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Entry
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- #609560 - MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2
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- OMIM
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<p>
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<span class="h4">#609560</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="/clinicalSynopsis/609560"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS603041"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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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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</ul>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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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 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 2 (MYOPATHIC 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=19793&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/NBK114628/" 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/8897" 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://medlineplus.gov/genetics/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=609560[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=254875" 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 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:0080120" 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/609560" 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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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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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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<strong>SNOMEDCT:</strong> 703527003<br />
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<strong>ORPHA:</strong> 254875<br />
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<strong>DO:</strong> 0080120<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<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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609560
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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>
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<span class="mim-font">
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MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2
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</span>
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</h3>
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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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<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>
|
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<span class="mim-font">
|
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MITOCHONDRIAL DNA DEPLETION MYOPATHY, TK2-RELATED
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</span>
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</h4>
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</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>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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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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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/16/511?start=-3&limit=10&highlight=511">
|
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16q21
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</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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Mitochondrial DNA depletion syndrome 2 (myopathic type)
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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/609560"> 609560 </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>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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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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TK2
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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/188250"> 188250 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/609560" 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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS603041" class="btn btn-info" role="button"> Phenotypic Series </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
|
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/609560" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/609560" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</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>
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<div>
|
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<p />
|
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</div>
|
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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|
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<div>
|
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<span class="mim-font">
|
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|
|
- 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 />
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|
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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>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
|
|
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|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Facial diplegia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836003&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836003</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001349" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001349</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001349" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001349</a>]</span><br />
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|
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</span>
|
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</div>
|
|
</div>
|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- External ophthalmoplegia, progressive (in some patients) <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 />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Respiratory insufficiency due to muscle weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806467&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806467</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002747" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002747</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002747" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002747</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409622000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409622000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409623005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409623005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J96.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J96.9</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
|
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|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
|
|
Muscle weakness, proximal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249939004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249939004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221629&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221629</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003701" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003701</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003701" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003701</a>]</span><br /> -
|
|
Gowers sign <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85905009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85905009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234182&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234182</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003391" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003391</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003391" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003391</a>]</span><br /> -
|
|
Muscle atrophy, diffuse <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1389113&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1389113</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003700" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003700</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003700" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003700</a>]</span><br /> -
|
|
Limb muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/713514005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">713514005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0587246&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0587246</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003690" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003690</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003690" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003690</a>]</span><br /> -
|
|
