strong>Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review.</strong>
J. Child Neurol. 5: 273-287, 1990.
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[<a href="https://doi.org/10.1177/088307389000500402" target="_blank">Full Text</a>]
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<a id="Huttenlocher1976" class="mim-anchor"></a>
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<p class="mim-text-font">
Huttenlocher, P. R., Solitare, G. B., Adams, G.
<strong>Infantile diffuse cerebral degeneration with hepatic cirrhosis.</strong>
Arch. Neurol. 33: 186-192, 1976.
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[<a href="https://doi.org/10.1001/archneur.1976.00500030042009" target="_blank">Full Text</a>]
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<a id="Isohanni2011" class="mim-anchor"></a>
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Isohanni, P., Hakonen, A. H., Euro, L., Paetau, I., Linnankivi, T., Liukkonen, E., Wallden, T., Luostarinen, L., Valanne, L., Paetau, A., Uusimaa, J., Lonnqvist, T., Suomalainen, A., Pihko, H.
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[<a href="https://doi.org/10.1212/WNL.0b013e31820e7b25" target="_blank">Full Text</a>]
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<a id="Kurt2010" class="mim-anchor"></a>
<div class="">
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Kurt, B., Jaeken, J., Van Hove, J., Lagae, L., Lofgren, A., Everman, D. B., Jayakar, P., Naini, A., Wierenga, K. J., Van Goethem, G., Copeland, W. C., DiMauro, S.
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Arch. Neurol. 67: 239-244, 2010.
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[<a href="https://doi.org/10.1001/archneurol.2009.332" target="_blank">Full Text</a>]
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<a id="Milone2010" class="mim-anchor"></a>
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Milone, M., Massie, R.
<strong>Polymerase gamma 1 mutations: clinical correlations.</strong>
Neurologist 16: 84-91, 2010.
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[<a href="https://doi.org/10.1097/NRL.0b013e3181c78a89" target="_blank">Full Text</a>]
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<a id="Morse1949" class="mim-anchor"></a>
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<p class="mim-text-font">
Morse, W. I.
<strong>Hereditary myoclonus epilepsy: two cases with pathological findings.</strong>
Bull. Johns Hopkins Hosp. 84: 116-134, 1949.
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<a id="Naviaux2004" class="mim-anchor"></a>
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Naviaux, R. K., Nguyen, K. V.
<strong>POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122711" 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/ana.20079" target="_blank">Full Text</a>]
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<a id="Naviaux2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Naviaux, R. K., Nguyen, K. V.
<strong>POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter)</strong>
Ann. Neurol. 58: 491 only, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130100" 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/ana.20544" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
<a id="Naviaux1999" class="mim-anchor"></a>
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Naviaux, R. K., Nyhan, W. L., Barshop, B. A., Poulton, J., Markusic, D., Karpinski, N. C., Haas, R. H.
<strong>Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome.</strong>
Ann. Neurol. 45: 54-58, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9894877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9894877</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9894877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1531-8249(199901)45:1&lt;54::aid-art10&gt;3.0.co;2-b" target="_blank">Full Text</a>]
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<a id="Nguyen2005" class="mim-anchor"></a>
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Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K.
<strong>POLG mutations in Alpers syndrome.</strong>
Neurology 65: 1493-1495, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177225" 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.0000182814.55361.70" target="_blank">Full Text</a>]
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<a id="25" class="mim-anchor"></a>
<a id="Palinsky1954" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Palinsky, M., Kozinn, P. J., Zahtz, H.
<strong>Acute familial infantile heredodegenerative disorder of the central nervous system.</strong>
J. Pediat. 45: 538-545, 1954.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13212595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13212595</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13212595" 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(54)80116-8" target="_blank">Full Text</a>]
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<a id="Sandbank1972" class="mim-anchor"></a>
<div class="">
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Sandbank, U., Lerman, P.
<strong>Progressive cerebral poliodystrophy--Alpers' disease: disorganized giant neuronal mitochondria on electron microscopy.</strong>
J. Neurol. Neurosurg. Psychiat. 35: 749-755, 1972.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4647849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4647849</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4647849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jnnp.35.6.749" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
<a id="Wefring1967" class="mim-anchor"></a>
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Wefring, K. W., Lamvik, J. O.
