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Entry
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- #616370 - MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 4; MMDS4
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- OMIM
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<p>
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<span class="h4">#616370</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/616370"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS605711"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME" 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=23727&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/NBK481904/" 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.ncbi.nlm.nih.gov/gtr/all/tests/?term=616370[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=457406" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-row">
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<div style="display: table-cell;">Animal Models</div>
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</a>
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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:0080136" 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/616370" 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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<div><a href="https://wormbase.org/resources/disease/DOID:0080136" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<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> 1208621008<br />
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<strong>ORPHA:</strong> 457406<br />
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<strong>DO:</strong> 0080136<br />
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">ICD+</a>
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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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616370
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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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MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 4; MMDS4
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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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<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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</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/14/387?start=-3&limit=10&highlight=387">
|
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14q24.3
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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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Multiple mitochondrial dysfunctions syndrome 4
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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/616370"> 616370 </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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</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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</td>
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<td>
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<span class="mim-font">
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ISCA2
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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/615317"> 615317 </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 class="btn-group ">
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<a href="/clinicalSynopsis/616370" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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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<a href="/phenotypicSeries/PS605711" 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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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/616370" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/616370" 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 />
|
|
</div>
|
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<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">
|
|
<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
|
<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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</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> HEAD & NECK </strong>
|
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</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Optic atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/76976005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">76976005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/377.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000648" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000648</a>]</span><br /> -
|
|
Loss of eye contact <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809180&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809180</a>]</span><br /> -
|
|
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br /> -
|
|
Visual impairment <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246635007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246635007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397540003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397540003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042798</a>, <a href="https://bioportal.bioontology.org/search?q=C3665347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665347</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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</div>
|
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|
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</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 /> -
|
|
Atrophic fibers seen on biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228898&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228898</a>]</span><br /> -
|
|
Some abnormal aggregation of mitochondria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228897&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228897</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Neurodevelopmental regression to a vegetative state <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228899&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228899</a>]</span><br /> -
|
|
Cognitive disability <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747803&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747803</a>]</span><br /> -
|
|
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
|
|
Hyperreflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
|
|
Absent speech <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854882&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854882</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001344" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001344</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001344" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001344</a>]</span><br /> -
|
|
Leukodystrophy of the subcortical region, cerebellum, brainstem, and spinal cord <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747804&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747804</a>]</span><br /> -
|
|
Periventricular white matter abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673431&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673431</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002518</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002518</a>]</span><br />