Delayed motor skills <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/430099007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">430099007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854301&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854301</a>, <a href="https://bioportal.bioontology.org/search?q=C1837658&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837658</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002194" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002194</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002194" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002194</a>]</span><br /> -
|
|
Inability to walk <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/282145008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">282145008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0560046&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0560046</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002540" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002540</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002540" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002540</a>]</span><br /> -
|
|
Loss of ability to walk in early childhood <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835993&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835993</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008945" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008945</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008945" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008945</a>]</span><br /> -
|
|
Myopathic changes seen on EMG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3276190&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3276190</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/129565002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">129565002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G72.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G72.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M62.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M62.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M60-M63" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M60-M63</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/359.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">359.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003198</a>]</span><br /> -
|
|
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 /> -
|
|
Skeletal muscle tissue shows 14 to 45% depletion of mitochondrial DNA (mtDNA) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835994</a>]</span><br /> -
|
|
Skeletal muscle may show less severe mtDNA deletion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013282&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013282</a>]</span><br /> -
|
|
Decreased activities of mitochondrial-encoded respiratory chain complexes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835995&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835995</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008972" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008972</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008972" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008972</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> METABOLIC FEATURES </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">
|
|
|
|
- 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 />
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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">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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|
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<div>
|
|
<span class="mim-font">
|
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|
|
- Increased serum creatine kinase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span><br /> -
|
|
Aminoaciduria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35912001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35912001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0238621&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0238621</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003355</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003355</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">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</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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|
|
- Onset usually by age 2 years<br /> -
|
|
Later onset has been reported<br /> -
|
|
Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><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 />
|
|
|
|
</span>
|
|
</div>
|
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|
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</div>
|
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the nuclear-encoded mitochondrial thymidine kinase gene (TK2, <a href="/entry/188250#0001">188250.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
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</div>
|
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</div>
|
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|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
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|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
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|
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|
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<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 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/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/10/214?start=-3&limit=10&highlight=214"> 10q21.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617156"> ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617156"> 617156 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600438"> TFAM </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600438"> 600438 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/10/489?start=-3&limit=10&highlight=489"> 10q24.31 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/271245"> Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/271245"> 271245 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606075"> TWNK </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606075"> 606075 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/13/158?start=-3&limit=10&highlight=158"> 13q14.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612073"> Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612073"> 612073 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603921"> SUCLA2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603921"> 603921 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/14/182?start=-3&limit=10&highlight=182"> 14q13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618811"> ?Mitochondrial DNA depletion syndrome 18 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618811"> 618811 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607571"> SLC25A21 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607571"> 607571 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/15/498?start=-3&limit=10&highlight=498"> 15q26.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613662"> Mitochondrial DNA depletion syndrome 4B (MNGIE type) </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613662"> 613662 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/174763"> POLG </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/174763"> 174763 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/15/498?start=-3&limit=10&highlight=498"> 15q26.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/203700"> Mitochondrial DNA depletion syndrome 4A (Alpers type) </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
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</td>
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<a href="/entry/619425"> ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type) </a>
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<a href="/entry/618528"> ?Mitochondrial DNA depletion syndrome 16 (hepatic type) </a>
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<a href="/entry/618972"> ?Mitochondrial DNA depletion syndrome 19 </a>
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<a href="/entry/606794"> SLC25A10 </a>
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<a href="/entry/615084"> Mitochondrial DNA depletion syndrome 11 </a>
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<a href="/entry/603041"> Mitochondrial DNA depletion syndrome 1 (MNGIE type) </a>
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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 (mtDNA) depletion syndrome-2 (MTDPS2) is caused by homozygous or compound heterozygous mutation in the mitochondrial thymidine kinase gene (TK2; <a href="/entry/188250">188250</a>) on chromosome 16q21.</p>
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<p>Mitochondrial DNA depletion syndrome-2 is an autosomal recessive disorder characterized primarily by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later childhood onset of a slowly progressive myopathy (<a href="#10" class="mim-tip-reference" title="Oskoui, M., Davidzon, G., Pascual, J., Erazo, R., Gurgel-Giannetti, J., Krishna, S., Bonilla, E., De Vivo, D. C., Shanske, S., DiMauro, S. <strong>Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene.</strong> Arch. Neurol. 63: 1122-1126, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908738</a>] [<a href="https://doi.org/10.1001/archneur.63.8.1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908738">Oskoui et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16908738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (<a href="/entry/603041">603041</a>).</p>