<strong>Familial progressive poliodystrophy with cirrhosis of the liver.</strong>
Acta Paediat. Scand. 56: 295-300, 1967.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6033104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6033104</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6033104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1651-2227.1967.tb15380.x" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
<a id="Wiltshire2008" class="mim-anchor"></a>
<div class="">
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Wiltshire, E., Davidzon, G., DiMauro, S., Akman, H. O., Sadleir, L., Haas, L., Zuccollo, J., McEwen, A., Thorburn, D. R.
<strong>Juvenile Alpers disease.</strong>
Arch. Neurol. 65: 121-124, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18195149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18195149</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18195149" 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/archneurol.2007.14" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
<a id="Wortmann2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wortmann, S. B., Rodenburg, R. J. T., Jonckheere, A., de Vries, M. C., Huizing, M., Heldt, K., van den Heuvel, L. P., Wendel, U., Kluijtmans, L. A., Engelke, U. F., Wevers, R. A., Smeitink, J. A. M., Morava, E.
<strong>Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy.</strong>
Brain 132: 136-146, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19015156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19015156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19015156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/brain/awn296" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 2/24/2015
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Cassandra L. Kniffin - updated : 12/3/2012<br>Cassandra L. Kniffin - updated : 4/14/2011<br>Cassandra L. Kniffin - updated : 12/10/2010<br>Cassandra L. Kniffin - updated : 5/11/2010<br>Cassandra L. Kniffin - updated : 3/23/2010<br>Cassandra L. Kniffin - updated : 3/22/2010<br>Cassandra L. Kniffin - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 1/12/2009<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Cassandra L. Kniffin - updated : 10/13/2005<br>Cassandra L. Kniffin - updated : 8/31/2005<br>Cassandra L. Kniffin - reorganized : 8/15/2003<br>Victor A. McKusick - updated : 8/8/2003
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Creation Date:
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Victor A. McKusick : 6/2/1986
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 12/02/2024
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carol : 05/24/2019<br>carol : 09/07/2016<br>carol : 06/08/2016<br>carol : 2/25/2015<br>mcolton : 2/24/2015<br>ckniffin : 2/24/2015<br>carol : 12/3/2012<br>carol : 12/3/2012<br>ckniffin : 12/3/2012<br>terry : 7/5/2012<br>terry : 1/13/2012<br>wwang : 4/29/2011<br>ckniffin : 4/14/2011<br>ckniffin : 1/21/2011<br>carol : 12/21/2010<br>ckniffin : 12/10/2010<br>wwang : 5/14/2010<br>ckniffin : 5/11/2010<br>wwang : 3/26/2010<br>ckniffin : 3/23/2010<br>ckniffin : 3/22/2010<br>wwang : 10/30/2009<br>ckniffin : 8/27/2009<br>wwang : 1/16/2009<br>ckniffin : 1/12/2009<br>wwang : 2/21/2007<br>ckniffin : 2/15/2007<br>carol : 11/15/2005<br>ckniffin : 10/13/2005<br>wwang : 9/6/2005<br>ckniffin : 8/31/2005<br>tkritzer : 8/13/2004<br>ckniffin : 8/4/2004<br>ckniffin : 7/12/2004<br>mgross : 3/17/2004<br>carol : 8/15/2003<br>ckniffin : 8/15/2003<br>carol : 8/8/2003<br>alopez : 6/10/1997<br>mimadm : 11/12/1995<br>terry : 4/21/1994<br>warfield : 3/7/1994<br>carol : 9/1/1993<br>supermim : 3/16/1992<br>supermim : 3/20/1990
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<span class="mim-font">
<strong>#</strong> 203700
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<span class="mim-font">
MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE); MTDPS4A
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
ALPERS DIFFUSE DEGENERATION OF CEREBRAL GRAY MATTER WITH HEPATIC CIRRHOSIS<br />
ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY<br />
ALPERS SYNDROME<br />
ALPERS-HUTTENLOCHER SYNDROME<br />
NEURONAL DEGENERATION OF CHILDHOOD WITH LIVER DISEASE, PROGRESSIVE; PNDC
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<strong>SNOMEDCT:</strong> 20415001; &nbsp;
<strong>ICD10CM:</strong> G31.81; &nbsp;
<strong>ORPHA:</strong> 726; &nbsp;
<strong>DO:</strong> 0080122; &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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<span class="mim-font">
15q26.1
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Mitochondrial DNA depletion syndrome 4A (Alpers type)
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<span class="mim-font">
203700
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Autosomal recessive
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3
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POLG
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174763