|
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|
|
</span>
|
|
</div>
|
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</div>
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|
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased CSF glycine, glutamate, and lactate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747805&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747805</a>]</span><br /> -
|
|
Fibroblasts show decreased mitochondrial complex II activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747806</a>]</span><br /> -
|
|
Mildly decreased complex IV activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747807&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747807</a>]</span><br /> -
|
|
Decreased mtDNA levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747808&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747808</a>]</span><br /> -
|
|
Decreased mitochondrial membrane potential <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747809&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747809</a>]</span><br /> -
|
|
Decreased oxidative phosphorylation and ATP production <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747810&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747810</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>
|
|
<div style="margin-left: 2em;">
|
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|
|
<div>
|
|
<span class="mim-font">
|
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|
|
- Onset in the first year of life<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 /> -
|
|
Death in early childhood may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844947&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844947</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001522</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001522</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
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|
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|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the iron-sulfur cluster assembly 2 gene (ISCA2, <a href="/entry/615317#0001">615317.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
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|
|
</div>
|
|
|
|
</div>
|
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|
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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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|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Multiple mitochondrial dysfunctions syndrome
|
|
- <a href="/phenotypicSeries/PS605711">PS605711</a>
|
|
- 11 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/1/1774?start=-3&limit=10&highlight=1774"> 1q42.13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615330"> Multiple mitochondrial dysfunctions syndrome 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615330"> 615330 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615316"> IBA57 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615316"> 615316 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/325?start=-3&limit=10&highlight=325"> 2p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605711"> Multiple mitochondrial dysfunctions syndrome 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605711"> 605711 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608100"> NFU1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608100"> 608100 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/373?start=-3&limit=10&highlight=373"> 2p13.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614299"> Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia </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/614299"> 614299 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613183"> BOLA3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613183"> 613183 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/475?start=-3&limit=10&highlight=475"> 2q11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620960"> Multiple mitochondrial dysfunctions syndrome 10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620960"> 620960 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604333"> CIAO1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604333"> 604333 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/555?start=-3&limit=10&highlight=555"> 7q22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617954"> Multiple mitochondrial dysfunctions syndrome 6 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617954"> 617954 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603131"> PMPCB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603131"> 603131 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/9/280?start=-3&limit=10&highlight=280"> 9q21.33 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617613"> Multiple mitochondrial dysfunctions syndrome 5 </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/617613"> 617613 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611006"> ISCA1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611006"> 611006 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/14/387?start=-3&limit=10&highlight=387"> 14q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616370"> Multiple mitochondrial dysfunctions syndrome 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616370"> 616370 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615317"> ISCA2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615317"> 615317 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/674?start=-3&limit=10&highlight=674"> 16q23.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620423"> Multiple mitochondrial dysfunctions syndrome 7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620423"> 620423 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/238330"> GCSH </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/238330"> 238330 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/923?start=-3&limit=10&highlight=923"> 17q25.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620887"> Multiple mitochondrial dysfunctions syndrome 9B </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/620887"> 620887 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/103270"> FDXR </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/103270"> 103270 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/923?start=-3&limit=10&highlight=923"> 17q25.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617717"> Auditory neuropathy and optic atrophy </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/617717"> 617717 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/103270"> FDXR </a>
|
|
</span>
|
|
</td>
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<p>A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-4 (MMDS4) is caused by homozygous or compound heterozygous mutation in the ISCA2 gene (<a href="/entry/615317">615317</a>) on chromosome 14q24.</p>
