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Entry
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- #603041 - MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE); MTDPS1
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- OMIM
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<span class="h4">#603041</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/603041"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS603041"> <strong>Phenotypic Series</strong> </a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</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="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE 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>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8030&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1179/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4833" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603041[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=298" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/a18fb4ce-5b07-4d45-ad50-63c3325a8783/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0080119" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/603041" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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|
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<strong>SNOMEDCT:</strong> 718214007<br />
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<strong>ORPHA:</strong> 298<br />
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<strong>DO:</strong> 0080119<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
|
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<span class="text-danger"><strong>#</strong></span>
|
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603041
|
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</span>
|
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</span>
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</div>
|
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
|
<span class="mim-font">
|
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|
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE); MTDPS1
|
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</span>
|
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</h3>
|
|
</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, TYMP-RELATED<br />
|
|
MNGIE, TYMP-RELATED<br />
|
|
MYONEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME<br />
|
|
POLYNEUROPATHY, OPHTHALMOPLEGIA, LEUKOENCEPHALOPATHY, AND INTESTINAL PSEUDOOBSTRUCTION<br />
|
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POLIP SYNDROME
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<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">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
|
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</th>
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<th>
|
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Gene/Locus <br /> MIM number
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</th>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
|
<a href="/geneMap/22/417?start=-3&limit=10&highlight=417">
|
|
22q13.33
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 1 (MNGIE type)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603041"> 603041 </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">
|
|
TYMP
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/131222"> 131222 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/603041" 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>
|
|
|
|
|
|
|
|
|
|
<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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/603041" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603041" 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> Weight </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Weight loss, progressive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/89362005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">89362005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/262285001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">262285001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/161832001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">161832001</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1262477&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1262477</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001824" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001824</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001824" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001824</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Thin body habitus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61294007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61294007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0039870&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039870</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001533" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001533</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001533" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001533</a>]</span><br /> -
|
|
Marked cachexia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3276122&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3276122</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238108007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238108007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/285384003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">285384003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R64</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.4</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004326</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> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hearing loss, sensorineural <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60700002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60700002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018784</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- External ophthalmoplegia, progressive (PEO) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/46252003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">46252003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H49.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H49.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/378.72" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">378.72</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162674&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162674</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000590" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000590</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000544" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000544</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000590" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000590</a>]</span><br /> -
|
|
Ptosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11934000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11934000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29696001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29696001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.409</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/374.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005745</a>, <a href="https://bioportal.bioontology.org/search?q=C0033377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Ptosis-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><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> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Gastrointestinal dysmotility <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836923&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836923</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002579</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002579</a>]</span><br /> -
|
|
Malabsorption <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32230006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32230006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197476001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197476001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/579.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024523&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024523</a>, <a href="https://bioportal.bioontology.org/search?q=C3714745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714745</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002024</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002024</a>]</span><br /> -
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Intermittent diarrhea <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239181</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002254</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002254</a>]</span><br /> -
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Chronic malnutrition <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0746367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0746367</a>]</span><br /> -
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Chronic intestinal pseudoobstruction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235828008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235828008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0238062&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0238062</a>]</span><br /> -
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Gastroparesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235675006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235675006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/196753007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">196753007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K31.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K31.84</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/536.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">536.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0152020&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0152020</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002578" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002578</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002578" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002578</a>]</span><br /> -
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Abdominal pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21522001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21522001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R10.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R10.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/789.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0000737&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0000737</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span><br /> -
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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 /> -
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Constipation, chronic <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236069009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236069009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.09" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.09</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0401149&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0401149</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012450" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012450</a>]</span><br /> -
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Diverticulosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63532004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63532004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/562" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">562</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1510475&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1510475</a>]</span><br /> -
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Diverticulitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/307496006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">307496006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18126004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18126004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0012813&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0012813</a>]</span><br /> -
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Intestinal perforation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56905009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56905009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/569.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">569.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021845&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021845</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031368</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031368</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MUSCLE, SOFT TISSUES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Mitochondrial myopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16851005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16851005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162670</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003737</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003737</a>]</span><br /> -
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Distal limb muscle weakness (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249942005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249942005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427065&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427065</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002460" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002460</a>]</span><br /> -
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Distal limb muscle atrophy (less common) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848736&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848736</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003693" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003693</a>]</span><br /> -
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Ragged red fibers seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151935&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151935</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003200" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003200</a>]</span><br /> -
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mtDNA depletion seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3148732&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3148732</a>]</span><br /> -
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Multiple mitochondrial DNA (mtDNA) deletions seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278615</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003689" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003689</a>]</span><br /> -
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Decreased activity of cytochrome c oxidase in most cases seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3276119&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3276119</a>]</span><br /> -
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Decreased activities of complexes I, III, and IV, variable <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3276120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3276120</a>]</span><br /> -