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because mitochondrial DNA (mtDNA) depletion syndrome-4A (MTDPS4A), which manifests as Alpers syndrome, is caused by homozygous or compound heterozygous mutation in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG; 174763) on chromosome 15q26.</p>
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<strong>Description</strong>
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<p>Mitochondrial DNA depletion syndrome-4A (MTDPS4A), also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. The disorder is progressive and often leads to death from hepatic failure or status epilepticus before age 3 years (review by Milone and Massie, 2010). </p><p>Some affected individuals may show mild intermittent 3-methylglutaconic aciduria and defects in mitochondrial oxidative phosphorylation (Wortmann et al., 2009). </p><p>For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).</p><p>Neuropathologic changes characteristic of Alpers syndrome, namely laminar cortical necrosis, may also be seen in some patients with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), caused by mutation in the FARS2 gene (611592), and COXPD24 (616239), caused by mutation in the NARS2 gene (612803).</p>
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<strong>Clinical Features</strong>
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<p>Bernard Alpers (1931) described the neuropathology and clinical features in a 4-month-old girl with a one-month illness characterized by intractable generalized seizures. He termed the disorder 'diffuse progressive degeneration of the gray matter of the cerebrum.' Morse (1949) reported a brother and sister with hereditary myoclonus epilepsy who were later reported by Ford et al. (1951) as having from 'familial degeneration of the cerebral gray matter in childhood,' similar to the cases of Alpers (1931). Familial cases were also reported by Palinsky et al. (1954) and Christensen and Hojgaard (1964). </p><p>Alberca-Serrano et al. (1965) reported a family in which 4 of 6 sibs were affected with spastic diplegia due to anoxic encephalopathy, which they termed 'Alpers' syndrome. The parents were unrelated. Several relatives of the father may have had the same disorder. All affected members had reacted to infections with violent convulsions. The authors suggested that this represented a familial susceptibility and that the cerebral damage was secondary to anoxia. </p><p>Blackwood et al. (1963) described 2 sibs in whom diffuse cerebral degeneration (Alpers disease) was associated with cirrhosis of the liver. Wefring and Lamvik (1967) described brother and sister who developed convulsions at ages 11 and 14 months, followed by progressive hypotonia, dementia, and jaundice 4 and 2 weeks before death at the ages of 15 and 20 months. In addition to the typical findings of Alpers disease, the liver showed extensive atrophy with fibrosis, inflammation and bile duct proliferation. The diagnosis was made at autopsy. </p><p>Sandbank and Lerman (1972) reported 3 sibs with Alpers disease, characterized by progressive mental retardation, seizures, rigidity, and degeneration of the cerebral cortex. Neuropathologic examination showed disorganization of the cerebral cortex with neuronal loss and astroglial proliferation. There were abnormal mitochondria of variable sizes, some with electron dense inclusions. The authors suggested autosomal recessive inheritance. </p><p>Huttenlocher et al. (1976) reported 2 sibships with 2 affected children in each. Clinical features included early onset (average 2 years) of delayed motor development, vomiting, multifocal seizures, status epilepticus, stupor, hypotonia, paralysis, increased CSF protein, and later onset of hepatic disease. Intermittent unexplained fever occurred frequently. None of the children survived beyond age 3 years. Pathologic examination showed degeneration of the cerebral gray matter with loss of neurons and reactive astrocytosis in the brain and fatty accumulation and cirrhosis in the liver. The authors rejected the idea of anoxic encephalopathy and suggested that the syndrome was a familial disorder with autosomal recessive inheritance. Huttenlocher et al. (1976) noted that hepatic involvement was absent in some cases reported earlier, including the case reported by Alpers (1931). </p><p>Harding (1990) reviewed the clinical, neurologic, electrophysiologic, and histopathologic features of Alpers syndrome in 32 patients. Birth was usually normal, with some developmental delay in infancy, often with hypotonia and bouts of vomiting. The seizure disorder usually had an abrupt onset and although clinical signs of liver disease often appeared later, biochemical evidence of liver disease was sometimes present before the onset of seizures. EEG and visual evoked potentials were abnormal. Most patients died before the age of 3 years. Less frequently, late presentation occurred, even up to 25 years of age. Some patients also had visual disturbances. Liver pathologic findings, including fatty changes, abnormal bile duct architecture, and fibrosis, were unrelated to anticonvulsant therapy. Neuropathology showed severe cortical neurodegeneration and astrocytosis. In 