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<p><a href="#4" class="mim-tip-reference" title="Boustany, R. N., Aprille, J. R., Halperin, J., Levy, H., DeLong, G. R. <strong>Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin.</strong> Ann. Neurol. 14: 462-470, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6314875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6314875</a>] [<a href="https://doi.org/10.1002/ana.410140411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6314875">Boustany et al. (1983)</a> reported a female infant with a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. Electron microscopy of skeletal muscle in the proband showed marked proliferation of enlarged mitochondria, many containing concentric rings of cristae, and biochemical studies showed severely decreased cytochrome c oxidase activity (less than 1% of normal). Mitochondria from kidney, liver, heart, lung, and brain examined postmortem had normal cytochromes and preserved cytochrome c oxidase activity. A second cousin, related through the maternal grandfather, died at 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement, consistent with the hepatocerebral form of the disorder. In the second cousin, liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. In an addendum, the authors noted that a sister of the proband presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. Findings of electron microscopy and biochemical analysis of muscle and liver biopsy specimens were identical to those in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6314875" 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 tissue samples from the original proband and second cousin reported by <a href="#4" class="mim-tip-reference" title="Boustany, R. N., Aprille, J. R., Halperin, J., Levy, H., DeLong, G. R. <strong>Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin.</strong> Ann. Neurol. 14: 462-470, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6314875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6314875</a>] [<a href="https://doi.org/10.1002/ana.410140411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6314875">Boustany et al. (1983)</a>, <a href="#9" class="mim-tip-reference" title="Moraes, C. T., Shanske, S., Tritschler, H.-J., Aprille, J. R., Andreetta, F., Bonilla, E., Schon, E. A., DiMauro, S. <strong>mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.</strong> Am. J. Hum. Genet. 48: 492-501, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1998336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1998336</a>]" pmid="1998336">Moraes et al. (1991)</a> found a quantitative defect of mtDNA restricted to skeletal muscle (2% of control values) in the proband, and involving liver (12% of control values) in the second cousin. A third unrelated patient had mtDNA deficiency in muscle only (3% of control values), and a fourth in muscle and kidney only (17% control values in both tissues). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. <a href="#9" class="mim-tip-reference" title="Moraes, C. T., Shanske, S., Tritschler, H.-J., Aprille, J. R., Andreetta, F., Bonilla, E., Schon, E. A., DiMauro, S. <strong>mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.</strong> Am. J. Hum. Genet. 48: 492-501, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1998336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1998336</a>]" pmid="1998336">Moraes et al. (1991)</a> concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1998336+6314875" 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="Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A. <strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong> Neurology 42: 209-217, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734306</a>] [<a href="https://doi.org/10.1212/wnl.42.1.209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1734306">Tritschler et al. (1992)</a> reported 5 children with mitochondrial myopathy manifesting within or soon after the first year of life. Muscle biopsies showed ragged-red fibers and decreased respiratory chain activity associated with a decreased amount (2 to 34% of normal) of muscle mitochondrial DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1734306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Vila, M. R., Segovia-Silvestre, T., Gamez, J., Marina, A., Naini, A. B., Meseguer, A., Lombes, A., Bonilla, E., DiMauro, S., Hirano, M., Andreu, A. L. <strong>Reversion of mtDNA depletion in a patient with TK2 deficiency.</strong> Neurology 60: 1203-1205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12682338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12682338</a>] [<a href="https://doi.org/10.1212/01.wnl.0000055928.58122.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12682338">Vila et al. (2003)</a> described an unusual case of a 14-year-old boy with the myopathic form of the disorder who was a compound heterozygote for mutations in the TK2 gene. Symptoms were manifest since birth, and muscle examination at ages 3 and 8 years showed ragged-red fibers, deficiency of cytochrome c oxidase, and severe depletion of mtDNA. Activities of mitochondrial respiratory chain enzymes at that time were normal. Reexamination at age 14 years showed progression of the disease and muscle biopsy showed severe muscle atrophy, no mtDNA depletion, and decreased activities of all respiratory chain enzymes. <a href="#15" class="mim-tip-reference" title="Vila, M. R., Segovia-Silvestre, T., Gamez, J., Marina, A., Naini, A. B., Meseguer, A., Lombes, A., Bonilla, E., DiMauro, S., Hirano, M., Andreu, A. L. <strong>Reversion of mtDNA depletion in a patient with TK2 deficiency.</strong> Neurology 60: 1203-1205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12682338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12682338</a>] [<a href="https://doi.org/10.1212/01.wnl.0000055928.58122.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12682338">Vila et al. (2003)</a> noted that the patient had an unusually long survival time and suggested that mtDNA-depleted muscle fibers had become atrophic or died over time, while fibers with normal mtDNA had survived. Respiratory enzyme deficiency was attributed to accumulation of somatic mitochondrial mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12682338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of skeletal muscle fibers from 2 sibs with mtDNA depletion myopathy due to TK2 mutations, who were previously reported by <a href="#8" class="mim-tip-reference" title="Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H. <strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong> Neurology 59: 1197-1202, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391347</a>] [<a href="https://doi.org/10.1212/01.wnl.0000028689.93049.9a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391347">Mancuso et al. (2002)</a>, <a href="#5" class="mim-tip-reference" title="Durham, S. E., Bonilla, E., Samuels, D. C., DiMauro, S., Chinnery, P. F. <strong>Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.</strong> Neurology 65: 453-455, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087914</a>] [<a href="https://doi.org/10.1212/01.wnl.0000171861.30277.88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087914">Durham et al. (2005)</a> determined that muscle fiber mtDNA density of 0.01 mtDNA per cubic micrometer was the minimal amount of mtDNA required to maintain residual cytochrome c oxidase (COX) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12391347+16087914" 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="Oskoui, M., Davidzon, G., Pascual, J., Erazo, R., Gurgel-Giannetti, J., Krishna, S., Bonilla, E., De Vivo, D. C., Shanske, S., DiMauro, S. <strong>Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene.</strong> Arch. Neurol. 63: 1122-1126, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908738</a>] [<a href="https://doi.org/10.1001/archneur.63.8.1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908738">Oskoui et al. (2006)</a> reported 4 unrelated patients with the myopathic form of mtDNA depletion syndrome due to TK2 mutations. There was significant clinical variability: 1 patient had a rapidly progressive course with death at age 19 months, whereas the others showed a more protracted course. One died at age 6 years and another at age 16 years. The fourth child was alive at age 9 years and could walk independently with lumbar lordosis and toe walking. She had facial diplegia, decreased muscle mass, diffuse muscle weakness, and normal pulmonary function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16908738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Paradas, C., Gutierrez Rios, P., Rivas, E., Carbonell, P., Hirano, M., DiMauro, S. <strong>TK2 mutation presenting as indolent myopathy.