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Subsarcolemmal accumulations of abnormally shaped mitochondria seen on electron microscopy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3276121&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3276121</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003548" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003548</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> NEUROLOGIC </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Central Nervous System </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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|
- Leukoencephalopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22811006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22811006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16058431000119104" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16058431000119104</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0270612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0270612</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002352</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002352" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002352</a>]</span><br /> -
|
|
Hypodensity of cerebral white matter seen on MRI <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864219&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864219</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Peripheral Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Peripheral neuropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42658009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42658009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302226006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302226006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G64</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/350-359.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">350-359.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4721453&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4721453</a>, <a href="https://bioportal.bioontology.org/search?q=C0031117&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031117</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009830" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009830</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000759" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000759</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001271" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001271</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009830" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009830</a>]</span><br /> -
|
|
Loss of distal sensation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847584</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002936</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002936</a>]</span><br /> -
|
|
Areflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37280007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37280007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234146</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001284" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001284</a>]</span><br /> -
|
|
Sensorimotor axonal/demyelinating neuropathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864221&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864221</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Lactic acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91273001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91273001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001125&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001125</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003128" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003128</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003128" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003128</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
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|
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|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Decreased activity of thymidine phosphorylase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864225</a>]</span><br /> -
|
|
Increased serum thymidine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864226&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864226</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034276</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034276</a>]</span><br /> -
|
|
Increased serum deoxyuridine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751975&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751975</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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|
|
</div>
|
|
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|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in second to fifth decade<br /> -
|
|
Progressive disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003676" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003676</a>]</span><br /> -
|
|
Early death in early adulthood often associated with diverticulitis and intestinal perforation<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 thymidine phosphorylase gene (TYMP, <a href="/entry/131222#0001">131222.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ 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>
|
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<td>
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<a href="/entry/174763"> POLG </a>
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<a href="/entry/174763"> 174763 </a>
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<a href="/geneMap/15/498?start=-3&limit=10&highlight=498"> 15q26.1 </a>
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<span class="mim-font">
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<a href="/entry/203700"> Mitochondrial DNA depletion syndrome 4A (Alpers type) </a>
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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/203700"> 203700 </a>
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<span class="mim-font">
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<a href="/entry/174763"> POLG </a>
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<span class="mim-font">
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<a href="/entry/174763"> 174763 </a>
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<a href="/geneMap/16/511?start=-3&limit=10&highlight=511"> 16q21 </a>
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<span class="mim-font">
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<a href="/entry/609560"> Mitochondrial DNA depletion syndrome 2 (myopathic type) </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/609560"> 609560 </a>
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<span class="mim-font">
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<a href="/entry/188250"> TK2 </a>
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<span class="mim-font">
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<a href="/entry/188250"> 188250 </a>
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<a href="/geneMap/17/413?start=-3&limit=10&highlight=413"> 17q12 </a>
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<span class="mim-font">
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<a href="/entry/619780"> Mitochondrial DNA depletion syndrome 20 (MNGIE type) </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/619780"> 619780 </a>
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<a href="/entry/600940"> LIG3 </a>
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<span class="mim-font">
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<a href="/entry/600940"> 600940 </a>
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<span class="mim-font">
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<a href="/geneMap/17/857?start=-3&limit=10&highlight=857"> 17q23.3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/619425"> ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type) </a>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/619425"> 619425 </a>
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<span class="mim-font">
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<a href="/entry/604983"> POLG2 </a>
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<span class="mim-font">
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<a href="/entry/604983"> 604983 </a>
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<a href="/geneMap/17/857?start=-3&limit=10&highlight=857"> 17q23.3 </a>
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<span class="mim-font">
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<a href="/entry/618528"> ?Mitochondrial DNA depletion syndrome 16 (hepatic type) </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<span class="mim-font">
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<a href="/entry/618528"> 618528 </a>
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<span class="mim-font">
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<a href="/entry/604983"> POLG2 </a>
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<span class="mim-font">
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<a href="/entry/604983"> 604983 </a>
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<span class="mim-font">
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<a href="/entry/618972"> ?Mitochondrial DNA depletion syndrome 19 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<a href="/entry/618972"> 618972 </a>
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<a href="/entry/606794"> SLC25A10 </a>
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<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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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/615084"> Mitochondrial DNA depletion syndrome 11 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<span class="mim-font">
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<a href="/entry/615084"> 615084 </a>
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<a href="/entry/615076"> MGME1 </a>
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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/603041"> Mitochondrial DNA depletion syndrome 1 (MNGIE type) </a>
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</td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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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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<span class="mim-font">
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<a href="/entry/131222"> 131222 </a>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-1 (MTDPS1), which manifests as a neurogastrointestinal encephalopathy (MNGIE), is caused by homozygous or compound heterozygous mutation in the nuclear-encoded thymidine phosphorylase gene (TYMP; <a href="/entry/131222">131222</a>) on chromosome 22q13.</p><p>See also MTDPS4B (<a href="/entry/613662">613662</a>) for a less common form of MNGIE caused by recessive mutation in the DNA polymerase gamma gene (POLG; <a href="/entry/174763">174763</a>).</p>
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<strong>Description</strong>
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<p>Mitochondrial DNA depletion syndrome-1 (MTDPS1) is an autosomal recessive progressive multisystem disorder clinically characterized by onset between the second and fifth decades of life of ptosis, progressive external ophthalmoplegia (PEO), gastrointestinal dysmotility (often pseudoobstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy, and mitochondrial dysfunction. Mitochondrial DNA abnormalities can include depletion, deletion, and point mutations (<a href="#30" class="mim-tip-reference" title="Taanman, J.-W., Daras, M., Albrecht, J., Davie, C. A., Mallam, E. A., Muddle, J. R., Weatherall, M., Warner, T. T., Schapira, A. H. V., Ginsberg, L. <strong>Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).</strong> Neuromusc. Disord. 19: 151-154, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056268</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056268">Taanman et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Genetic Heterogeneity of Mitochondrial DNA Depletion Syndromes</em></strong>
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<div class="mim-changed mim-change"><p>Mitochondrial DNA depletion syndromes are clinically and genetically heterogeneous, and most are autosomal recessive disorders. See also MTDPS2 (<a href="/entry/609560">609560</a>), caused by mutation in the TK2 gene (<a href="/entry/188250">188250</a>); MTDPS3 (<a href="/entry/251880">251880</a>), caused by mutation in the DGUOK gene (<a href="/entry/601465">601465</a>); MTDPS4A (<a href="/entry/203700">203700</a>) and MTDPS4B (<a href="/entry/613662">613662</a>), both caused by mutation in the POLG gene (<a href="/entry/174763">174763</a>); MTDPS5 (<a href="/entry/612073">612073</a>), caused by mutation in the SUCLA2 gene (<a href="/entry/603921">603921</a>); MTDPS6 (<a href="/entry/256810">256810</a>), caused by mutation in the MPV17 gene (<a href="/entry/137960">137960</a>); MTDPS7 (<a href="/entry/271245">271245</a>), caused by mutation in the C10ORF2 gene (<a href="/entry/606075">606075</a>); MTDPS8A (<a href="/entry/612075">612075</a>) and MTDPS8B (see <a href="/entry/612075">612075</a>), both caused by mutation in the RRM2B gene (<a href="/entry/604712">604712</a>); MTDPS9 (<a href="/entry/245400">245400</a>), caused by mutation in the SUCLG1 gene (<a href="/entry/611224">611224</a>); MTDPS10 (<a href="/entry/212350">212350</a>), caused by mutation in the AGK gene (<a href="/entry/610345">610345</a>); MTDPS11 (<a href="/entry/615084">615084</a>), caused by mutation in the MGME1 gene (<a href="/entry/615076">615076</a>); MTDPS12A (<a href="/entry/617184">617184</a>) and MTDPS12B (<a href="/entry/615418">615418</a>), both caused by mutation in the SLC25A4 gene (<a href="/entry/103220">103220</a>); MTDPS13 (<a href="/entry/615471">615471</a>), caused by mutation in the FBXL4 gene (<a href="/entry/605654">605654</a>); MTDPS14 (<a href="/entry/616896">616896</a>), caused by mutation in the OPA1 gene (<a href="/entry/605290">605290</a>); MTDPS15 (<a href="/entry/617156">617156</a>), caused by mutation in the TFAM gene (<a href="/entry/600438">600438</a>); MTDPS16 (<a href="/entry/618528">618528</a>), caused by mutation in the POLG2 gene (<a href="/entry/604983">604983</a>); MTDPS17 (<a href="/entry/618567">618567</a>), caused by mutation in the MRM2 gene (<a href="/entry/606906">606906</a>); MTDPS18 (<a href="/entry/618811">618811</a>), caused by mutation in the SLC25A21 gene (<a href="/entry/607571">607571</a>); MTDPS19 (<a href="/entry/618972">618972</a>), caused by mutation in the SLC25A10 gene (<a href="/entry/606794">606794</a>); MTDPS20 (<a href="/entry/619780">619780</a>), caused by mutation in the LIG3 gene (<a href="/entry/600940">600940</a>); and MTDPS21 (<a href="/entry/621071">621071</a>), caused by mutation in the GUK1 gene (<a href="/entry/139270">139270</a>).</p></div>