12 of the 26 families in their series, 2 or 3 sibs were affected, including one pair of twins. </p><p>Frydman et al. (1993) reported the cases of 8 patients from 2 families. Onset in the first family was prenatal; in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity, were found. The second family presented with an early infantile form. All of the affected offspring had micrognathia and 1 had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all of the infants died before age 20 months. Comprehensive biochemical and metabolic studies in both families yielded normal results, and the diagnosis was supported by demonstration of extensive progressive brain atrophy on computerized tomography and typical histologic findings; for example, the parietal cortex showed spongy state with focally accentuated severe loss of neurons. The cerebellar cortex showed severe loss of almost all granular cells and persistent Purkinje cells. Anomalies of dendritic arborization were also seen. Both families were of Israeli Arab ethnicity and the parents were first cousins in both cases. </p><p>Harding et al. (1995) reported the unusual cases of 2 unrelated girls, aged 17 and 18, with a progressive encephalopathy, visual signs and symptoms, multiple types of drug-resistant seizures, and liver failure. Brain imaging showed lesions in the occipital lobe, and EEG showed slow waves with polyspikes. Both patients had a rapid degenerative course and died within 8 months of onset. </p><p>De Vries et al. (2007) reported 3 unrelated patients with Alpers syndrome due to POLG mutations. Age at onset was 4 to 8 months, and all died by 17 months of age. All showed severe failure to thrive, developmental retardation, hypotonia, seizures, and liver insufficiency. Two had delayed cerebral myelination and 1 had cerebral atrophy. Urinary amino acids showed different patterns, including intermediates of the tricarboxylic acid cycle, 3-methylglutaconic aciduria, ethylmalonic aciduria, dicarbonic aciduria and high lactate levels. All 3 patients also had significant decreases in ATP production, consistent with a defect in mitochondrial oxidative phosphorylation. </p><p>Wiltshire et al. (2008) reported a 17-year-old girl who presented with intractable epilepsy and recent onset of mild clumsiness. Developmental milestones, intelligence, vision, and hearing were otherwise normal. During the next 2 months, she had repeated admissions for status epilepticus or encephalopathy, and showed stepwise neurologic deterioration with memory impairment, slurred speech, and hemiparesis. Treatment with a variety of anticonvulsant agents coincided with progressive liver deterioration. MRI findings were initially normal but showed progressive abnormality with increased signal on T2-weighted images in the cortical and subcortical white matter and basal ganglia. She died at age 17 years, 9 months, of respiratory failure secondary to her neurologic condition. Genetic analysis identified compound heterozygous mutations in the POLG gene. </p><p>Among 136 children with a variety of severe neurologic defects, Isohanni et al. (2011) identified 7 patients from 6 families with compound heterozygous POLG mutations. Disease onset was acute or subacute, often with preceding infection. All had a severe encephalopathic phenotype with intractable epilepsy and liver involvement, except 1 patient who did not have liver involvement. All those exposed to valproate developed fatal liver toxicity. Isohanni et al. (2011) concluded that although POLG mutations are not a common cause of isolated epilepsy or ataxia in childhood, the POLG gene should be studied in children with a progressive epileptic encephalopathy with liver involvement. </p><p><strong><em>Clinical Variability</em></strong></p><p>
Kurt et al. (2010) reported 4 patients with a POLG-related hepatocerebral disorder with psychomotor delay, seizures, and liver disease, most consistent with Alpers syndrome. An unrelated girl and boy were compound heterozygous for the P1073L (174763.0022) and A467T (174763.0002) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; 613662). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for P1073L and W748S (174763.0013) and G848S (174763.0006), respectively. One child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. Kurt et al. (2010) emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the 4 children had gastrointestinal dysmotility, suggesting that the P1073L mutation may be associated with that particular feature. </p>
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<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
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<span class="mim-text-font">