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<p>MMDS4 is an autosomal recessive neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased CSF glycine and decreased activity of mitochondrial complex II; there may be additional biochemical evidence of mitochondrial dysfunction (summary by <a href="#2" class="mim-tip-reference" title="Alaimo, J. T., Besse, A., Alston, C. L., Pang, K., Appadurai, V., Samanta, M., Smpokou, P. McFarland, R., Taylor, R. W., Bonnen, P. E. <strong>Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.</strong> Hum. Mutat. 39: 537-549, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29297947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29297947</a>] [<a href="https://doi.org/10.1002/humu.23396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29297947">Alaimo et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29297947" 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 general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (<a href="/entry/605711">605711</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others. <strong>ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.</strong> J. Med. Genet. 52: 186-194, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25539947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25539947</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25539947">Al-Hassnan et al. (2015)</a> reported 5 unrelated consanguineous Arab families in which 6 children had a severe neurologic disorder characterized by onset of neuroregression between ages 3 and 7 months. Two of the families had similarly affected children who were deceased. All 6 patients regressed to a vegetative state with no speech; 4 died before age 5 years. There were no dysmorphic features, but all had spasticity and optic atrophy. Brain imaging showed extensive diffuse bilateral signal abnormalities in multiple brain regions. Skeletal muscle biopsy revealed atrophic and angulated fibers, and patient fibroblasts showed a depletion of mitochondrial DNA copy number and decreased activity of mitochondrial respiratory complex I. No metabolic abnormalities were detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25539947" 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="Alaimo, J. T., Besse, A., Alston, C. L., Pang, K., Appadurai, V., Samanta, M., Smpokou, P. McFarland, R., Taylor, R. W., Bonnen, P. E. <strong>Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.</strong> Hum. Mutat. 39: 537-549, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29297947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29297947</a>] [<a href="https://doi.org/10.1002/humu.23396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29297947">Alaimo et al. (2018)</a> reported 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4. The patients had normal development in the first few months of life, but then showed motor regression with hypotonia, spasticity, loss of eye contact, and loss of social interaction. Additional features included optic atrophy with absent visual evoked potentials. One patient had mild skeletal abnormalities, including joint laxity, short fourth metacarpals, and cutaneous toe syndactyly. Laboratory studies in 1 of the patients showed increased CSF glycine, glutamate, and lactate, and decreased 5-methyltetrahydrofolate, although these were all normal in plasma. Metabolic studies in the other patient were not performed. Brain imaging in both patients showed significant leukodystrophy affecting subcortical regions, cerebellum, and brainstem, with extensive involvement of the spinal cord. Both families had a history of several additional patients with fatal infantile leukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29297947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Alfadhel, M., Nashabat, M., Alrifai, M. T., Alshaalan, H., Al Mutairi, F., Al-Shahrani, S. A., Plecko, B., Almass, R., Alsagob, M., Almutairi, F. B., Al-Rumayyan, A., Al-Twaijri, W., Al-Owain, M., Taylor, R. W., Kaya, N. <strong>Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.</strong> Europ. J. Paediat. Neurol. 22: 46-55, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29122497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29122497</a>] [<a href="https://doi.org/10.1016/j.ejpn.2017.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29122497">Alfadhel et al. (2018)</a> reported 10 children from 9 unrelated consanguineous Saudi families with MMDS4. Many of the families had a history of death of other sibs affected with a similar disorder or of recurrent miscarriages. The patients all had normal early development, but presented between 3 and 7 months of age with loss of developmental milestones, including visual fixation, motor, and language skills, as well as the onset of nystagmus. They had axial hypotonia, poor feeding due to swallowing weakness, peripheral spasticity, and optic atrophy. Three patients had seizures, 2 of whom had single or rare controllable seizures. All patients deteriorated to a vegetative state with a feeding tube. Laboratory studies, when performed, showed inconsistent results: 2 patients had increased CSF glycine and CSF lactate, 3 patients had increased plasma glycine and/or lactate, and several patients had normal plasma levels of glycine and lactate. Brain imaging, performed on most patients, showed white matter abnormalities in the cerebrum, cerebellum, and brainstem, with sparing of the basal ganglia. Five patients died between 11 and 28 months of age, usually due to recurrent chest infections. <a href="#3" class="mim-tip-reference" title="Alfadhel, M., Nashabat, M., Alrifai, M. T., Alshaalan, H., Al Mutairi, F., Al-Shahrani, S. A., Plecko, B., Almass, R., Alsagob, M., Almutairi, F. B., Al-Rumayyan, A., Al-Twaijri, W., Al-Owain, M., Taylor, R. W., Kaya, N. <strong>Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.</strong> Europ. J. Paediat. Neurol. 22: 46-55, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29122497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29122497</a>] [<a href="https://doi.org/10.1016/j.ejpn.2017.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29122497">Alfadhel et al. (2018)</a> noted the phenotypic similarity to LBSL (<a href="/entry/611105">611105</a>), which is caused by mutation in the DARS2 gene (<a href="/entry/610956">610956</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29122497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Toldo, I., Nosadini, M., Boscardin, C., Talenti, G., Manara, R., Lamantea, E., Legati, A., Ghezzi, D., Perilongo, G., Sartori, S. <strong>Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.</strong> Metab. Brain Dis. 33: 805-812, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29359243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29359243</a>] [<a href="https://doi.org/10.1007/s11011-017-0181-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29359243">Toldo et al. (2018)</a> reported a female infant of Italian descent with MMDS4. She presented at age 2 months with progressive axial hypotonia, motor regression, feeding difficulties, nystagmus, and brisk tendon reflexes. EEG showed generalized slow wave activity. CSF showed increased lactate, and brain imaging showed diffuse T2-weighted hyperintensities in the cortex with extensive involvement of the spinal cord. Analysis of muscle tissue showed reduced activity of mitochondrial complexes II and IV. The patient developed rapidly progressive respiratory failure resulting in death at age 3 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29359243" 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 transmission pattern of MMDS4 in the families reported by <a href="#1" class="mim-tip-reference" title="Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others. <strong>ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.</strong> J. Med. Genet. 52: 186-194, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25539947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25539947</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25539947">Al-Hassnan et al. (2015)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25539947" 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 6 children from 5 unrelated consanguineous Arab families with MMDS4, <a href="#1" class="mim-tip-reference" title="Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others. <strong>ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.