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<p><a href="#2" class="mim-tip-reference" title="Bardosi, A., Creutzfeldt, W., DiMauro, S., Felgenhauer, K., Friede, R. L., Goebel, H. H., Kohlschutter, A., Mayer, G., Rahlf, G., Servidei, S., Van Lessen, G., Wetterling, T. <strong>Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase: a new mitochondrial multisystem disorder.</strong> Acta Neuropath. 74: 248-258, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2823522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2823522</a>] [<a href="https://doi.org/10.1007/BF00688189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2823522">Bardosi et al. (1987)</a> reported a 42-year-old woman with a 10-year history of external ophthalmoplegia, malabsorption resulting in chronic malnutrition, muscle atrophy, and polyneuropathy. Computerized tomography showed hypodensity of her cerebral white matter. A metabolic disturbance consisted of lactic acidosis after moderate glucose loads with increased excretion of hydroxybutyric and fumaric acids. Postmortem studies demonstrated gastrointestinal scleroderma as the morphologic manifestation of her malabsorption syndrome, ocular and skeletal myopathy with ragged-red fibers, peripheral neuropathy, and vascular abnormalities of meningeal and peripheral nerve vessels. Liver and muscle tissues showed a partial defect of cytochrome c oxidase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2823522" 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 5 members of 2 Jewish-Iranian families, <a href="#6" class="mim-tip-reference" title="Faber, J., Fich, A., Steinberg, A., Steiner, I., Granot, E., Alon, I., Rachmilevitz, D., Freier, S., Gilai, A. <strong>Familial intestinal pseudoobstruction dominated by a progressive neurologic disease at a young age.</strong> Gastroenterology 92: 786-790, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3028897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3028897</a>] [<a href="https://doi.org/10.1016/0016-5085(87)90033-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3028897">Faber et al. (1987)</a> described chronic neuropathic intestinal pseudoobstruction associated with an identical, progressive, severe neuronal disease. It appeared within the first 2 decades of life and consisted of external ophthalmoplegia, ptosis, and severe sensory and motor peripheral neuropathy. Three patients also had neuronal hearing loss. There was no evidence of central nervous system involvement, and all patients were mentally intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3028897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Blake, D., Lombes, A., Minetti, C., Bonilla, E., Hays, A. P., Lovelace, A. E., Butler, I., DiMauro, S. <strong>MNGIE syndrome: report of 2 new patients. (Abstract)</strong> Neurology 40 (suppl. 1): 294, 1990."None>Blake et al. (1990)</a> described 2 patients of German extraction: a 41-year-old man and his 35-year-old sister. Since childhood, both had had intermittent diarrhea and both developed bilateral ptosis and ophthalmoplegia in their twenties and progressive neurosensory hearing loss in their thirties. Both were short, thin, and cachectic. There was mild proximal limb weakness. MRI in the man showed diffusely decreased signal in the white matter of the brain. Muscle biopsies showed ragged-red fibers, scattered fibers devoid of cytochrome c oxidase activity, and features of denervation. Biochemically, an isolated muscle mitochondria showed a partial defect of cytochrome c oxidase in both patients.</p><p><a href="#26" class="mim-tip-reference" title="Simon, L. T., Horoupian, D. S., Dorfman, L. J., Marks, M., Herrick, M. K., Wasserstein, P., Smith, M. E. <strong>Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction: POLIP syndrome.</strong> Ann. Neurol. 28: 349-360, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173474</a>] [<a href="https://doi.org/10.1002/ana.410280308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2173474">Simon et al. (1990)</a> described 5 persons in 3 separate families with a progressive neurologic disorder characterized by sensorimotor peripheral polyneuropathy, cranial neuropathies (external ophthalmoplegia and deafness), and chronic intestinal pseudoobstruction. In 2 of the patients so studied, magnetic resonance imaging showed widespread abnormality of the cerebral and cerebellar white matter. Autopsy in 3 of them showed widespread endoneural fibrosis and demyelination in the peripheral nervous system, possibly secondary to axonal atrophy, and poorly defined leukoencephalopathy. The cranial nerves and spinal roots were less severely involved; the neurons in the brainstem and spinal cord were intact. The fatal gastrointestinal dysmotility was due to severe visceral neuropathy. In 2 families, 2 brothers were affected; in the third family, a brother and sister. There was no recognized parental consanguinity. <a href="#26" class="mim-tip-reference" title="Simon, L. T., Horoupian, D. S., Dorfman, L. J., Marks, M., Herrick, M. K., Wasserstein, P., Smith, M. E. <strong>Polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction: POLIP syndrome.</strong> Ann. Neurol. 28: 349-360, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173474</a>] [<a href="https://doi.org/10.1002/ana.410280308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2173474">Simon et al. (1990)</a> suggested the acronym POLIP, summarizing the cardinal features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2173474" 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="#31" class="mim-tip-reference" title="Threlkeld, A. B., Miller, N. R., Golnik, K. C., Griffin, J. W., Kuncl, R. W., Johns, D. R., Lehar, M., Hurko, O. <strong>Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome.</strong> Am. J. Ophthal. 114: 322-328, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1524123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1524123</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)71799-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1524123">Threlkeld et al. (1992)</a> described a 26-year-old woman with a history of polycystic ovaries who had acute onset of nausea, vomiting, and lower abdominal pain 3 years previously. She was found to have numerous diverticula in the small intestine and a ruptured jejunal diverticulum. Histopathologic examination of the surgically removed jejunal specimen and appendix showed incomplete longitudinal muscle with ganglion cells located just below the serosa. Myoelectric studies disclosed no propagation of migratory motor complexes. Gastrostomy tube feedings failed because of dysmotility as did also a jejunostomy. Parenteral alimentation was necessary. Prokinetic agents, including erythromycin and cisapride, were unsuccessful in improving intestinal motility. Although the patient had no ocular complaints, she demonstrated blepharoptosis and ophthalmoparesis. She had proximal muscle weakness and mild ataxia. Magnetic resonance imaging of the head showed diffuse white matter disease, notably in the periventricular and subcortical areas as well as in the pons. Electrocardiography showed no conduction defects. Biopsy of the sural nerve confirmed a demyelinating neuropathy with a mild degree of axonal degeneration, which had been suspected from the findings of neuroelectric studies. Muscle biopsy revealed variation in myofiber size, with numerous scattered atrophic fibers and a few degenerating fibers, but no ragged-red fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1524123" 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="Hirano, M., Silvestri, G., Blake, D. M., Lombes, A., Minetti, C., Bonilla, E., Hays, A. P., Lovelace, R. E., Butler, I., Bertorini, T. E., Threlkeld, A. B., Mitsumoto, H., Salberg, L. M., Rowland, L. P., DiMauro, S. <strong>Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder.</strong> Neurology 44: 721-727, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164833</a>] [<a href="https://doi.org/10.1212/wnl.44.4.721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164833">Hirano et al. (1994)</a> suggested that the acronym MNGIE be preserved but that the disorder be called mitochondrial neurogastrointestinal encephalomyopathy to emphasize that this is a mitochondrial disorder. They found 21 reported patients who met their criteria for this diagnosis. In 16 of 22 patients, symptoms began before age 20. In 20 of 24 patients, the initial symptoms were gastrointestinal, ocular, or both. The neurologic manifestations were predominantly outside the central nervous system, although many patients showed signs of leukoencephalopathy on brain MRI scans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8164833" 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>As reviewed by <a href="#12" class="mim-tip-reference" title="Hirano, M., Garcia-de-Yebenes, J., Jones, A. C., Nishino, I., DiMauro, S., Carlo, J. R., Bender, A. N., Hahn, A. F., Salberg, L. M., Weeks, D. E., Nygaard, T. G. <strong>Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.</strong> Am. J. Hum. Genet. 63: 526-533, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683610</a>] [<a href="https://doi.org/10.1086/301979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683610">Hirano et al. (1998)</a>, laboratory studies of MNGIE patients demonstrated defects in oxidative phosphorylation, including lactic acidosis, ragged-red fibers in skeletal muscle biopsies, ultrastructurally abnormal mitochondria, and decreased activities of the mitochondrial electron-transport enzymes. <a href="#12" class="mim-tip-reference" title="Hirano, M., Garcia-de-Yebenes, J., Jones, A. C., Nishino, I., DiMauro, S., Carlo, J. R., Bender, A. N., Hahn, A. F., Salberg, L. M., Weeks, D. E., Nygaard, T. G. <strong>Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.</strong> Am. J. Hum. Genet. 63: 526-533, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683610</a>] [<a href="https://doi.org/10.1086/301979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683610">Hirano et al. (1998)</a> studied 4 ethnically distinct MNGIE families. Probands from each family were shown by Southern blot analysis to have multiple mtDNA deletions in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683610" 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="#23" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., and 15 others. <strong>Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.</strong> Ann. Neurol. 47: 792-800, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852545</a>]" pmid="10852545">Nishino et al. (2000)</a> identified 35 MNGIE patients and reviewed the clinical findings. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudoobstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26 to 58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. Leukocyte TP activity was reduced drastically in 16 patients tested (0.009 +/- 0.021 micromol/hr/mg) compared with 19 control individuals (0.67 +/- 0.21 micromol/hr/mg). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M. <strong>Phenotypic variability in a Spanish family with MNGIE.</strong> Neurology 59: 455-457, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12177387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12177387</a>] [<a href="https://doi.org/10.1212/wnl.59.3.455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12177387">Gamez et al. (2002)</a> reported 2 Spanish sisters who were shown to have homozygous mutations in the TYMP gene (<a href="/entry/131222#0009">131222.0009</a>), thus confirming a diagnosis of MNGIE. The proband presented with severe gastrointestinal dysmotility, mild eye movement abnormalities, muscle weakness, and a sensorimotor polyneuropathy. Her sister presented with marked ophthalmoparesis and ptosis and asymptomatic gastroparesis. MRI of both patients showed diffuse leukoencephalopathy. Thymidine phosphorylase activity was undetectable in both patients and plasma thymidine levels were high. <a href="#9" class="mim-tip-reference" title="Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M. <strong>Phenotypic variability in a Spanish family with MNGIE.</strong> Neurology 59: 455-457, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12177387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12177387</a>] [<a href="https://doi.org/10.1212/wnl.59.3.455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12177387">Gamez et al. (2002)</a> commented on the clinical variability present in members of the same family with the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12177387" 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="Fried, K., Arlozorov, A., Spria, R. <strong>Autosomal recessive oculopharyngeal muscular dystrophy.</strong> J. Med. Genet. 12: 416-418, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1219124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1219124</a>] [<a href="https://doi.org/10.1136/jmg.12.4.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1219124">Fried et al. (1975)</a> described 2 sisters, born of consanguineous unaffected Ashkenazi Jewish parents of Hungarian origin, who had onset at ages 34 and 35 years, respectively, of bilateral ptosis. Both patients showed decreased gag reflex, but only 1 complained of dysphagia for liquids and dysarthria. Both patients had limited eye movements, particularly in the upwards direction. One patient had foot drop and the other had difficulty climbing stairs and standing up from a recumbent position. Both had absent ankle reflexes. A distant cousin, the product of a first-cousin marriage, was said to have been identically affected. <a href="#8" class="mim-tip-reference" title="Fried, K., Arlozorov, A., Spria, R. <strong>Autosomal recessive oculopharyngeal muscular dystrophy.</strong> J. Med. Genet. 12: 416-418, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1219124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1219124</a>] [<a href="https://doi.org/10.1136/jmg.12.4.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1219124">Fried et al. (1975)</a> suggested that these patients had an autosomal recessive inheritance form of oculopharyngeal muscular dystrophy (see <a href="/entry/164300">164300</a>). However, <a href="#25" class="mim-tip-reference" title="Sadeh, M. <strong>Personal Communication.</strong> Holon, Israel 2/6/2008."None>Sadeh (2008)</a> reported that he had studied the 2 sisters and found that they had typical MNGIE with mitochondrial DNA deletions. Both sisters died from malnutrition associated with MNGIE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1219124" 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="Giordano, C., Sebastiani, M., De Giorgio, R., Travaglini, C., Tancredi, A., Valentino, M. L., Bellan, M., Cossarizza, A., Hirano, M., d'Amati, G., Carelli, V. <strong>Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion.</strong> Am. J. Path. 173: 1120-1128, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18787099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18787099</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18787099[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.2353/ajpath.2008.080252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18787099">Giordano et al. (2008)</a> reported 5 unrelated patients with TYMP-related MNGIE. Age and symptoms at onset were variable, ranging from childhood appearance of ptosis and/or gastrointestinal symptoms to PEO at age 26. One patient developed foot numbness at age 18. All developed variable features of MNGIE, such as borborygmi, diarrhea, abdominal pain and cramps, and pseudoobstruction, leading to severe weight loss and cachexia. Other features included PEO, demyelinating sensorimotor polyneuropathy, and white matter hyperintensities on brain MRI. Two had sensorineural deafness. Death occurred between ages 28 and 39 years, suggesting that decreased life span is associated with this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18787099" 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="#30" class="mim-tip-reference" title="Taanman, J.-W., Daras, M., Albrecht, J., Davie, C. A., Mallam, E. A., Muddle, J. R., Weatherall, M., Warner, T. T., Schapira, A. H. V., Ginsberg, L. <strong>Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).</strong> Neuromusc. Disord. 