<p>Cases with a disturbance in pyruvate metabolism and NADH oxidation (Gabreels et al. (1981, 1984)) have been described. </p><p>In a patient with mtDNA depletion and Alpers syndrome, Naviaux et al. (1999) found global reduction in respiratory chain complex I, II/III, and IV activity and deficiency of mitochondrial DNA polymerase gamma activity. </p><p>Gauthier-Villars et al. (2001) confirmed the mitochondrial respiratory chain abnormalities in the liver of 4 unrelated patients with Alpers syndrome. One patient had a complex I deficiency, another a complex IV deficiency, and 2 had a combined deficiency of complexes I and IV. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Naviaux and Nguyen (2004) demonstrated autosomal recessive inheritance of mitochondrial DNA depletion syndrome-4A. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Naviaux and Nguyen (2004) reported 3 patients with Alpers syndrome who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (174763.0002). Naviaux and Nguyen (2005) stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. The clinical features of the family had been described by Naviaux et al. (1999). </p><p>In 4 patients with Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0006 and 174763.0013). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes. </p><p>Ferrari et al. (2005) identified mutations in the POLG gene in 8 patients with Alpers syndrome. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Nguyen et al. (2005) reported a child with Alpers syndrome who was homozygous for the A467T mutation in the POLG gene (174763.0002). Unlike other children with the disorder, he showed late onset at age 8.5 years and death by age 9 years. </p><p>In a study of the cellular phenotype derived from 24 children with biallelic POLG mutations, 21 of whom had a clinical diagnosis of Alpers syndrome, Ashley et al. (2008) found that the cellular mtDNA content reflected the genotype. Those with mtDNA depletion in the liver and/or muscle had at least 1 missense or nonsense mutation in a catalytic domain, either the polymerase or exonuclease region. Four of 10 patients analyzed in detail showed a progressive, mosaic pattern of mtDNA depletion in fibroblasts, and all had biallelic mutations in POLG catalytic domains. These patients had a severe clinical phenotype with early onset before 1 year of age, hepatic involvement, and death by 16 months of age. Their cells showed respiratory chain defects. Patients with 2 mutations in the linker region of the gene did not show mtDNA depletion and had the mildest phenotype with onset in childhood or adolescence and little liver involvement. The study also found that the average mtDNA content declined with serial passage in cell culture in patients with mtDNA depletion, which Ashley et al. (2008) postulated was a result of mtDNA replication stalling, indicating the requirement for both catalytic actions of POLG in mitochondrial replication. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Heterogeneity</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Genetic Heterogeneity</em></strong></p><p>
Wortmann et al. (2009) reported 3 unrelated patients, 2 of Dutch and 1 of German origin, with mild intermittent 3-methylglutaconic aciduria associated with a hepatocerebral syndrome. The first patient had subepidermal hemorrhage and bilateral mild periventricular leukomalacia at birth. At age 3.5 months, she had epilepsy, hypertonia, and delayed psychomotor development. From age 2 years, she had unexplained encephalopathic periods with atonia, apneas, and stupor. Brain MRI showed mild periventricular leukomalacia, irregularly widened ventricles, gracile corpus callosum, and partial pachygyria. She also had transient elevation of liver enzymes, indicating hepatic involvement. She died of cardiorespiratory failure in an encephalopathic state at age 3 years. The second patient was born at 26 weeks' gestation with intrauterine growth retardation. He had an infantile encephalopathy with epilepsy, delayed psychomotor development, hypo- and hyperthermia, resistance to pain, and severe failure to thrive. At age 9 years he had a stroke-like episode with hemiplegia after valproic acid administration. He also had multiorgan failure with liver dysfunction, but recovered. The third patient had severe microcephaly, dysmorphic features, psychomotor retardation, no development, hypotonia, epilepsy, and failure to thrive. She suffered from recurrent episodes of hyperthermia, liver dysfunction, and intractable seizures, and died at the age of 2.5 years. Biochemical studies of all these patients suggested a defect in mitochondrial oxidative phosphorylation. Although a molecular basis for the disorder was not established, Wortmann et al. (2009) noted that the patients had a similar phenotype to those reported by De Vries et al. (2007), who had Alpers syndrome. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>As noted by Harding (1990) in a review of Alpers syndrome, there was much confusion in the past regarding the nosology, pathogenesis, and diagnosis of the disease. Some reported cases seemed to be caused by anoxia at birth or illness, whereas others were familial with normal births. Cerebral damage was also thought to be a result of intractable seizures or hepatic toxicity, and hepatic damage was believed in some cases to be caused by anticonvulsive drugs. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
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<li>
<p class="mim-text-font">
Alpers, B. J.