</strong> J. Med. Genet. 52: 186-194, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25539947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25539947</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25539947">Al-Hassnan et al. (2015)</a> identified a homozygous missense mutation in the ISCA2 gene (G77S; <a href="/entry/615317#0001">615317.0001</a>). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the families, and haplotype analysis indicated a founder effect. Patient cells showed decreased expression of ISCA2, ISCA1 (<a href="/entry/611006">611006</a>), and IBA57 (<a href="/entry/615316">615316</a>). Functional studies of the ISCA2 variant were not performed, but <a href="#1" class="mim-tip-reference" title="Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others. <strong>ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.</strong> J. Med. Genet. 52: 186-194, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25539947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25539947</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25539947">Al-Hassnan et al. (2015)</a> noted that the ISCA2 gene is an essential component involved in the assembly of a mitochondrial iron-sulfur cluster (4Fe-4S) important for electron transfer and mitochondrial function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25539947" 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 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4, <a href="#2" class="mim-tip-reference" title="Alaimo, J. T., Besse, A., Alston, C. L., Pang, K., Appadurai, V., Samanta, M., Smpokou, P. McFarland, R., Taylor, R. W., Bonnen, P. E. <strong>Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.</strong> Hum. Mutat. 39: 537-549, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29297947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29297947</a>] [<a href="https://doi.org/10.1002/humu.23396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29297947">Alaimo et al. (2018)</a> identified a homozygous G77S mutation in the ISCA2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Dermal fibroblasts from 1 of the patients showed diminished mitochondrial membrane potential, variably decreased or increased mitochondrial enzyme complexes, decreased oxygen consumption, and decreased ATP production compared to controls, consistent with mitochondrial dysfunction. There was a decrease in complex II activity and mildly decreased complex IV activity, with intact complexes I and III. The mitochondria also showed morphologic defects as well as decreased mtDNA content, to about 25% of normal values. Patient cells also showed decreased levels of protein lipoylation, indicating a defect in the production of lipoic acid, presumably due to faulty Fe-S cluster generation and specifically affecting the 4Fe-4S-dependent enzyme LIAS (<a href="/entry/607031">607031</a>). Knockdown of ISCA2 using shRNA resulted in similar cellular abnormalities and defects involving 4Fe-4S-dependent proteins, but not 2Fe-2S proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29297947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 10 children from 9 unrelated consanguineous Saudi families with MMDS4, <a href="#3" class="mim-tip-reference" title="Alfadhel, M., Nashabat, M., Alrifai, M. T., Alshaalan, H., Al Mutairi, F., Al-Shahrani, S. A., Plecko, B., Almass, R., Alsagob, M., Almutairi, F. B., Al-Rumayyan, A., Al-Twaijri, W., Al-Owain, M., Taylor, R. W., Kaya, N. <strong>Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.</strong> Europ. J. Paediat. Neurol. 22: 46-55, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29122497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29122497</a>] [<a href="https://doi.org/10.1016/j.ejpn.2017.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29122497">Alfadhel et al. (2018)</a> identified the homozygous G77S founder mutation in the ISCA2 gene. Specific functional studies of the variant were not performed, but laboratory studies suggested a defect in the 4Fe-4S cluster. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29122497" 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 an Italian infant with MMDS4, <a href="#4" class="mim-tip-reference" title="Toldo, I., Nosadini, M., Boscardin, C., Talenti, G., Manara, R., Lamantea, E., Legati, A., Ghezzi, D., Perilongo, G., Sartori, S. <strong>Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.</strong> Metab. Brain Dis. 33: 805-812, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29359243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29359243</a>] [<a href="https://doi.org/10.1007/s11011-017-0181-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29359243">Toldo et al. (2018)</a> identified compound heterozygous mutations in the ISCA2 gene (c.295delT, <a href="/entry/615317#0002">615317.0002</a> and S112G, <a href="/entry/615317#0003">615317.0003</a>). The mutations, which were found by next-generation sequencing of a panel of genes associated with mitochondrial disorders, segregated with the disorder in the family. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29359243" 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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Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others.
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<strong>ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.</strong>
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J. Med. Genet. 52: 186-194, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25539947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25539947</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25539947" 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/10.1136/jmedgenet-2014-102592" target="_blank">Full Text</a>]
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Alaimo, J. T., Besse, A., Alston, C. L., Pang, K., Appadurai, V., Samanta, M., Smpokou, P. McFarland, R., Taylor, R. W., Bonnen, P. E.
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<strong>Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.</strong>
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Hum. Mutat. 39: 537-549, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29297947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29297947</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29297947" 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/humu.23396" target="_blank">Full Text</a>]
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Alfadhel, M., Nashabat, M., Alrifai, M. T., Alshaalan, H., Al Mutairi, F., Al-Shahrani, S. A., Plecko, B., Almass, R., Alsagob, M., Almutairi, F. B., Al-Rumayyan, A., Al-Twaijri, W., Al-Owain, M., Taylor, R. W., Kaya, N.
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<strong>Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.</strong>
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Europ. J. Paediat. Neurol. 22: 46-55, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29122497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29122497</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29122497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejpn.2017.10.003" target="_blank">Full Text</a>]
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Toldo, I., Nosadini, M., Boscardin, C., Talenti, G., Manara, R., Lamantea, E., Legati, A., Ghezzi, D., Perilongo, G., Sartori, S.