</strong> Neurology 80: 504-506, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23303857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23303857</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827f0ff7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23303857">Paradas et al. (2013)</a> reported a 22-year-old man, born of consanguineous parents, with genetically confirmed MTDPS2 (T108M; <a href="/entry/188250#0003">188250.0003</a>) and a somewhat protracted course. He had normal development until age 24 months, when he showed proximal muscle weakness of the lower limbs resulting in a waddling gait. At age 20, he had a nasal voice and mild proximal arm weakness. After sudden onset of respiratory arrest triggered by pneumonia, he had rapid worsening of the muscle weakness and became wheelchair-bound. He had severe axial and proximal muscle weakness, facial weakness without ptosis, pectoral atrophy, scapular winging, and ankle contractures. He also had significant gynecomastia of unclear etiology. Laboratory studies showed increased serum creatine kinase and normal serum lactate. Muscle samples showed dystrophic features, endomysial fibrosis, abnormally shaped mitochondria, decreased mitochondrial complex I activity (35% of normal), and multiple mtDNA deletions (45% residual mtDNA). Family history revealed a 3-year-old sister who died of respiratory failure due to muscular dystrophy as well as 2 infant deaths in previous generations. The report was notable for significant intrafamilial phenotypic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23303857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al. (2012)</a> reported 3 unrelated patients with genetically confirmed MTDPS2 who had a milder course and slower progression than usually associated with this disorder. Although all patients reported some form of hypotonia, early fatigue, or delayed walking in early childhood and 2 had proximal muscle weakness in childhood, all presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and 1 could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal in all patients. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. However, there were no genotype/phenotype correlations, as 2 patients were homozygous for a previously reported mutation (T108M; <a href="/entry/188250#0003">188250.0003</a>) that had been observed in children with a more severe form of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" 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>In patients with the myopathic form of mtDNA depletion syndrome, <a href="#13" class="mim-tip-reference" title="Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O. <strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong> Nature Genet. 29: 342-344, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>] [<a href="https://doi.org/10.1038/ng751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687801">Saada et al. (2001)</a> identified mutations in the mitochondrial thymidine kinase gene, H90N and I181N, now H163N (<a href="/entry/188250#0001">188250.0001</a>) and I254N (<a href="/entry/188250#0002">188250.0002</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687801" 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>To further characterize the frequency and clinical spectrum of the causative mutations, <a href="#8" class="mim-tip-reference" title="Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H. <strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong> Neurology 59: 1197-1202, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391347</a>] [<a href="https://doi.org/10.1212/01.wnl.0000028689.93049.9a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391347">Mancuso et al. (2002)</a> screened 20 patients with myopathic mtDNA depletion syndrome. No patient had mutations in the deoxyguanosine kinase gene (DGUOK; <a href="/entry/601465">601465</a>), but 4 patients from 2 families had TK2 mutations. Two sibs were compound heterozygotes for a previously reported H163N mutation (<a href="/entry/188250#0001">188250.0001</a>) and a novel T77M mutation (now T150M; <a href="/entry/188250#0003">188250.0003</a>). Another pair of sibs harbored a homozygous I22M mutation (now I95M; <a href="/entry/188250#0004">188250.0004</a>), and 1 had evidence of lower motor neuron disease. Thus, the clinical expression of TK2 mutations is not limited to myopathy. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28 to 37% of controls). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391347" 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 family originally described by <a href="#14" class="mim-tip-reference" title="Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A. <strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong> Neurology 42: 209-217, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734306</a>] [<a href="https://doi.org/10.1212/wnl.42.1.209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1734306">Tritschler et al. (1992)</a> in which 3 sibs had myopathic mtDNA depletion syndrome, <a href="#7" class="mim-tip-reference" title="Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., DiMauro, S. <strong>Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.</strong> Arch. Neurol. 60: 1007-1009, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12873860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12873860</a>] [<a href="https://doi.org/10.1001/archneur.60.7.1007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12873860">Mancuso et al. (2003)</a> identified homozygosity for the T150M mutation. The patients had 80 to 90% mtDNA depletion in muscle biopsy specimens, and all died by age 40 months. The authors noted that exon 5 is a hotspot for TK2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1734306+12873860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The human mitochondrial transcription factor A (TFAM; <a href="/entry/600438">600438</a>) is a 25-kD protein that may be an important regulator of both transcription and replication of mtDNA. Deficiency of the yeast homolog, ABF2, is associated with loss of mtDNA. This prompted <a href="#12" class="mim-tip-reference" title="Poulton, J., Morten, K., Freeman-Emmerson, C., Potter, C., Sewry, C., Dubowitz, V., Kidd, H., Stephenson, J., Whitehouse, W., Hansen, F. J., Parisi, M., Brown, G. <strong>Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion.</strong> Hum. Molec. Genet. 3: 1763-1769, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849699</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849699">Poulton et al. (1994)</a> to investigate both protein and mRNA levels for this factor in cell lines experimentally depleted of mtDNA and in patients with myopathic mtDNA depletion to determine whether these conditions are associated with a deficiency of TFAM. They found that the ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle from the 3 patients and in other tissues in 1. Furthermore, TFAM was low in cells depleted either permanently or transiently of mtDNA, and this reduction roughly paralleled mtDNA levels. They concluded that deficiency of TFAM may be a marker of, or possibly a cause of, mtDNA depletion in some patients with this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Wang, L., Saada, A., Eriksson, S. <strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong> J. Biol. Chem. 278: 6963-6968, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12493767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12493767</a>] [<a href="https://doi.org/10.1074/jbc.M206143200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12493767">Wang et al. (2003)</a> found that recombinant human TK2 with either the H163N (<a href="/entry/188250#0001">188250.0001</a>) or the I254N (<a href="/entry/188250#0002">188250.0002</a>) mutation, which they called H121N and I212N, respectively, had a similar subunit structure compared with wildtype TK2. The I212N mutant enzyme showed less than 1% activity compared with wildtype TK2 with all deoxynucleosides. The H121N mutant enzyme had normal Km values for thymidine and deoxycytidine, but 2- and 3-fold lower Vmax values, respectively, compared with wildtype TK2 and markedly increased Km values for ATP, leading to decreased enzyme efficiency. Competition experiments revealed that thymidine and deoxycytidine interacted differently with the H121N mutant compared with wildtype TK2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12493767" 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="#1" class="mim-tip-reference" title="Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M. <strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong> Hum. Molec. Genet. 17: 2433-2440, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18467430[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/ddn143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18467430">Akman et al. (2008)</a> created mice harboring a his126-to-asn (H126N) mutation in the Tk2 gene, which is homologous to the H163N mutation (<a href="/entry/188250#0001">188250.0001</a>) in humans. Homozygous mutant mice (Tk2 -/-) were obtained at the expected mendelian frequency and appeared normal at birth. However, at postnatal day 10, they showed several defects relative to wildtype and heterozygous mutant littermates, including growth retardation, reduced spontaneous activity, generalized coarse tremor, and impaired gait. They rapidly developed weakness, leading to severe stress or death by 2 weeks of age. Tk2 -/- animals showed reduced Tk2 activity in all tissues analyzed, with activity reduced to 1.7% of wildtype in brain, the most severely affected tissue. In Tk2 -/- mice, brain mitochondria had a dTTP concentration about 20% of wildtype, and liver mitochondria showed reduced levels of both dTTP and dCTP. The content of other dNTPs in these tissues was unchanged, and dNTP levels in other tissues were not affected. Depletion of mtDNA was most prominent in brain, where it was 12.5% of wildtype, and only brain showed decreased activities of respiratory chain enzymes, primarily complexes I and IV, and reduced ATP levels and ATP/ADP ratios. Spinal cord neurons had abnormal vacuolar changes, and the white matter of spinal cord and cortex showed evidence of activated glial cells. <a href="#1" class="mim-tip-reference" title="Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M. <strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong> Hum. Molec. Genet. 