19: 151-154, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056268</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056268">Taanman et al. (2009)</a> reported a 22-year-old English woman with genetically confirmed MNGIE. She had postprandial vomiting since infancy, sensorineural hearing loss since age 13 years, a 12-month history of weight loss, and 6 weeks of progressive pain, numbness, and weakness in the limbs. Laboratory studies showed a demyelinating neuropathy, asymptomatic diffuse white matter lesions on MRI, sparse ragged-red fibers on skeletal muscle biopsy, and increased plasma thymidine and deoxyuridine. There were low levels of deleted mtDNA, with normal mtDNA content, and cultured patient fibroblasts showed a progressive loss of MTCO1 expression (<a href="/entry/516030">516030</a>) during serial passage, which was not found in controls. Immunochemical studies showed lack of the TYMP protein in patient fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056268" 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>Because the skeletal muscle of the patient of <a href="#31" class="mim-tip-reference" title="Threlkeld, A. B., Miller, N. R., Golnik, K. C., Griffin, J. W., Kuncl, R. W., Johns, D. R., Lehar, M., Hurko, O. <strong>Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome.</strong> Am. J. Ophthal. 114: 322-328, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1524123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1524123</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)71799-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1524123">Threlkeld et al. (1992)</a> showed evidence of cytochrome c oxidase dysfunction, <a href="#15" class="mim-tip-reference" title="Johns, D. R., Threlkeld, A. B., Miller, N. R., Hurko, O. <strong>Multiple mitochondrial DNA deletions in myo-neuro-gastrointestinal encephalopathy syndrome. (Letter)</strong> Am. J. Ophthal. 115: 108-109, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8420360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8420360</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)73533-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8420360">Johns et al. (1993)</a> sequenced the cytochrome oxidase subunits II (MTCO2; <a href="/entry/516040">516040</a>) and III (MTCO3; <a href="/entry/516050">516050</a>) in their entirety. No missense mutations were found in either gene; specifically, they detected none of the 3 point mutations in mitochondrial transfer RNAs reported in a patient with a similar syndrome (<a href="#17" class="mim-tip-reference" title="Lauber, J., Marsac, C., Kadenbach, B., Seibel, P. <strong>Mutations in mitochondrial tRNA genes: a frequent cause of neuromuscular diseases.</strong> Nucleic Acids Res. 19: 1393, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709275</a>] [<a href="https://doi.org/10.1093/nar/19.7.1393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709275">Lauber et al., 1991</a>). However, studies of gross mitochondrial DNA structure revealed multiple, large scale mitochondrial DNA deletions in relatively low abundance. One was a 4.591-kb deletion from nucleotide position 11480 (ND4 gene; <a href="/entry/516003">516003</a>) to 16071 (displacement-loop); a second was a 7.663-kb deletion from 6342 (COX I gene; <a href="/entry/516030">516030</a>) to 14005 (MTND5 gene; <a href="/entry/516005">516005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8420360+1524123+1709275" 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="#24" class="mim-tip-reference" title="Papadimitriou, A., Comi, G. P., Hadjigeorgiou, G. M., Bordoni, A., Sciacco, M., Napoli, L., Prelle, A., Moggio, M., Fagiolari, G., Bresolin, N., Salani, S., Anastasopoulos, I., Giassakis, G., Divari, R., Scarlato, G. <strong>Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome.</strong> Neurology 51: 1086-1092, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781534</a>] [<a href="https://doi.org/10.1212/wnl.51.4.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781534">Papadimitriou et al. (1998)</a> examined skeletal muscle of 3 sibs, including a pair of monozygotic twins, with MNGIE. All showed ragged-red and cytochrome c oxidase (COX)-negative fibers, as well as partial deficiency of complexes I and IV. Southern blot analyses showed mtDNA depletion in all patients, and PCR analysis detected multiple mtDNA deletions. <a href="#24" class="mim-tip-reference" title="Papadimitriou, A., Comi, G. P., Hadjigeorgiou, G. M., Bordoni, A., Sciacco, M., Napoli, L., Prelle, A., Moggio, M., Fagiolari, G., Bresolin, N., Salani, S., Anastasopoulos, I., Giassakis, G., Divari, R., Scarlato, G. <strong>Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome.</strong> Neurology 51: 1086-1092, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781534</a>] [<a href="https://doi.org/10.1212/wnl.51.4.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781534">Papadimitriou et al. (1998)</a> suggested that the combination of partial depletion and multiple deletions of mtDNA was consistent with derangement of a common genetic mechanism controlling mtDNA copy number and integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781534" 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>As pointed out by <a href="#28" class="mim-tip-reference" title="Suomalainen, A., Kaukonen, J. <strong>Diseases caused by nuclear genes affecting mtDNA stability.</strong> Am. J. Med. Genet. 106 (suppl.): 53-61, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11579425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11579425</a>] [<a href="https://doi.org/10.1002/ajmg.1379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11579425">Suomalainen and Kaukonen (2001)</a>, the common mechanism underlying the defects in MNGIE and autosomal dominant progressive external ophthalmoplegia (<a href="/entry/157640">157640</a>) may be disturbed mitochondrial nucleoside pools, the building blocks of mtDNA. They pointed out that mitochondrial DNA stability is tightly controlled in mammals. In Saccharomyces cerevisiae, over 100 genes are known that result in mtDNA loss when defective (<a href="#4" class="mim-tip-reference" title="Contamine, V., Picard, M. <strong>Maintenance and integrity of the mitochondrial genome: a plethora of nuclear genes in the budding yeast.</strong> Microbiol. Molec. Biol. Rev. 64: 281-315, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839818</a>] [<a href="https://doi.org/10.1128/MMBR.64.2.281-315.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839818">Contamine and Picard, 2000</a>). Mitochondrial DNA depletion can also be caused by environmental influences, such as exposure to nucleoside analogs or zidovudine (<a href="#1" class="mim-tip-reference" title="Arnaudo, E., Dalakas, M., Shanske, S., Moraes, C. T., DiMauro, S., Schon, E. A. <strong>Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy.</strong> Lancet 337: 508-510, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671889</a>] [<a href="https://doi.org/10.1016/0140-6736(91)91294-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1671889">Arnaudo et al., 1991</a>), a drug used to treat HIV-infected patients. In these cases the depletion is reversible, and the mtDNA levels are restored after withdrawal of the drug. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11579425+1671889+10839818" 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="Fairbanks, L. D., Marinaki, A. M., Carrey, E. A., Hammans, S. R., Duley, J. A. <strong>Deoxyuridine accumulation in urine in thymidine phosphorylase deficiency (MNGIE).</strong> J. Inherit. Metab. Dis. 25: 603-604, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12638947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12638947</a>] [<a href="https://doi.org/10.1023/a:1022007827133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12638947">Fairbanks et al. (2002)</a> reported the presence of an unusual nucleoside deoxyuridine in the urine of a patient with MNGIE due to thymidine phosphorylase deficiency. Thymidine, uracil, and thymine were also elevated. <a href="#7" class="mim-tip-reference" title="Fairbanks, L. D., Marinaki, A. M., Carrey, E. A., Hammans, S. R., Duley, J. A. <strong>Deoxyuridine accumulation in urine in thymidine phosphorylase deficiency (MNGIE).</strong> J. Inherit. Metab. Dis. 25: 603-604, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12638947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12638947</a>] [<a href="https://doi.org/10.1023/a:1022007827133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12638947">Fairbanks et al. (2002)</a> proposed that inhibition of thymidylate synthetase by thymidylate (TMP) leads to the accumulation of dUMP which may be degraded to deoxyuridine or metabolized to dUTP. Incorporation of dUTP into mitochondrial DNA may explain the multiple deletions characteristic of thymidine phosphorylase deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12638947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Marti, R., Nishigaki, Y., Hirano, M. <strong>Elevated plasma deoxyuridine in patients with thymidine phosphorylase deficiency.</strong> Biochem. Biophys. Res. Commun. 303: 14-18, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646159</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00294-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646159">Marti et al. (2003)</a> also reported the accumulation of deoxyuridine in MNGIE. In patients, circulating levels ranged from 5.5 to 24.4 microM (average 14.2) and were undetectable in both heterozygous ECGF1 (TYMP; <a href="/entry/131222">131222</a>) mutation carriers and in controls. The authors proposed that accumulation of deoxyuridine may contribute to nucleotide pool imbalances and, together with increased levels of thymidine, is likely to contribute to the pathogenesis of MNGIE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646159" 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="#27" class="mim-tip-reference" title="Song, S., Wheeler, L. J., Mathews, C. K. <strong>Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA.</strong> J. Biol. Chem. 278: 43893-43896, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13679382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13679382</a>] [<a href="https://doi.org/10.1074/jbc.C300401200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13679382">Song et al. (2003)</a> demonstrated that increased thymidine in cultured HeLa cells caused an imbalance in mitochondrial nucleoside pools resulting in multiple mtDNA deletions and point mutations. The mutagenic mechanism often involved T-G mispairing followed by a next-nucleotide effect involving T insertion opposite A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13679382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Nishigaki, Y., Marti, R., Hirano, M. <strong>ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy.</strong> Hum. Molec. Genet. 13: 91-101, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14613972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14613972</a>] [<a href="https://doi.org/10.1093/hmg/ddh010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14613972">Nishigaki et al. (2004)</a> identified 5 major forms of mtDNA deletions in the skeletal muscle of MNGIE patients. Direct repeats and imperfectly homologous sequences appeared to mediate the formation of mtDNA deletions, and the MTND5 gene was a hotspot for these rearrangements. A novel aspect of mtDNA deletions in MNGIE was the presence of microdeletions at the imperfectly homologous breakpoints. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14613972" 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="Hirano, M., Lagier-Tourenne, C., Valentino, M. L., Marti, R., Nishigaki, Y. <strong>Thymidine phosphorylase mutations cause instability of mitochondrial DNA.</strong> Gene 354: 152-156, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15975738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15975738</a>] [<a href="https://doi.org/10.1016/j.gene.2005.04.041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15975738">Hirano et al. (2005)</a> summarized the studies of mitochondrial nucleoside imbalances in thymidine phosphorylase deficiency, and concluded that these imbalances generate mtDNA alterations, such as depletion, deletion, and point mutations, that differ between tissues and result in clinical features. They also noted the 'muscle paradox': although TYMP is not expressed in skeletal muscle, that tissue nevertheless shows mitochondrial abnormalities in most cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15975738" 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>By postmortem examination of 5 unrelated patients with TYMP-related MNGIE, <a href="#10" class="mim-tip-reference" title="Giordano, C., Sebastiani, M., De Giorgio, R., Travaglini, C., Tancredi, A., Valentino, M. L., Bellan, M., Cossarizza, A., Hirano, M., d'Amati, G., Carelli, V. <strong>Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion.</strong> Am. J. Path. 173: 1120-1128, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18787099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18787099</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18787099[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.2353/ajpath.2008.080252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18787099">Giordano et al. (2008)</a> found atrophy and vacuolization of smooth muscle cells and interstitial fibrosis in the external layer of the muscularis propria, stomach, and small intestine. There was also marked mitochondrial proliferation and COX-negative staining in smooth muscle cells in the muscularis propria and in endothelial cells and smooth muscle cells from small arteries in visceral organs. Marked mtDNA depletion was found in small intestine and stomach tissue homogenates, but mtDNA deletions were not found in smooth muscle cells. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. The findings indicated that visceral mitochondrial myopathy likely causes the gastrointestinal dysmotility in these patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in small vessel walls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18787099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Kripps, K. A., Nakayuenyongsuk, W., Shayota, B. J., Berquist, W., Gomez-Ospina, N., Esquivel, C. O., Concepcion, W., Sampson, J. B., Cristin, D. J., Jackson, W. E., Gilliland, S., Pomfret, E. A., and 11 others. <strong>Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).</strong> Molec. Genet. Metab. 130: 58-64, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32173240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32173240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32173240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2020.