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<strong>Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.</strong>
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Metab. Brain Dis. 33: 805-812, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29359243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29359243</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29359243" 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/10.1007/s11011-017-0181-3" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 06/12/2018
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Cassandra L. Kniffin : 5/14/2015
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carol : 06/15/2018<br>ckniffin : 06/12/2018<br>carol : 02/26/2016<br>alopez : 5/19/2015<br>mcolton : 5/18/2015<br>mcolton : 5/18/2015<br>ckniffin : 5/18/2015
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MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 4; MMDS4
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<strong>SNOMEDCT:</strong> 1208621008;
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<strong>ORPHA:</strong> 457406;
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Multiple mitochondrial dysfunctions syndrome 4
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<p>A number sign (#) is used with this entry because of evidence that multiple mitochondrial dysfunctions syndrome-4 (MMDS4) is caused by homozygous or compound heterozygous mutation in the ISCA2 gene (615317) on chromosome 14q24.</p>
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<p>MMDS4 is an autosomal recessive neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased CSF glycine and decreased activity of mitochondrial complex II; there may be additional biochemical evidence of mitochondrial dysfunction (summary by Alaimo et al., 2018). </p><p>For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).</p>
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<p>Al-Hassnan et al. (2015) reported 5 unrelated consanguineous Arab families in which 6 children had a severe neurologic disorder characterized by onset of neuroregression between ages 3 and 7 months. Two of the families had similarly affected children who were deceased. All 6 patients regressed to a vegetative state with no speech; 4 died before age 5 years. There were no dysmorphic features, but all had spasticity and optic atrophy. Brain imaging showed extensive diffuse bilateral signal abnormalities in multiple brain regions. Skeletal muscle biopsy revealed atrophic and angulated fibers, and patient fibroblasts showed a depletion of mitochondrial DNA copy number and decreased activity of mitochondrial respiratory complex I. No metabolic abnormalities were detected. </p><p>Alaimo et al. (2018) reported 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4. The patients had normal development in the first few months of life, but then showed motor regression with hypotonia, spasticity, loss of eye contact, and loss of social interaction. Additional features included optic atrophy with absent visual evoked potentials. One patient had mild skeletal abnormalities, including joint laxity, short fourth metacarpals, and cutaneous toe syndactyly. Laboratory studies in 1 of the patients showed increased CSF glycine, glutamate, and lactate, and decreased 5-methyltetrahydrofolate, although these were all normal in plasma. Metabolic studies in the other patient were not performed. Brain imaging in both patients showed significant leukodystrophy affecting subcortical regions, cerebellum, and brainstem, with extensive involvement of the spinal cord. Both families had a history of several additional patients with fatal infantile leukodystrophy. </p><p>Alfadhel et al. (2018) reported 10 children from 9 unrelated consanguineous Saudi families with MMDS4. Many of the families had a history of death of other sibs affected with a similar disorder or of recurrent miscarriages. The patients all had normal early development, but presented between 3 and 7 months of age with loss of developmental milestones, including visual fixation, motor, and language skills, as well as the onset of nystagmus. They had axial hypotonia, poor feeding due to swallowing weakness, peripheral spasticity, and optic atrophy. Three patients had seizures, 2 of whom had single or rare controllable seizures. All patients deteriorated to a vegetative state with a feeding tube. Laboratory studies, when performed, showed inconsistent results: 2 patients had increased CSF glycine and CSF lactate, 3 patients had increased plasma glycine and/or lactate, and several patients had normal plasma levels of glycine and lactate. Brain imaging, performed on most patients, showed white matter abnormalities in the cerebrum, cerebellum, and brainstem, with sparing of the basal ganglia. Five patients died between 11 and 28 months of age, usually due to recurrent chest infections. Alfadhel et al. (2018) noted the phenotypic similarity to LBSL (611105), which is caused by mutation in the DARS2 gene (610956). </p><p>Toldo et al. (2018) reported a female infant of Italian descent with MMDS4. She presented at age 2 months with progressive axial hypotonia, motor regression, feeding difficulties, nystagmus, and brisk tendon reflexes. EEG showed generalized slow wave activity. CSF showed increased lactate, and brain imaging showed diffuse T2-weighted hyperintensities in the cortex with extensive involvement of the spinal cord. Analysis of muscle tissue showed reduced activity of mitochondrial complexes II and IV. The patient developed rapidly progressive respiratory failure resulting in death at age 3 months. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of MMDS4 in the families reported by Al-Hassnan et al. (2015) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>In 6 children from 5 unrelated consanguineous Arab families with MMDS4, Al-Hassnan et al. (2015) identified a homozygous missense mutation in the ISCA2 gene (G77S; 615317.0001). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the families, and haplotype analysis indicated a founder effect. Patient cells showed decreased expression of ISCA2, ISCA1 (611006), and IBA57 (615316). Functional studies of the ISCA2 variant were not performed, but Al-Hassnan et al. (2015) noted that the ISCA2 gene is an essential component involved in the assembly of a mitochondrial iron-sulfur cluster (4Fe-4S) important for electron transfer and mitochondrial function. </p><p>In 2 unrelated patients, each born of consanguineous Saudi parents, with MMDS4, Alaimo et al. (2018) identified a homozygous G77S mutation in the ISCA2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Dermal fibroblasts from 1 of the patients showed diminished mitochondrial membrane potential, variably decreased or increased mitochondrial enzyme complexes, decreased oxygen consumption, and decreased ATP production compared to controls, consistent with mitochondrial dysfunction. There was a decrease in complex II activity and mildly decreased complex IV activity, with intact complexes I and III. The mitochondria also showed morphologic defects as well as decreased mtDNA content, to about 25% of normal values. Patient cells also showed decreased levels of protein lipoylation, indicating a defect in the production of lipoic acid, presumably due to faulty Fe-S cluster generation and specifically affecting the 4Fe-4S-dependent enzyme LIAS (607031). Knockdown of ISCA2 using shRNA resulted in similar cellular abnormalities and defects involving 4Fe-4S-dependent proteins, but not 2Fe-2S proteins. </p><p>In 10 children from 9 unrelated consanguineous Saudi families with MMDS4, Alfadhel et al. (2018) identified the homozygous G77S founder mutation in the ISCA2 gene. Specific functional studies of the variant were not performed, but laboratory studies suggested a defect in the 4Fe-4S cluster. </p><p>In an Italian infant with MMDS4, Toldo et al. (2018) identified compound heterozygous mutations in the ISCA2 gene (c.295delT, 615317.0002 and S112G, 615317.0003). The mutations, which were found by next-generation sequencing of a panel of genes associated with mitochondrial disorders, segregated with the disorder in the family. Functional studies of the variant were not performed. </p>
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<strong>REFERENCES</strong>
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Al-Hassnan, Z. N., Al-Dosary, M., Alfadhel, M., Faqeih, E. A., Alsagob, M., Kenana, R., Almass, R., Al-Harazi, O. S., Al-Hindi, H., Malibari, O. I., Almutari, F. B., Tulbah, S., and 9 others.
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<strong>ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.</strong>
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J. Med. Genet. 52: 186-194, 2015.
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[PubMed: 25539947]
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[Full Text: https://doi.org/10.1136/jmedgenet-2014-102592]
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Alaimo, J. T., Besse, A., Alston, C. L., Pang, K., Appadurai, V., Samanta, M., Smpokou, P. McFarland, R., Taylor, R. W., Bonnen, P. E.
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<strong>Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.</strong>
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Hum. Mutat. 39: 537-549, 2018.
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[PubMed: 29297947]
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[Full Text: https://doi.org/10.1002/humu.23396]
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Alfadhel, M., Nashabat, M., Alrifai, M. T., Alshaalan, H., Al Mutairi, F., Al-Shahrani, S. A., Plecko, B., Almass, R., Alsagob, M., Almutairi, F. B., Al-Rumayyan, A., Al-Twaijri, W., Al-Owain, M., Taylor, R. W., Kaya, N.
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<strong>Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.</strong>
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Europ. J. Paediat. Neurol. 22: 46-55, 2018.
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[PubMed: 29122497]
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[Full Text: https://doi.org/10.1016/j.ejpn.2017.10.003]
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Toldo, I., Nosadini, M., Boscardin, C., Talenti, G., Manara, R., Lamantea, E., Legati, A., Ghezzi, D., Perilongo, G., Sartori, S.
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<strong>Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.</strong>
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Metab. Brain Dis. 33: 805-812, 2018.
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[PubMed: 29359243]
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[Full Text: https://doi.org/10.1007/s11011-017-0181-3]
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Contributors:
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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 - updated : 06/12/2018
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Creation Date:
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Cassandra L. Kniffin : 5/14/2015
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carol : 06/18/2018<br>carol : 06/15/2018<br>ckniffin : 06/12/2018<br>carol : 02/26/2016<br>alopez : 5/19/2015<br>mcolton : 5/18/2015<br>mcolton : 5/18/2015<br>ckniffin : 5/18/2015
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