17: 2433-2440, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18467430[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/ddn143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18467430">Akman et al. (2008)</a> concluded that, in contrast to the muscle-specific phenotype observed in patients with the H163N mutation, mice homozygous for the H126N mutation showed a rapidly progressive encephalomyelopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18467430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bartesaghi, S., Betts-Henderson, J., Cain, K., Dinsdale, D., Zhou, X., Karlsson, A., Salomoni, P., Nicotera, P. <strong>Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.</strong> Hum. Molec. Genet. 19: 1669-1677, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123860[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/ddq043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123860">Bartesaghi et al. (2010)</a> demonstrated that in vivo loss of Tk2 activity in mice led to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In Tk2-deficient cerebellar neurons, these abnormalities were associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure, and degeneration of selected neuronal types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20123860" 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="#6" class="mim-tip-reference" title="Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M. <strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong> Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34338329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34338329</a>] [<a href="https://doi.org/10.1002/ana.26185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34338329">Lopez-Gomez et al. (2021)</a> evaluated the effects of AAV gene therapy with and without pyrimidine deoxynucleoside (deoxycytidine (dC) and thymidine (dT)) treatment in a mouse model of Tk2 deficiency. AAV9 delivery of TK2 cDNA (AAV9-TK2) to the mutant mice on postnatal day 1 rescued Tk2 activity in liver, brain, and muscle but not in kidneys. The treated mutant mice had delayed disease onset and longer lifespan compared to untreated mutant mice. When the mice were treated with sequential AAV dosing, a dose of AAV9-TK2 on postnatal day 1 and then a dose of AAV2-TK2 on day 29, vector induction was not increased in the kidneys and vector genomes per nucleus were decreased in the brain and muscle compared to the mice treated with only AAV9-TK2. However, survival of the AAV9-TK2/AAV2-TK2 treated mice was significantly increased compared to the AAV9-TK2 treated and untreated mutant mice. Growth curves, motor function, and strength were similar in the AAV9-TK2/AAV2-TK2 treated mice and the AAV9-TK2 treated mice, and neither treatment cohort developed head tremors. The mutant mice were also treated with sequential AAV9-TK2/AAV2-TK2 dosing and with oral dC and dT from postnatal day 21 and had improved growth, survival, and mtDNA copy number in liver and kidneys compared to the other treatment cohorts of mutant mice. <a href="#6" class="mim-tip-reference" title="Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M. <strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong> Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34338329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34338329</a>] [<a href="https://doi.org/10.1002/ana.26185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34338329">Lopez-Gomez et al. (2021)</a> concluded that dC and dT supplementation enhances the effects of TK2 gene therapy and supports the potential for future combination therapy in patients with TK2 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34338329" 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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Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M.
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<strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong>
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Hum. Molec. Genet. 17: 2433-2440, 2008.
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[<a href="https://doi.org/10.1093/hmg/ddn143" target="_blank">Full Text</a>]
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Bartesaghi, S., Betts-Henderson, J., Cain, K., Dinsdale, D., Zhou, X., Karlsson, A., Salomoni, P., Nicotera, P.
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<strong>Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.</strong>
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Hum. Molec. Genet. 19: 1669-1677, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123860[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=20123860" 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/10.1093/hmg/ddq043" target="_blank">Full Text</a>]
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Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A.
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[<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410140411" target="_blank">Full Text</a>]
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Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M.
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<strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong>
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Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34338329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34338329</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34338329" 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/10.1002/ana.26185" target="_blank">Full Text</a>]
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Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., DiMauro, S.
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<strong>Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12873860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12873860</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12873860" 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/10.1001/archneur.60.7.1007" target="_blank">Full Text</a>]
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Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391347" 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/10.1212/01.wnl.0000028689.93049.9a" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16908738" 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/10.1001/archneur.63.8.1122" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Paradas2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Paradas, C., Gutierrez Rios, P., Rivas, E., Carbonell, P., Hirano, M., DiMauro, S.
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<strong>TK2 mutation presenting as indolent myopathy.</strong>
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Neurology 80: 504-506, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23303857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23303857</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23303857" 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/10.1212/WNL.0b013e31827f0ff7" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Poulton1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Poulton, J., Morten, K., Freeman-Emmerson, C., Potter, C., Sewry, C., Dubowitz, V., Kidd, H., Stephenson, J., Whitehouse, W., Hansen, F. J., Parisi, M., Brown, G.
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<strong>Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion.</strong>
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Hum. Molec. Genet. 3: 1763-1769, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849699</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849699" 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/10.1093/hmg/3.10.1763" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Saada2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O.
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<strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong>
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Nature Genet. 29: 342-344, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687801" 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/ng751" target="_blank">Full Text</a>]
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</p>
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<a id="14" class="mim-anchor"></a>
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<a id="Tritschler1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A.
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<strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong>
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Neurology 42: 209-217, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1734306" 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/10.1212/wnl.42.1.209" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Vila2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vila, M. R., Segovia-Silvestre, T., Gamez, J., Marina, A., Naini, A. B., Meseguer, A., Lombes, A., Bonilla, E., DiMauro, S., Hirano, M., Andreu, A. L.
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<strong>Reversion of mtDNA depletion in a patient with TK2 deficiency.</strong>
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Neurology 60: 1203-1205, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12682338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12682338</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12682338" 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/10.1212/01.wnl.0000055928.58122.47" target="_blank">Full Text</a>]
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Wang2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, L., Saada, A., Eriksson, S.