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32173240">Kripps et al. (2020)</a> reported the outcomes of liver transplantation in 4 patients with MTDPS1. The first patient presented at age 14 months with emesis, elevated transaminases, hyperbilirubinemia, and coagulopathy. Brain MRI showed T2-hyperintense white matter lesions. He had developmental delay, decreased tone and decreased patellar reflexes. Following liver transplantation at age 26 months, his thymidine levels dropped more than 20-fold. MRI at age 3 years 7 months showed stability of the T2-hyperintense lesions. There was no evidence of gastrointestinal dysmotility. His nonverbal IQ score at age 4 years 9 months was 91. The second patient was diagnosed at age 36 years with findings of increased T2-hyperintense lesions on brain MRI, external ophthalmoplegia, ptosis, fatigue, and peripheral neuropathy. Following liver transplantation at age 37, her thymidine levels decreased by 11-fold. She had increased energy levels and decreased neuropathic pain. Ophthalmoplegia, ptosis, and peripheral neuropathy were stable 10 months posttransplantation. The third patient was diagnosed at age 20 years with features of peripheral neuropathy, diabetes, and severe gastrointestinal symptoms. At age 21, brain MRI showed diffuse leukoencephalopathy, and she developed a decreased left ventricular ejection fraction. Following liver transplantation, her thymidine levels normalized. She had improved gastrointestinal symptoms, normalization of her hemoglobin A1C, and normalization of her left ventricular ejection fraction. She reported no improvement in strength and stable peripheral neuropathy symptoms. The fourth patient was diagnosed at age 22 years with symptoms of peripheral neuropathy, liver cirrhosis, gastrointestinal dysmotility, and fatigue. Following liver transplantation at age 23, his thymidine levels decreased by 24-fold. Four months posttransplantation, his gastrointestinal symptoms, strength, and proprioception improved. He continued to have decreased muscle mass, ophthalmoplegia, and paresthesia. <a href="#16" class="mim-tip-reference" title="Kripps, K. A., Nakayuenyongsuk, W., Shayota, B. J., Berquist, W., Gomez-Ospina, N., Esquivel, C. O., Concepcion, W., Sampson, J. B., Cristin, D. J., Jackson, W. E., Gilliland, S., Pomfret, E. A., and 11 others. <strong>Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).</strong> Molec. Genet. Metab. 130: 58-64, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32173240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32173240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32173240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2020.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32173240">Kripps et al. (2020)</a> concluded that liver transplantation in these 4 patients resulted in 100% short-term survival, stabilization of disease symptoms, decrease in thymidine levels, and some clinical improvements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32173240" 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="#14" class="mim-tip-reference" title="Hirano, M., Silvestri, G., Blake, D. M., Lombes, A., Minetti, C., Bonilla, E., Hays, A. P., Lovelace, R. E., Butler, I., Bertorini, T. E., Threlkeld, A. B., Mitsumoto, H., Salberg, L. M., Rowland, L. P., DiMauro, S. <strong>Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder.</strong> Neurology 44: 721-727, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164833</a>] [<a href="https://doi.org/10.1212/wnl.44.4.721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164833">Hirano et al. (1994)</a> suggested that this disorder is an autosomal recessive trait. They based this on the fact that 19 of 25 patients had affected sibs and 5 were the children of 3 pairs of consanguineous parents. Only 5 cases were sporadic. Of 8 patients studied by <a href="#14" class="mim-tip-reference" title="Hirano, M., Silvestri, G., Blake, D. M., Lombes, A., Minetti, C., Bonilla, E., Hays, A. P., Lovelace, R. E., Butler, I., Bertorini, T. E., Threlkeld, A. B., Mitsumoto, H., Salberg, L. M., Rowland, L. P., DiMauro, S. <strong>Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder.</strong> Neurology 44: 721-727, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164833</a>] [<a href="https://doi.org/10.1212/wnl.44.4.721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164833">Hirano et al. (1994)</a>, 4 were found to have multiple deletions of mitochondrial DNA on Southern blot. They commented that this finding 'merits further investigation.' One of the patients with multiple deletions was the same patient as that reported by <a href="#31" class="mim-tip-reference" title="Threlkeld, A. B., Miller, N. R., Golnik, K. C., Griffin, J. W., Kuncl, R. W., Johns, D. R., Lehar, M., Hurko, O. <strong>Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome.</strong> Am. J. Ophthal. 114: 322-328, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1524123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1524123</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)71799-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1524123">Threlkeld et al. (1992)</a> and <a href="#15" class="mim-tip-reference" title="Johns, D. R., Threlkeld, A. B., Miller, N. R., Hurko, O. <strong>Multiple mitochondrial DNA deletions in myo-neuro-gastrointestinal encephalopathy syndrome. (Letter)</strong> Am. J. Ophthal. 115: 108-109, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8420360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8420360</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)73533-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8420360">Johns et al. (1993)</a>. It is possible that this is an autosomal recessive equivalent of the phenomenon of multiple mitochondrial deletions resulting from a dominant nuclear mutation as observed by <a href="#32" class="mim-tip-reference" title="Zeviani, M., Servidei, S., Gellera, C., Bertini, E., DiMauro, S., DiDonato, S. <strong>An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region.</strong> Nature 339: 309-311, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2725645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2725645</a>] [<a href="https://doi.org/10.1038/339309a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2725645">Zeviani et al. (1989)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8164833+1524123+8420360+2725645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Douglas, G. V., Wiszniewska, J., Lipson, M. H., Witt, D. R., McDowell, T., Sifry-Platt, M., Hirano, M., Craigen, W. J., Wong, L.-J. C. <strong>Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis.</strong> J. Hum. Genet. 56: 834-839, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22011815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22011815</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22011815[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/jhg.2011.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22011815">Douglas et al. (2011)</a> reported a patient, born of unrelated northern European parents, with classic MNGIE due to an apparently homozygous mutation in the TYMP gene. However, analysis of parental DNA showed that only the mother carried the mutation in the heterozygous state. Analysis of patient tissue ruled out gene deletion, and SNP array analysis showed a block of copy-neutral absence of heterozygosity, consistent with segmental uniparental isodisomy for an 11.3-Mb region of chromosome 22 including the TYMP gene. The findings had implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22011815" 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>Although some findings, particularly multiple mtDNA deletions, point to MNGIE being a mitochondrial disorder, other characteristics suggest autosomal recessive inheritance with a defect in intergenomic communication. Autosomal recessive inheritance has been inferred because of (1) the high recurrence rate among sibs (14 of 49 sibs of probands), (2) the lack of affected parents and progeny, and (3) the relatively high rate of consanguinity (4 of 19 families) (<a href="#14" class="mim-tip-reference" title="Hirano, M., Silvestri, G., Blake, D. M., Lombes, A., Minetti, C., Bonilla, E., Hays, A. P., Lovelace, R. E., Butler, I., Bertorini, T. E., Threlkeld, A. B., Mitsumoto, H., Salberg, L. M., Rowland, L. P., DiMauro, S. <strong>Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder.</strong> Neurology 44: 721-727, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8164833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8164833</a>] [<a href="https://doi.org/10.1212/wnl.44.4.721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8164833">Hirano et al., 1994</a>; <a href="#12" class="mim-tip-reference" title="Hirano, M., Garcia-de-Yebenes, J., Jones, A. C., Nishino, I., DiMauro, S., Carlo, J. R., Bender, A. N., Hahn, A. F., Salberg, L. M., Weeks, D. E., Nygaard, T. G. <strong>Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.</strong> Am. J. Hum. Genet. 63: 526-533, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683610</a>] [<a href="https://doi.org/10.1086/301979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683610">Hirano et al., 1998</a>). For this reason, <a href="#12" class="mim-tip-reference" title="Hirano, M., Garcia-de-Yebenes, J., Jones, A. C., Nishino, I., DiMauro, S., Carlo, J. R., Bender, A. N., Hahn, A. F., Salberg, L. M., Weeks, D. E., Nygaard, T. G. <strong>Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.</strong> Am. J. Hum. Genet. 63: 526-533, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683610</a>] [<a href="https://doi.org/10.1086/301979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683610">Hirano et al. (1998)</a> performed linkage analysis in 4 families of diverse ethnic extraction and mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum 2-point lod score of 6.80 at locus D22S526. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8164833+9683610" 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="#22" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified homozygous and compound heterozygous mutations in the TYMP gene in 12 MNGIE probands (see <a href="/entry/131222#0001">131222.0001</a>-<a href="/entry/131222#0008">131222.0008</a>). <a href="#23" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., and 15 others. <strong>Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.</strong> Ann. Neurol. 47: 792-800, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852545</a>]" pmid="10852545">Nishino et al. (2000)</a> reported a total of 16 TYMP mutations identified in 21 probands. Homozygous or compound heterozygous mutations were present in all 35 patients tested. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10852545+9924029" 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 a classic MNGIE clinical presentation but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, <a href="#29" class="mim-tip-reference" title="Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. <strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong> J. Med. Genet. 41: 125-129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757860</a>] [<a href="https://doi.org/10.1136/jmg.2003.013789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757860">Szigeti et al. (2004)</a> identified a homozygous splice site mutation in the TYMP gene (<a href="/entry/131222#0010">131222.0010</a>). <a href="#29" class="mim-tip-reference" title="Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. <strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong> J. Med. Genet. 41: 125-129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757860</a>] [<a href="https://doi.org/10.1136/jmg.2003.013789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757860">Szigeti et al. (2004)</a> concluded that it is important to examine the most significantly affected tissue and to measure thymidine phosphorylase activity and plasma thymidine to arrive at an accurate diagnosis in this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757860" 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="#20" class="mim-tip-reference" title="Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. <strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong> Ann. Neurol. 58: 649-652, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>] [<a href="https://doi.org/10.1002/ana.20615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178026">Marti et al. (2005)</a> reported 3 unrelated patients with late-onset MNGIE confirmed by the identification of TYMP mutations (<a href="/entry/131222#0011">131222.0011</a>-<a href="/entry/131222#0014">131222.0014</a>). The patients developed symptoms at ages 40 to 52 years, later than that observed in patients with typical MNGIE. Plasma deoxythymidine levels were mildly elevated, ranging from 0.4 to 1.4 microM, indicating that even low levels are pathogenic. Biochemical analysis showed 9 to 16% residual TYMP activity, which likely accounted for the later onset in these patients. Unaffected heterozygous mutation carriers had 26 to 35% residual TYMP activity, suggesting a minimal level required to prevent disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" 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>Murine uridine phosphorylate, unlike human UPP1 (<a href="/entry/191730">191730</a>), cleaves thymidine as well as uridine. To knock out Tymp activity in mice, <a href="#11" class="mim-tip-reference" title="Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others. <strong>Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.</strong> Molec. Cell. Biol. 22: 5212-5221, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12077348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12077348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12077348[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.22.14.5212-5221.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12077348">Haraguchi et al. (2002)</a> created Upp1/Tymp double-knockout mice. They found no alterations in mitochondrial DNA or pathologic changes in the muscles of double-knockout mice, even when these mice were fed thymidine for 7 months. However, they found intense lesions in the brain on T2-weighted MRI, and axonal edema by electron microscopic study of the brain of double-knockout mice. <a href="#11" class="mim-tip-reference" title="Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others. <strong>Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.</strong> Molec. Cell. Biol. 22: 5212-5221, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12077348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12077348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12077348[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.22.14.5212-5221.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12077348">Haraguchi et al. (2002)</a> concluded that inhibition of TYMP activity causes elevation of pyrimidine levels in plasma and consequent axonal swelling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12077348" 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>Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. <a href="#18" class="mim-tip-reference" title="Lopez, L. C., Akman, H. O., Garcia-Cazorla, A., Dorado, B., Marti, R., Nishino, I., Tadesse, S., Pizzorno, G., Shungu, D., Bonilla, E., Tanji, K., Hirano, M. <strong>Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice.</strong> Hum. Molec. Genet. 18: 714-722, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19028666[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19028666">Lopez et al. (2009)</a> generated Tymp-/- Upp1-/- double-knockout mice, which showed severe Tymp deficiency, increased thymidine and deoxyuridine in tissues, and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, the brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes, and encephalopathy. These findings largely account for the pathogenesis of MNGIE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19028666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1128/MMBR.64.2.281-315.2000" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.12.4.416" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.59.3.455" target="_blank">Full Text</a>]
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Giordano, C., Sebastiani, M., De Giorgio, R., Travaglini, C., Tancredi, A., Valentino, M. L., Bellan, M., Cossarizza, A., Hirano, M., d'Amati, G., Carelli, V.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18787099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18787099</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18787099[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18787099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.2353/ajpath.2008.080252" target="_blank">Full Text</a>]
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Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others.