<strong>Diffuse progressive degeneration of gray matter of cerebrum.</strong>
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</p>
</li>
<li>
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Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R., Zeviani, M.
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Ford, F. R., Livingston, S., Pryles, C. V.
<strong>Familial degeneration of the cerebral gray matter in childhood with convulsions, myoclonus, spasticity, cerebral ataxia, choreoathetosis, dementia, and death in status epilepticus. Differentiation of infantile and juvenile types.</strong>
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</p>
</li>
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Frydman, M., Jager-Roman, E., de Vries, L., Stoltenburg-Didinger, G., Nussinovitch, M., Sirota, L.
<strong>Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome.</strong>
Am. J. Med. Genet. 47: 31-36, 1993.
[PubMed: 8368248]
[Full Text: https://doi.org/10.1002/ajmg.1320470107]
</p>
</li>
<li>
<p class="mim-text-font">
Gabreels, F. J. M., Prick, M. J. J., Renier, W. O., Willems, J. L., Trijbels, J. M. F., Ter Laak, H. J., Jaspar, H. H. J., Slooff, J. L., Van Haelst, U. J. G. M., Sengers, R. C. A.
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</p>
</li>
<li>
<p class="mim-text-font">
Gabreels, F. J., Prick, M. J., Trijbels, J. M., Renier, W. O., Jaspar, H. H., Janssen, A. J., Slooff, J. L.
<strong>Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy.</strong>
Acta Neurol. Scand. 70: 145-154, 1984.
[PubMed: 6439001]
[Full Text: https://doi.org/10.1111/j.1600-0404.1984.tb00813.x]
</p>
</li>
<li>
<p class="mim-text-font">
Gauthier-Villars, M., Landrieu, P., Cormier-Daire, V., Jacquemin, E., Chretien, D., Rotig, A., Rustin, P., Munnich, A., de Lonlay, P.
<strong>Respiratory chain deficiency in Alpers syndrome.</strong>
Neuropediatrics 32: 150-152, 2001.
[PubMed: 11521212]
[Full Text: https://doi.org/10.1055/s-2001-16614]
</p>
</li>
<li>
<p class="mim-text-font">
Harding, B. N., Alsanjari, N., Smith, S. J. M., Wiles, C. M., Thrush, D., Miller, D. H., Scaravilli, F., Harding, A. E.
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<p class="mim-text-font">
Harding, B. N.
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Huttenlocher, P. R., Solitare, G. B., Adams, G.
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Isohanni, P., Hakonen, A. H., Euro, L., Paetau, I., Linnankivi, T., Liukkonen, E., Wallden, T., Luostarinen, L., Valanne, L., Paetau, A., Uusimaa, J., Lonnqvist, T., Suomalainen, A., Pihko, H.
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Kurt, B., Jaeken, J., Van Hove, J., Lagae, L., Lofgren, A., Everman, D. B., Jayakar, P., Naini, A., Wierenga, K. J., Van Goethem, G., Copeland, W. C., DiMauro, S.
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</p>
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Morse, W. I.
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Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K.
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Sandbank, U., Lerman, P.
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</li>
<li>
<p class="mim-text-font">
Wortmann, S. B., Rodenburg, R. J. T., Jonckheere, A., de Vries, M. C., Huizing, M., Heldt, K., van den Heuvel, L. P., Wendel, U., Kluijtmans, L. A., Engelke, U. F., Wevers, R. A., Smeitink, J. A. M., Morava, E.
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