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<strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong>
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J. Biol. Chem. 278: 6963-6968, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12493767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12493767</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12493767" 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/10.1074/jbc.M206143200" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/11/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 12/3/2014<br>Cassandra L. Kniffin - updated : 10/25/2012<br>George E. Tiller - updated : 12/2/2011<br>Cassandra L. Kniffin - updated : 12/9/2010<br>Matthew B. Gross - updated : 11/3/2009<br>Patricia A. Hartz - updated : 11/3/2009<br>Cassandra L. Kniffin - updated : 8/29/2007<br>Cassandra L. Kniffin - updated : 7/27/2007<br>Cassandra L. Kniffin - updated : 11/8/2006<br>Cassandra L. Kniffin - updated : 10/31/2005
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 8/31/2005
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/17/2022
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 11/11/2021<br>carol : 08/12/2016<br>ckniffin : 08/11/2016<br>carol : 06/08/2016<br>carol : 6/22/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>alopez : 12/15/2014<br>mcolton : 12/12/2014<br>ckniffin : 12/3/2014<br>carol : 11/5/2012<br>ckniffin : 10/25/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>carol : 12/21/2010<br>ckniffin : 12/9/2010<br>mgross : 11/3/2009<br>mgross : 11/3/2009<br>ckniffin : 10/12/2009<br>wwang : 5/28/2008<br>ckniffin : 5/22/2008<br>wwang : 9/4/2007<br>ckniffin : 8/29/2007<br>alopez : 8/8/2007<br>ckniffin : 7/27/2007<br>wwang : 11/9/2006<br>ckniffin : 11/8/2006<br>wwang : 11/3/2005<br>ckniffin : 10/31/2005<br>ckniffin : 9/20/2005<br>carol : 9/20/2005<br>ckniffin : 8/31/2005
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<span class="mim-font">
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<strong>#</strong> 609560
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE); MTDPS2
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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MITOCHONDRIAL DNA DEPLETION MYOPATHY, TK2-RELATED
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 703527003;
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<strong>ORPHA:</strong> 254875;
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<strong>DO:</strong> 0080120;
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</span>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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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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<td>
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<span class="mim-font">
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16q21
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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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Mitochondrial DNA depletion syndrome 2 (myopathic type)
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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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609560
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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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Autosomal recessive
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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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3
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</td>
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<td>
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<span class="mim-font">
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TK2
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</td>
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<td>
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<span class="mim-font">
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188250
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because mitochondrial DNA (mtDNA) depletion syndrome-2 (MTDPS2) is caused by homozygous or compound heterozygous mutation in the mitochondrial thymidine kinase gene (TK2; 188250) on chromosome 16q21.</p>
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</span>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Mitochondrial DNA depletion syndrome-2 is an autosomal recessive disorder characterized primarily by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later childhood onset of a slowly progressive myopathy (Oskoui et al., 2006). </p><p>For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).</p>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</h4>
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<span class="mim-text-font">
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<p>Boustany et al. (1983) reported a female infant with a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. Electron microscopy of skeletal muscle in the proband showed marked proliferation of enlarged mitochondria, many containing concentric rings of cristae, and biochemical studies showed severely decreased cytochrome c oxidase activity (less than 1% of normal). Mitochondria from kidney, liver, heart, lung, and brain examined postmortem had normal cytochromes and preserved cytochrome c oxidase activity. A second cousin, related through the maternal grandfather, died at 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement, consistent with the hepatocerebral form of the disorder. In the second cousin, liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. In an addendum, the authors noted that a sister of the proband presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. Findings of electron microscopy and biochemical analysis of muscle and liver biopsy specimens were identical to those in the proband. </p><p>In tissue samples from the original proband and second cousin reported by Boustany et al. (1983), Moraes et al. (1991) found a quantitative defect of mtDNA restricted to skeletal muscle (2% of control values) in the proband, and involving liver (12% of control values) in the second cousin. A third unrelated patient had mtDNA deficiency in muscle only (3% of control values), and a fourth in muscle and kidney only (17% control values in both tissues). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. Moraes et al. (1991) concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients. </p><p>Tritschler et al. (1992) reported 5 children with mitochondrial myopathy manifesting within or soon after the first year of life. Muscle biopsies showed ragged-red fibers and decreased respiratory chain activity associated with a decreased amount (2 to 34% of normal) of muscle mitochondrial DNA. </p><p>Vila et al. (2003) described an unusual case of a 14-year-old boy with the myopathic form of the disorder who was a compound heterozygote for mutations in the TK2 gene. Symptoms were manifest since birth, and muscle examination at ages 3 and 8 years showed ragged-red fibers, deficiency of cytochrome c oxidase, and severe depletion of mtDNA. Activities of mitochondrial respiratory chain enzymes at that time were normal. Reexamination at age 14 years showed progression of the disease and muscle biopsy showed severe muscle atrophy, no mtDNA depletion, and decreased activities of all respiratory chain enzymes. Vila et al. (2003) noted that the patient had an unusually long survival time and suggested that mtDNA-depleted muscle fibers had become atrophic or died over time, while fibers with normal mtDNA had survived. Respiratory enzyme deficiency was attributed to accumulation of somatic mitochondrial mutations. </p><p>In a study of skeletal muscle fibers from 2 sibs with mtDNA depletion myopathy due to TK2 mutations, who were previously reported by Mancuso et al. (2002), Durham et al. (2005) determined that muscle fiber mtDNA density of 0.01 mtDNA per cubic micrometer was the minimal amount of mtDNA required to maintain residual cytochrome c oxidase (COX) activity. </p><p>Oskoui et al. (2006) reported 4 unrelated patients with the myopathic form of mtDNA depletion syndrome due to TK2 mutations. There was significant clinical variability: 1 patient had a rapidly progressive course with death at age 19 months, whereas the others showed a more protracted course. One died at age 6 years and another at age 16 years. The fourth child was alive at age 9 years and could walk independently with lumbar lordosis and toe walking. She had facial diplegia, decreased muscle mass, diffuse muscle weakness, and normal pulmonary function. </p><p>Paradas et al. (2013) reported a 22-year-old man, born of consanguineous parents, with genetically confirmed MTDPS2 (T108M; 188250.0003) and a somewhat protracted course. He had normal development until age 24 months, when he showed proximal muscle weakness of the lower limbs resulting in a waddling gait. At age 20, he had a nasal voice and mild proximal arm weakness. After sudden onset of respiratory arrest triggered by pneumonia, he had rapid worsening of the muscle weakness and became wheelchair-bound. He had severe axial and proximal muscle weakness, facial weakness without ptosis, pectoral atrophy, scapular winging, and ankle contractures. He also had significant gynecomastia of unclear etiology. Laboratory studies showed increased serum creatine kinase and normal serum lactate. Muscle samples showed dystrophic features, endomysial fibrosis, abnormally shaped mitochondria, decreased mitochondrial complex I activity (35% of normal), and multiple mtDNA deletions (45% residual mtDNA). Family history revealed a 3-year-old sister who died of respiratory failure due to muscular dystrophy as well as 2 infant deaths in previous generations. The report was notable for significant intrafamilial phenotypic heterogeneity. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Behin et al. (2012) reported 3 unrelated patients with genetically confirmed MTDPS2 who had a milder course and slower progression than usually associated with this disorder. Although all patients reported some form of hypotonia, early fatigue, or delayed walking in early childhood and 2 had proximal muscle weakness in childhood, all presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and 1 could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal in all patients. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. However, there were no genotype/phenotype correlations, as 2 patients were homozygous for a previously reported mutation (T108M; 188250.0003) that had been observed in children with a more severe form of the disorder. </p>
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<h4>
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>In patients with the myopathic form of mtDNA depletion syndrome, Saada et al. (2001) identified mutations in the mitochondrial thymidine kinase gene, H90N and I181N, now H163N (188250.0001) and I254N (188250.0002), respectively. </p><p>To further characterize the frequency and clinical spectrum of the causative mutations, Mancuso et al. (2002) screened 20 patients with myopathic mtDNA depletion syndrome. No patient had mutations in the deoxyguanosine kinase gene (DGUOK; 601465), but 4 patients from 2 families had TK2 mutations. Two sibs were compound heterozygotes for a previously reported H163N mutation (188250.0001) and a novel T77M mutation (now T150M; 188250.0003). Another pair of sibs harbored a homozygous I22M mutation (now I95M; 188250.0004), and 1 had evidence of lower motor neuron disease. Thus, the clinical expression of TK2 mutations is not limited to myopathy. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28 to 37% of controls). </p><p>In a family originally described by Tritschler et al. (1992) in which 3 sibs had myopathic mtDNA depletion syndrome, Mancuso et al. (2003) identified homozygosity for the T150M mutation. The patients had 80 to 90% mtDNA depletion in muscle biopsy specimens, and all died by age 40 months. The authors noted that exon 5 is a hotspot for TK2 mutations. </p>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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<span class="mim-text-font">
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<p>The human mitochondrial transcription factor A (TFAM; 600438) is a 25-kD protein that may be an important regulator of both transcription and replication of mtDNA. Deficiency of the yeast homolog, ABF2, is associated with loss of mtDNA. This prompted Poulton et al. (1994) to investigate both protein and mRNA levels for this factor in cell lines experimentally depleted of mtDNA and in patients with myopathic mtDNA depletion to determine whether these conditions are associated with a deficiency of TFAM. They found that the ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle from the 3 patients and in other tissues in 1. Furthermore, TFAM was low in cells depleted either permanently or transiently of mtDNA, and this reduction roughly paralleled mtDNA levels. They concluded that deficiency of TFAM may be a marker of, or possibly a cause of, mtDNA depletion in some patients with this condition. </p><p>Wang et al. (2003) found that recombinant human TK2 with either the H163N (188250.0001) or the I254N (188250.0002) mutation, which they called H121N and I212N, respectively, had a similar subunit structure compared with wildtype TK2. The I212N mutant enzyme showed less than 1% activity compared with wildtype TK2 with all deoxynucleosides. The H121N mutant enzyme had normal Km values for thymidine and deoxycytidine, but 2- and 3-fold lower Vmax values, respectively, compared with wildtype TK2 and markedly increased Km values for ATP, leading to decreased enzyme efficiency. Competition experiments revealed that thymidine and deoxycytidine interacted differently with the H121N mutant compared with wildtype TK2. </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>
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</h4>
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<span class="mim-text-font">
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<p>Akman et al. (2008) created mice harboring a his126-to-asn (H126N) mutation in the Tk2 gene, which is homologous to the H163N mutation (188250.0001) in humans. Homozygous mutant mice (Tk2 -/-) were obtained at the expected mendelian frequency and appeared normal at birth. However, at postnatal day 10, they showed several defects relative to wildtype and heterozygous mutant littermates, including growth retardation, reduced spontaneous activity, generalized coarse tremor, and impaired gait. They rapidly developed weakness, leading to severe stress or death by 2 weeks of age. Tk2 -/- animals showed reduced Tk2 activity in all tissues analyzed, with activity reduced to 1.7% of wildtype in brain, the most severely affected tissue. In Tk2 -/- mice, brain mitochondria had a dTTP concentration about 20% of wildtype, and liver mitochondria showed reduced levels of both dTTP and dCTP. The content of other dNTPs in these tissues was unchanged, and dNTP levels in other tissues were not affected. Depletion of mtDNA was most prominent in brain, where it was 12.5% of wildtype, and only brain showed decreased activities of respiratory chain enzymes, primarily complexes I and IV, and reduced ATP levels and ATP/ADP ratios. Spinal cord neurons had abnormal vacuolar changes, and the white matter of spinal cord and cortex showed evidence of activated glial cells. Akman et al. (2008) concluded that, in contrast to the muscle-specific phenotype observed in patients with the H163N mutation, mice homozygous for the H126N mutation showed a rapidly progressive encephalomyelopathy. </p><p>Bartesaghi et al. (2010) demonstrated that in vivo loss of Tk2 activity in mice led to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In Tk2-deficient cerebellar neurons, these abnormalities were associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure, and degeneration of selected neuronal types. </p><p>Lopez-Gomez et al. (2021) evaluated the effects of AAV gene therapy with and without pyrimidine deoxynucleoside (deoxycytidine (dC) and thymidine (dT)) treatment in a mouse model of Tk2 deficiency. AAV9 delivery of TK2 cDNA (AAV9-TK2) to the mutant mice on postnatal day 1 rescued Tk2 activity in liver, brain, and muscle but not in kidneys. The treated mutant mice had delayed disease onset and longer lifespan compared to untreated mutant mice. When the mice were treated with sequential AAV dosing, a dose of AAV9-TK2 on postnatal day 1 and then a dose of AAV2-TK2 on day 29, vector induction was not increased in the kidneys and vector genomes per nucleus were decreased in the brain and muscle compared to the mice treated with only AAV9-TK2. However, survival of the AAV9-TK2/AAV2-TK2 treated mice was significantly increased compared to the AAV9-TK2 treated and untreated mutant mice. Growth curves, motor function, and strength were similar in the AAV9-TK2/AAV2-TK2 treated mice and the AAV9-TK2 treated mice, and neither treatment cohort developed head tremors. The mutant mice were also treated with sequential AAV9-TK2/AAV2-TK2 dosing and with oral dC and dT from postnatal day 21 and had improved growth, survival, and mtDNA copy number in liver and kidneys compared to the other treatment cohorts of mutant mice. Lopez-Gomez et al. (2021) concluded that dC and dT supplementation enhances the effects of TK2 gene therapy and supports the potential for future combination therapy in patients with TK2 deficiency. </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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<ol>
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<strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong>
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Bartesaghi, S., Betts-Henderson, J., Cain, K., Dinsdale, D., Zhou, X., Karlsson, A., Salomoni, P., Nicotera, P.