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<strong>Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.</strong>
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Molec. Cell. Biol. 22: 5212-5221, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12077348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12077348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12077348[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12077348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.22.14.5212-5221.2002" target="_blank">Full Text</a>]
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Hirano, M., Garcia-de-Yebenes, J., Jones, A. C., Nishino, I., DiMauro, S., Carlo, J. R., Bender, A. N., Hahn, A. F., Salberg, L. M., Weeks, D. E., Nygaard, T. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683610</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/301979" target="_blank">Full Text</a>]
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Hirano, M., Lagier-Tourenne, C., Valentino, M. L., Marti, R., Nishigaki, Y.
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<strong>Thymidine phosphorylase mutations cause instability of mitochondrial DNA.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056268</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2008.11.002" target="_blank">Full Text</a>]
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Threlkeld, A. B., Miller, N. R., Golnik, K. C., Griffin, J. W., Kuncl, R. W., Johns, D. R., Lehar, M., Hurko, O.
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<strong>Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome.</strong>
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Am. J. Ophthal. 114: 322-328, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1524123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1524123</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1524123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0002-9394(14)71799-4" target="_blank">Full Text</a>]
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Zeviani, M., Servidei, S., Gellera, C., Bertini, E., DiMauro, S., DiDonato, S.
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<strong>An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region.</strong>
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Nature 339: 309-311, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2725645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2725645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2725645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/339309a0" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 06/11/2020
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Cassandra L. Kniffin - updated : 2/18/2013<br>Cassandra L. Kniffin - updated : 1/5/2012<br>Cassandra L. Kniffin - updated : 12/9/2010<br>Cassandra L. Kniffin - updated : 10/27/2009<br>George E. Tiller - updated : 8/21/2009<br>Cassandra L. Kniffin - updated : 7/9/2009<br>George E. Tiller - updated : 2/17/2006<br>Cassandra L. Kniffin - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 11/4/2004<br>Marla J. F. O'Neill - updated : 9/20/2004<br>Ada Hamosh - updated : 9/23/2003<br>Cassandra L. Kniffin - updated : 11/8/2002<br>Cassandra L. Kniffin - updated : 10/3/2002<br>Victor A. McKusick - updated : 7/24/2001<br>Ada Hamosh - updated : 1/28/1999
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Victor A. McKusick : 9/17/1998
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alopez : 01/24/2025
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alopez : 03/14/2022<br>ckniffin : 03/08/2022<br>carol : 06/14/2021<br>carol : 08/04/2020<br>ckniffin : 08/03/2020<br>carol : 06/11/2020<br>alopez : 03/18/2020<br>ckniffin : 03/16/2020<br>alopez : 09/04/2019<br>alopez : 08/12/2019<br>ckniffin : 08/08/2019<br>carol : 08/05/2019<br>carol : 03/29/2018<br>carol : 11/14/2016<br>ckniffin : 11/14/2016<br>alopez : 10/17/2016<br>ckniffin : 10/13/2016<br>alopez : 04/07/2016<br>ckniffin : 4/5/2016<br>carol : 10/8/2014<br>carol : 10/14/2013<br>ckniffin : 10/10/2013<br>carol : 9/30/2013<br>ckniffin : 9/18/2013<br>carol : 2/19/2013<br>ckniffin : 2/18/2013<br>carol : 2/17/2012<br>carol : 2/3/2012<br>ckniffin : 2/2/2012<br>terry : 1/31/2012<br>carol : 1/5/2012<br>ckniffin : 1/5/2012<br>carol : 11/22/2011<br>carol : 12/21/2010<br>ckniffin : 12/9/2010<br>carol : 8/18/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 11/16/2009<br>ckniffin : 10/27/2009<br>wwang : 8/21/2009<br>wwang : 8/3/2009<br>ckniffin : 7/9/2009<br>carol : 2/7/2008<br>wwang : 3/7/2006<br>terry : 2/17/2006<br>wwang : 12/5/2005<br>ckniffin : 12/1/2005<br>terry : 3/3/2005<br>ckniffin : 2/7/2005<br>carol : 11/16/2004<br>carol : 11/4/2004<br>carol : 11/4/2004<br>tkritzer : 11/4/2004<br>tkritzer : 9/20/2004<br>alopez : 9/23/2003<br>ckniffin : 11/8/2002<br>carol : 10/21/2002<br>ckniffin : 10/3/2002<br>mcapotos : 8/8/2001<br>terry : 7/24/2001<br>alopez : 4/11/2001<br>alopez : 9/5/2000<br>carol : 9/8/1999<br>alopez : 1/28/1999<br>dkim : 9/21/1998<br>carol : 9/17/1998
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<strong>#</strong> 603041
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MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE); MTDPS1
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MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME, TYMP-RELATED<br />
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MNGIE, TYMP-RELATED<br />
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MYONEUROGASTROINTESTINAL ENCEPHALOPATHY SYNDROME<br />
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POLYNEUROPATHY, OPHTHALMOPLEGIA, LEUKOENCEPHALOPATHY, AND INTESTINAL PSEUDOOBSTRUCTION<br />
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POLIP SYNDROME
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<strong>SNOMEDCT:</strong> 718214007;
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<strong>ORPHA:</strong> 298;
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<strong>DO:</strong> 0080119;
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22q13.33
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Mitochondrial DNA depletion syndrome 1 (MNGIE type)
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603041
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Autosomal recessive
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3
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TYMP
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131222
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<p>A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-1 (MTDPS1), which manifests as a neurogastrointestinal encephalopathy (MNGIE), is caused by homozygous or compound heterozygous mutation in the nuclear-encoded thymidine phosphorylase gene (TYMP; 131222) on chromosome 22q13.</p><p>See also MTDPS4B (613662) for a less common form of MNGIE caused by recessive mutation in the DNA polymerase gamma gene (POLG; 174763).</p>
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<p>Mitochondrial DNA depletion syndrome-1 (MTDPS1) is an autosomal recessive progressive multisystem disorder clinically characterized by onset between the second and fifth decades of life of ptosis, progressive external ophthalmoplegia (PEO), gastrointestinal dysmotility (often pseudoobstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy, and mitochondrial dysfunction. Mitochondrial DNA abnormalities can include depletion, deletion, and point mutations (Taanman et al., 2009). </p><p><strong><em>Genetic Heterogeneity of Mitochondrial DNA Depletion Syndromes</em></strong></p><p>
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Mitochondrial DNA depletion syndromes are clinically and genetically heterogeneous, and most are autosomal recessive disorders. See also MTDPS2 (609560), caused by mutation in the TK2 gene (188250); MTDPS3 (251880), caused by mutation in the DGUOK gene (601465); MTDPS4A (203700) and MTDPS4B (613662), both caused by mutation in the POLG gene (174763); MTDPS5 (612073), caused by mutation in the SUCLA2 gene (603921); MTDPS6 (256810), caused by mutation in the MPV17 gene (137960); MTDPS7 (271245), caused by mutation in the C10ORF2 gene (606075); MTDPS8A (612075) and MTDPS8B (see 612075), both caused by mutation in the RRM2B gene (604712); MTDPS9 (245400), caused by mutation in the SUCLG1 gene (611224); MTDPS10 (212350), caused by mutation in the AGK gene (610345); MTDPS11 (615084), caused by mutation in the MGME1 gene (615076); MTDPS12A (617184) and MTDPS12B (615418), both caused by mutation in the SLC25A4 gene (103220); MTDPS13 (615471), caused by mutation in the FBXL4 gene (605654); MTDPS14 (616896), caused by mutation in the OPA1 gene (605290); MTDPS15 (617156), caused by mutation in the TFAM gene (600438); MTDPS16 (618528), caused by mutation in the POLG2 gene (604983); MTDPS17 (618567), caused by mutation in the MRM2 gene (606906); MTDPS18 (618811), caused by mutation in the SLC25A21 gene (607571); MTDPS19 (618972), caused by mutation in the SLC25A10 gene (606794); MTDPS20 (619780), caused by mutation in the LIG3 gene (600940); and MTDPS21 (621071), caused by mutation in the GUK1 gene (139270).</p>
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<strong>Clinical Features</strong>
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<p>Bardosi et al. (1987) reported a 42-year-old woman with a 10-year history of external ophthalmoplegia, malabsorption resulting in chronic malnutrition, muscle atrophy, and polyneuropathy. Computerized tomography showed hypodensity of her cerebral white matter. A metabolic disturbance consisted of lactic acidosis after moderate glucose loads with increased excretion of hydroxybutyric and fumaric acids. Postmortem studies demonstrated gastrointestinal scleroderma as the morphologic manifestation of her malabsorption syndrome, ocular and skeletal myopathy with ragged-red fibers, peripheral neuropathy, and vascular abnormalities of meningeal and peripheral nerve vessels. Liver and muscle tissues showed a partial defect of cytochrome c oxidase. </p><p>In 5 members of 2 Jewish-Iranian families, Faber et al. (1987) described chronic neuropathic intestinal pseudoobstruction associated with an identical, progressive, severe neuronal disease. It appeared within the first 2 decades of life and consisted of external ophthalmoplegia, ptosis, and severe sensory and motor peripheral neuropathy. Three patients also had neuronal hearing loss. There was no evidence of central nervous system involvement, and all patients were mentally intact. </p><p>Blake et al. (1990) described 2 patients of German extraction: a 41-year-old man and his 35-year-old sister. Since childhood, both had had intermittent diarrhea and both developed bilateral ptosis and ophthalmoplegia in their twenties and progressive neurosensory hearing loss in their thirties. Both were short, thin, and cachectic. There was mild proximal limb weakness. MRI in the man showed diffusely decreased signal in the white matter of the brain. Muscle biopsies showed ragged-red fibers, scattered fibers devoid of cytochrome c oxidase activity, and features of denervation. Biochemically, an isolated muscle mitochondria showed a partial defect of cytochrome c oxidase in both patients.</p><p>Simon et al. (1990) described 5 persons in 3 separate families with a progressive neurologic disorder characterized by sensorimotor peripheral polyneuropathy, cranial neuropathies (external ophthalmoplegia and deafness), and chronic intestinal pseudoobstruction. In 2 of the patients so studied, magnetic resonance imaging showed widespread abnormality of the cerebral and cerebellar white matter. Autopsy in 3 of them showed widespread endoneural fibrosis and demyelination in the peripheral nervous system, possibly secondary to axonal atrophy, and poorly defined leukoencephalopathy. The cranial nerves and spinal roots were less severely involved; the neurons in the brainstem and spinal cord were intact. The fatal gastrointestinal dysmotility was due to severe visceral neuropathy. In 2 families, 2 brothers were affected; in the third family, a brother and sister. There was no recognized parental consanguinity. Simon et al. (1990) suggested the acronym POLIP, summarizing the cardinal features. </p><p>Threlkeld et al. (1992) described a 26-year-old woman with a history of polycystic ovaries who had acute onset of nausea, vomiting, and lower abdominal pain 3 years previously. She was found to have numerous diverticula in the small intestine and a ruptured jejunal diverticulum. Histopathologic examination of the surgically removed jejunal specimen and appendix showed incomplete longitudinal muscle with ganglion cells located just below the serosa. Myoelectric studies disclosed no propagation of migratory motor complexes. Gastrostomy tube feedings failed because of dysmotility as did also a jejunostomy. Parenteral alimentation was necessary. Prokinetic agents, including erythromycin and cisapride, were unsuccessful in improving intestinal motility. Although the patient had no ocular complaints, she demonstrated blepharoptosis and ophthalmoparesis. She had proximal muscle weakness and mild ataxia. Magnetic resonance imaging of the head showed diffuse white matter disease, notably in the periventricular and subcortical areas as well as in the pons. Electrocardiography showed no conduction defects. Biopsy of the sural nerve confirmed a demyelinating neuropathy with a mild degree of axonal degeneration, which had been suspected from the findings of neuroelectric studies. Muscle biopsy revealed variation in myofiber size, with numerous scattered atrophic fibers and a few degenerating fibers, but no ragged-red fibers. </p><p>Hirano et al. (1994) suggested that the acronym MNGIE be preserved but that the disorder be called mitochondrial neurogastrointestinal encephalomyopathy to emphasize that this is a mitochondrial disorder. They found 21 reported patients who met their criteria for this diagnosis. In 16 of 22 patients, symptoms began before age 20. In 20 of 24 patients, the initial symptoms were gastrointestinal, ocular, or both. The neurologic manifestations were predominantly outside the central nervous system, although many patients showed signs of leukoencephalopathy on brain MRI scans. </p><p>As reviewed by Hirano et al. (1998), laboratory studies of MNGIE patients demonstrated defects in oxidative phosphorylation, including lactic acidosis, ragged-red fibers in skeletal muscle biopsies, ultrastructurally abnormal mitochondria, and decreased activities of the mitochondrial electron-transport enzymes. Hirano et al. (1998) studied 4 ethnically distinct MNGIE families. Probands from each family were shown by Southern blot analysis to have multiple mtDNA deletions in skeletal muscle. </p><p>Nishino et al. (2000) identified 35 MNGIE patients and reviewed the clinical findings. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudoobstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26 to 58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. Leukocyte TP activity was reduced drastically in 16 patients tested (0.009 +/- 0.021 micromol/hr/mg) compared with 19 control individuals (0.67 +/- 0.21 micromol/hr/mg). </p><p>Gamez et al. (2002) reported 2 Spanish sisters who were shown to have homozygous mutations in the TYMP gene (131222.0009), thus confirming a diagnosis of MNGIE. The proband presented with severe gastrointestinal dysmotility, mild eye movement abnormalities, muscle weakness, and a sensorimotor polyneuropathy. Her sister presented with marked ophthalmoparesis and ptosis and asymptomatic gastroparesis. MRI of both patients showed diffuse leukoencephalopathy. Thymidine phosphorylase activity was undetectable in both patients and plasma thymidine levels were high. Gamez et al. (2002) commented on the clinical variability present in members of the same family with the same mutation. </p><p>Fried et al. (1975) described 2 sisters, born of consanguineous unaffected Ashkenazi Jewish parents of Hungarian origin, who had onset at ages 34 and 35 years, respectively, of bilateral ptosis. Both patients showed decreased gag reflex, but only 1 complained of dysphagia for liquids and dysarthria. Both patients had limited eye movements, particularly in the upwards direction. One patient had foot drop and the other had difficulty climbing stairs and standing up from a recumbent position. Both had absent ankle reflexes. A distant cousin, the product of a first-cousin marriage, was said to have been identically affected. Fried et al. (1975) suggested that these patients had an autosomal recessive inheritance form of oculopharyngeal muscular dystrophy (see 164300). However, Sadeh (2008) reported that he had studied the 2 sisters and found that they had typical MNGIE with mitochondrial DNA deletions. Both sisters died from malnutrition associated with MNGIE. </p><p>Giordano et al. (2008) reported 5 unrelated patients with TYMP-related MNGIE. Age and symptoms at onset were variable, ranging from childhood appearance of ptosis and/or gastrointestinal symptoms to PEO at age 26. One patient developed foot numbness at age 18. All developed variable features of MNGIE, such as borborygmi, diarrhea, abdominal pain and cramps, and pseudoobstruction, leading to severe weight loss and cachexia. Other features included PEO, demyelinating sensorimotor polyneuropathy, and white matter hyperintensities on brain MRI. Two had sensorineural deafness. Death occurred between ages 28 and 39 years, suggesting that decreased life span is associated with this disorder. </p><p>Taanman et al. (2009) reported a 22-year-old English woman with genetically confirmed MNGIE. She had postprandial vomiting since infancy, sensorineural hearing loss since age 13 years, a 12-month history of weight loss, and 6 weeks of progressive pain, numbness, and weakness in the limbs. Laboratory studies showed a demyelinating neuropathy, asymptomatic diffuse white matter lesions on MRI, sparse ragged-red fibers on skeletal muscle biopsy, and increased plasma thymidine and deoxyuridine. There were low levels of deleted mtDNA, with normal mtDNA content, and cultured patient fibroblasts showed a progressive loss of MTCO1 expression (516030) during serial passage, which was not found in controls. Immunochemical studies showed lack of the TYMP protein in patient fibroblasts. </p>
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<strong>Pathogenesis</strong>
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<p>Because the skeletal muscle of the patient of Threlkeld et al. (1992) showed evidence of cytochrome c oxidase dysfunction, Johns et al. (1993) sequenced the cytochrome oxidase subunits II (MTCO2; 516040) and III (MTCO3; 516050) in their entirety. No missense mutations were found in either gene; specifically, they detected none of the 3 point mutations in mitochondrial transfer RNAs reported in a patient with a similar syndrome (Lauber et al., 1991). However, studies of gross mitochondrial DNA structure revealed multiple, large scale mitochondrial DNA deletions in relatively low abundance. One was a 4.591-kb deletion from nucleotide position 11480 (ND4 gene; 516003) to 16071 (displacement-loop); a second was a 7.663-kb deletion from 6342 (COX I gene; 516030) to 14005 (MTND5 gene; 516005). </p><p>Papadimitriou et al. (1998) examined skeletal muscle of 3 sibs, including a pair of monozygotic twins, with MNGIE. All showed ragged-red and cytochrome c oxidase (COX)-negative fibers, as well as partial deficiency of complexes I and IV. Southern blot analyses showed mtDNA depletion in all patients, and PCR analysis detected multiple mtDNA deletions. Papadimitriou et al. (1998) suggested that the combination of partial depletion and multiple deletions of mtDNA was consistent with derangement of a common genetic mechanism controlling mtDNA copy number and integrity. </p><p>As pointed out by Suomalainen and Kaukonen (2001), the common mechanism underlying the defects in MNGIE and autosomal dominant progressive external ophthalmoplegia (157640) may be disturbed mitochondrial nucleoside pools, the building blocks of mtDNA. They pointed out that mitochondrial DNA stability is tightly controlled in mammals. In Saccharomyces cerevisiae, over 100 genes are known that result in mtDNA loss when defective (Contamine and Picard, 2000). Mitochondrial DNA depletion can also be caused by environmental influences, such as exposure to nucleoside analogs or zidovudine (Arnaudo et al., 1991), a drug used to treat HIV-infected patients. In these cases the depletion is reversible, and the mtDNA levels are restored after withdrawal of the drug. </p><p>Fairbanks et al. (2002) reported the presence of an unusual nucleoside deoxyuridine in the urine of a patient with MNGIE due to thymidine phosphorylase deficiency. Thymidine, uracil, and thymine were also elevated. Fairbanks et al. (2002) proposed that inhibition of thymidylate synthetase by thymidylate (TMP) leads to the accumulation of dUMP which may be degraded to deoxyuridine or metabolized to dUTP. Incorporation of dUTP into mitochondrial DNA may explain the multiple deletions characteristic of thymidine phosphorylase deficiency. </p><p>Marti et al. (2003) also reported the accumulation of deoxyuridine in MNGIE. In patients, circulating levels ranged from 5.5 to 24.4 microM (average 14.2) and were undetectable in both heterozygous ECGF1 (TYMP; 131222) mutation carriers and in controls. The authors proposed that accumulation of deoxyuridine may contribute to nucleotide pool imbalances and, together with increased levels of thymidine, is likely to contribute to the pathogenesis of MNGIE. </p><p>Song et al. (2003) demonstrated that increased thymidine in cultured HeLa cells caused an imbalance in mitochondrial nucleoside pools resulting in multiple mtDNA deletions and point mutations. The mutagenic mechanism often involved T-G mispairing followed by a next-nucleotide effect involving T insertion opposite A. </p><p>Nishigaki et al. (2004) identified 5 major forms of mtDNA deletions in the skeletal muscle of MNGIE patients. Direct repeats and imperfectly homologous sequences appeared to mediate the formation of mtDNA deletions, and the MTND5 gene was a hotspot for these rearrangements. A novel aspect of mtDNA deletions in MNGIE was the presence of microdeletions at the imperfectly homologous breakpoints. </p><p>Hirano et al. (2005) summarized the studies of mitochondrial nucleoside imbalances in thymidine phosphorylase deficiency, and concluded that these imbalances generate mtDNA alterations, such as depletion, deletion, and point mutations, that differ between tissues and result in clinical features. They also noted the 'muscle paradox': although TYMP is not expressed in skeletal muscle, that tissue nevertheless shows mitochondrial abnormalities in most cases. </p><p>By postmortem examination of 5 unrelated patients with TYMP-related MNGIE, Giordano et al. (2008) found atrophy and vacuolization of smooth muscle cells and interstitial fibrosis in the external layer of the muscularis propria, stomach, and small intestine. There was also marked mitochondrial proliferation and COX-negative staining in smooth muscle cells in the muscularis propria and in endothelial cells and smooth muscle cells from small arteries in visceral organs. Marked mtDNA depletion was found in small intestine and stomach tissue homogenates, but mtDNA deletions were not found in smooth muscle cells. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. The findings indicated that visceral mitochondrial myopathy likely causes the gastrointestinal dysmotility in these patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in small vessel walls. </p>