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Boustany, R. N., Aprille, J. R., Halperin, J., Levy, H., DeLong, G. R.
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<strong>Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin.</strong>
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Durham, S. E., Bonilla, E., Samuels, D. C., DiMauro, S., Chinnery, P. F.
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Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M.
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<strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong>
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Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.
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Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., DiMauro, S.
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<strong>Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.</strong>
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Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H.
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<strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong>
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Moraes, C. T., Shanske, S., Tritschler, H.-J., Aprille, J. R., Andreetta, F., Bonilla, E., Schon, E. A., DiMauro, S.
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Oskoui, M., Davidzon, G., Pascual, J., Erazo, R., Gurgel-Giannetti, J., Krishna, S., Bonilla, E., De Vivo, D. C., Shanske, S., DiMauro, S.
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Paradas, C., Gutierrez Rios, P., Rivas, E., Carbonell, P., Hirano, M., DiMauro, S.
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<strong>TK2 mutation presenting as indolent myopathy.</strong>
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Neurology 80: 504-506, 2013.
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Poulton, J., Morten, K., Freeman-Emmerson, C., Potter, C., Sewry, C., Dubowitz, V., Kidd, H., Stephenson, J., Whitehouse, W., Hansen, F. J., Parisi, M., Brown, G.
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<strong>Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion.</strong>
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[PubMed: 7849699]
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Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O.
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<strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong>
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Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A.
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<strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong>
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<p class="mim-text-font">
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Vila, M. R., Segovia-Silvestre, T., Gamez, J., Marina, A., Naini, A. B., Meseguer, A., Lombes, A., Bonilla, E., DiMauro, S., Hirano, M., Andreu, A. L.
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<strong>Reversion of mtDNA depletion in a patient with TK2 deficiency.</strong>
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Neurology 60: 1203-1205, 2003.
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[PubMed: 12682338]
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[Full Text: https://doi.org/10.1212/01.wnl.0000055928.58122.47]
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</p>
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<p class="mim-text-font">
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Wang, L., Saada, A., Eriksson, S.
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<strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong>
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J. Biol. Chem. 278: 6963-6968, 2003.
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[PubMed: 12493767]
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[Full Text: https://doi.org/10.1074/jbc.M206143200]
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</p>
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</li>
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</ol>
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</div>
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Hilary J. Vernon - updated : 11/11/2021<br>Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 12/3/2014<br>Cassandra L. Kniffin - updated : 10/25/2012<br>George E. Tiller - updated : 12/2/2011<br>Cassandra L. Kniffin - updated : 12/9/2010<br>Matthew B. Gross - updated : 11/3/2009<br>Patricia A. Hartz - updated : 11/3/2009<br>Cassandra L. Kniffin - updated : 8/29/2007<br>Cassandra L. Kniffin - updated : 7/27/2007<br>Cassandra L. Kniffin - updated : 11/8/2006<br>Cassandra L. Kniffin - updated : 10/31/2005
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Cassandra L. Kniffin : 8/31/2005
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carol : 06/17/2022<br>carol : 11/11/2021<br>carol : 08/12/2016<br>ckniffin : 08/11/2016<br>carol : 06/08/2016<br>carol : 6/22/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>alopez : 12/15/2014<br>mcolton : 12/12/2014<br>ckniffin : 12/3/2014<br>carol : 11/5/2012<br>ckniffin : 10/25/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>carol : 12/21/2010<br>ckniffin : 12/9/2010<br>mgross : 11/3/2009<br>mgross : 11/3/2009<br>ckniffin : 10/12/2009<br>wwang : 5/28/2008<br>ckniffin : 5/22/2008<br>wwang : 9/4/2007<br>ckniffin : 8/29/2007<br>alopez : 8/8/2007<br>ckniffin : 7/27/2007<br>wwang : 11/9/2006<br>ckniffin : 11/8/2006<br>wwang : 11/3/2005<br>ckniffin : 10/31/2005<br>ckniffin : 9/20/2005<br>carol : 9/20/2005<br>ckniffin : 8/31/2005
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