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<strong>Clinical Management</strong>
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<p>Kripps et al. (2020) reported the outcomes of liver transplantation in 4 patients with MTDPS1. The first patient presented at age 14 months with emesis, elevated transaminases, hyperbilirubinemia, and coagulopathy. Brain MRI showed T2-hyperintense white matter lesions. He had developmental delay, decreased tone and decreased patellar reflexes. Following liver transplantation at age 26 months, his thymidine levels dropped more than 20-fold. MRI at age 3 years 7 months showed stability of the T2-hyperintense lesions. There was no evidence of gastrointestinal dysmotility. His nonverbal IQ score at age 4 years 9 months was 91. The second patient was diagnosed at age 36 years with findings of increased T2-hyperintense lesions on brain MRI, external ophthalmoplegia, ptosis, fatigue, and peripheral neuropathy. Following liver transplantation at age 37, her thymidine levels decreased by 11-fold. She had increased energy levels and decreased neuropathic pain. Ophthalmoplegia, ptosis, and peripheral neuropathy were stable 10 months posttransplantation. The third patient was diagnosed at age 20 years with features of peripheral neuropathy, diabetes, and severe gastrointestinal symptoms. At age 21, brain MRI showed diffuse leukoencephalopathy, and she developed a decreased left ventricular ejection fraction. Following liver transplantation, her thymidine levels normalized. She had improved gastrointestinal symptoms, normalization of her hemoglobin A1C, and normalization of her left ventricular ejection fraction. She reported no improvement in strength and stable peripheral neuropathy symptoms. The fourth patient was diagnosed at age 22 years with symptoms of peripheral neuropathy, liver cirrhosis, gastrointestinal dysmotility, and fatigue. Following liver transplantation at age 23, his thymidine levels decreased by 24-fold. Four months posttransplantation, his gastrointestinal symptoms, strength, and proprioception improved. He continued to have decreased muscle mass, ophthalmoplegia, and paresthesia. Kripps et al. (2020) concluded that liver transplantation in these 4 patients resulted in 100% short-term survival, stabilization of disease symptoms, decrease in thymidine levels, and some clinical improvements. </p>
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<strong>Inheritance</strong>
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<p>Hirano et al. (1994) suggested that this disorder is an autosomal recessive trait. They based this on the fact that 19 of 25 patients had affected sibs and 5 were the children of 3 pairs of consanguineous parents. Only 5 cases were sporadic. Of 8 patients studied by Hirano et al. (1994), 4 were found to have multiple deletions of mitochondrial DNA on Southern blot. They commented that this finding 'merits further investigation.' One of the patients with multiple deletions was the same patient as that reported by Threlkeld et al. (1992) and Johns et al. (1993). It is possible that this is an autosomal recessive equivalent of the phenomenon of multiple mitochondrial deletions resulting from a dominant nuclear mutation as observed by Zeviani et al. (1989). </p><p>Douglas et al. (2011) reported a patient, born of unrelated northern European parents, with classic MNGIE due to an apparently homozygous mutation in the TYMP gene. However, analysis of parental DNA showed that only the mother carried the mutation in the heterozygous state. Analysis of patient tissue ruled out gene deletion, and SNP array analysis showed a block of copy-neutral absence of heterozygosity, consistent with segmental uniparental isodisomy for an 11.3-Mb region of chromosome 22 including the TYMP gene. The findings had implications for genetic counseling. </p>
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<strong>Mapping</strong>
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</span>
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<span class="mim-text-font">
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<p>Although some findings, particularly multiple mtDNA deletions, point to MNGIE being a mitochondrial disorder, other characteristics suggest autosomal recessive inheritance with a defect in intergenomic communication. Autosomal recessive inheritance has been inferred because of (1) the high recurrence rate among sibs (14 of 49 sibs of probands), (2) the lack of affected parents and progeny, and (3) the relatively high rate of consanguinity (4 of 19 families) (Hirano et al., 1994; Hirano et al., 1998). For this reason, Hirano et al. (1998) performed linkage analysis in 4 families of diverse ethnic extraction and mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum 2-point lod score of 6.80 at locus D22S526. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Nishino et al. (1999) identified homozygous and compound heterozygous mutations in the TYMP gene in 12 MNGIE probands (see 131222.0001-131222.0008). Nishino et al. (2000) reported a total of 16 TYMP mutations identified in 21 probands. Homozygous or compound heterozygous mutations were present in all 35 patients tested. </p><p>In a patient with a classic MNGIE clinical presentation but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, Szigeti et al. (2004) identified a homozygous splice site mutation in the TYMP gene (131222.0010). Szigeti et al. (2004) concluded that it is important to examine the most significantly affected tissue and to measure thymidine phosphorylase activity and plasma thymidine to arrive at an accurate diagnosis in this condition. </p>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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<p>Marti et al. (2005) reported 3 unrelated patients with late-onset MNGIE confirmed by the identification of TYMP mutations (131222.0011-131222.0014). The patients developed symptoms at ages 40 to 52 years, later than that observed in patients with typical MNGIE. Plasma deoxythymidine levels were mildly elevated, ranging from 0.4 to 1.4 microM, indicating that even low levels are pathogenic. Biochemical analysis showed 9 to 16% residual TYMP activity, which likely accounted for the later onset in these patients. Unaffected heterozygous mutation carriers had 26 to 35% residual TYMP activity, suggesting a minimal level required to prevent disease. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Murine uridine phosphorylate, unlike human UPP1 (191730), cleaves thymidine as well as uridine. To knock out Tymp activity in mice, Haraguchi et al. (2002) created Upp1/Tymp double-knockout mice. They found no alterations in mitochondrial DNA or pathologic changes in the muscles of double-knockout mice, even when these mice were fed thymidine for 7 months. However, they found intense lesions in the brain on T2-weighted MRI, and axonal edema by electron microscopic study of the brain of double-knockout mice. Haraguchi et al. (2002) concluded that inhibition of TYMP activity causes elevation of pyrimidine levels in plasma and consequent axonal swelling. </p><p>Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. Lopez et al. (2009) generated Tymp-/- Upp1-/- double-knockout mice, which showed severe Tymp deficiency, increased thymidine and deoxyuridine in tissues, and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, the brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes, and encephalopathy. These findings largely account for the pathogenesis of MNGIE. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<p class="mim-text-font">
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Arnaudo, E., Dalakas, M., Shanske, S., Moraes, C. T., DiMauro, S., Schon, E. A.
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<strong>Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy.</strong>
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Lancet 337: 508-510, 1991.
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Bardosi, A., Creutzfeldt, W., DiMauro, S., Felgenhauer, K., Friede, R. L., Goebel, H. H., Kohlschutter, A., Mayer, G., Rahlf, G., Servidei, S., Van Lessen, G., Wetterling, T.
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<strong>Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase: a new mitochondrial multisystem disorder.</strong>
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Blake, D., Lombes, A., Minetti, C., Bonilla, E., Hays, A. P., Lovelace, A. E., Butler, I., DiMauro, S.
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Contamine, V., Picard, M.
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Douglas, G. V., Wiszniewska, J., Lipson, M. H., Witt, D. R., McDowell, T., Sifry-Platt, M., Hirano, M., Craigen, W. J., Wong, L.-J. C.
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Faber, J., Fich, A., Steinberg, A., Steiner, I., Granot, E., Alon, I., Rachmilevitz, D., Freier, S., Gilai, A.
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<strong>Familial intestinal pseudoobstruction dominated by a progressive neurologic disease at a young age.</strong>
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Gastroenterology 92: 786-790, 1987.
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Fairbanks, L. D., Marinaki, A. M., Carrey, E. A., Hammans, S. R., Duley, J. A.
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Fried, K., Arlozorov, A., Spria, R.
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<p class="mim-text-font">
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Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M.
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<strong>Phenotypic variability in a Spanish family with MNGIE.</strong>
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[PubMed: 12177387]
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Giordano, C., Sebastiani, M., De Giorgio, R., Travaglini, C., Tancredi, A., Valentino, M. L., Bellan, M., Cossarizza, A., Hirano, M., d'Amati, G., Carelli, V.
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<strong>Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion.</strong>
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Am. J. Path. 173: 1120-1128, 2008.
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