2962 lines
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Entry
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- #616271 - 3-METHYLGLUTACONIC ACIDURIA, TYPE VIIB; MGCA7B
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- OMIM
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<p>
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<span class="h4">#616271</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/616271"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS250950"> <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="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<div style="display: table-cell;">External Links</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=3-METHYLGLUTACONIC ACIDURIA, TYPE VIIB" 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=23516&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/NBK396257/" 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://medlineplus.gov/genetics/condition/clpb-deficiency" 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=616271[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=445038" 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 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 class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/search?q=DOID:0081134 OR DOID:0110003" 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/616271" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<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>ORPHA:</strong> 445038<br />
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<strong>DO:</strong> 0081134, 0110003<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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616271
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</span>
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</span>
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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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3-METHYLGLUTACONIC ACIDURIA, TYPE VIIB; MGCA7B
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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="alternativeTitles" class="mim-anchor"></a>
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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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MGCA7<br />
|
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3-METHYLGLUTACONIC ACIDURIA WITH CATARACTS, NEUROLOGIC INVOLVEMENT, AND NEUTROPENIA, AUTOSOMAL RECESSIVE; MEGCANN
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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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<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/11/722?start=-3&limit=10&highlight=722">
|
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11q13.4
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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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3-methylglutaconic aciduria, type VIIB, 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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<a href="/entry/616271"> 616271 </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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<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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<span class="mim-font">
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CLPB
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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/616254"> 616254 </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 class="btn-group ">
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<a href="/clinicalSynopsis/616271" 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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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS250950" 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">
|
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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/616271" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/616271" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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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<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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<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> GROWTH </strong>
|
|
</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">
|
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<em> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Poor growth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span><br />
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</span>
|
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</div>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Microcephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Dysmorphic facial features (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248200007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248200007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424503&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424503</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001999" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001999</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001999" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001999</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cataracts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/193570009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">193570009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247053007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247053007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95722004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95722004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H26.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H26.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/366" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">366</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/366.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">366.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086543&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086543</a>, <a href="https://bioportal.bioontology.org/search?q=C0521707&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521707</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000518</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000518</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
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|
|
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|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
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|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Delayed psychomotor development (in most patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
|
|
Impaired intellectual development (in most patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747273</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
Poor or absent speech <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278212&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278212</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000750" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000750</a>]</span><br /> -
|
|
Walking difficulties <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/719232003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">719232003</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/719.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">719.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0311394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0311394</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002355</a>]</span><br /> -
|
|
Ataxic gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25136009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25136009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R26.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R26.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751837&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751837</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002066</a>]</span><br /> -
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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 /> -
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Axial hypotonia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853743&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853743</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008936</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008936" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008936</a>]</span><br /> -
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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 /> -
|
|
Developmental regression (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/609225004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">609225004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836830&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836830</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002376" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002376</a>]</span><br /> -
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Pyramidal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14648003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14648003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234132&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234132</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007256</a>]</span><br /> -
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Extrapyramidal signs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43378000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43378000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002071" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002071</a>]</span><br /> -
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Abnormal movements <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/9748009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">9748009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225606002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225606002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013384&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013384</a>, <a href="https://bioportal.bioontology.org/search?q=C0558189&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0558189</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100660" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100660</a>]</span><br /> -
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Seizures, various types (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228249</a>]</span><br /> -
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Brain imaging abnormalities, variable <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5563427&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5563427</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/442731005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">442731005</a>]</span><br /> -
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Cerebellar atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0740279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0740279</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001272" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001272</a>]</span><br /> -
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Cerebral atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span><br /> -
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Atrophy of the basal ganglia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013636&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013636</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> IMMUNOLOGY </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Neutropenia (in most patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/303011007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">303011007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165517008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165517008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84828003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84828003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.819</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D70.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.50</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853697</a>, <a href="https://bioportal.bioontology.org/search?q=C0027947&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027947</a>, <a href="https://bioportal.bioontology.org/search?q=C0023530&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023530</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001875</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001882" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001882</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001875</a>]</span><br /> -
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Bone marrow shows deficient granulopoiesis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4229227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4229227</a>]</span><br /> -
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Recurrent infections (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/451991000124106" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">451991000124106</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239998&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239998</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</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> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Increased urinary 3-methylglutaconic acid <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2678443&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2678443</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> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Onset at birth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836142&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836142</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003577</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003577" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003577</a>]</span><br /> -
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Onset in utero in severely affected patients<br /> -
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Highly variable phenotype <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839039&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839039</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
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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 /> -
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Death often in childhood<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> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the caseinolytic peptidase B gene (CLPB, <a href="/entry/616254#0001">616254.0001</a>)<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 class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small">
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<div class="row">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<h5>
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3-Methylglutaconic aciduria
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- <a href="/phenotypicSeries/PS250950">PS250950</a>
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- 9 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<tr>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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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/2/389?start=-3&limit=10&highlight=389"> 2p13.1 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/617248"> 3-methylglutaconic aciduria, type VIII </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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<a href="/entry/617248"> 617248 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/606441"> HTRA2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/606441"> 606441 </a>
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</span>
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</td>
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</tr>
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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/3/888?start=-3&limit=10&highlight=888"> 3q26.33 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/610198"> 3-methylglutaconic aciduria, type V </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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<a href="/entry/610198"> 610198 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/608977"> DNAJC19 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/608977"> 608977 </a>
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</span>
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</td>
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</tr>
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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/6/982?start=-3&limit=10&highlight=982"> 6q25.3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/614739"> 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome </a>
|
|
</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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<a href="/entry/614739"> 614739 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614725"> SERAC1 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614725"> 614725 </a>
|
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</span>
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</td>
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</tr>
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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/9/298?start=-3&limit=10&highlight=298"> 9q22.31 </a>
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/250950"> 3-methylglutaconic aciduria, type I </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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<a href="/entry/250950"> 250950 </a>
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600529"> AUH </a>
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600529"> 600529 </a>
|
|
</span>
|
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</td>
|
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</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/722?start=-3&limit=10&highlight=722"> 11q13.4 </a>
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|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616271"> 3-methylglutaconic aciduria, type VIIB, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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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>
|
|
<span class="mim-font">
|
|
<a href="/entry/616271"> 616271 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616254"> CLPB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616254"> 616254 </a>
|
|
</span>
|
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</td>
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</tr>
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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/19/684?start=-3&limit=10&highlight=684"> 19q13.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617698"> 3-methylglutaconic aciduria, type IX </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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|
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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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|
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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/617698"> 617698 </a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/607381"> TIMM50 </a>
|
|
</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/607381"> 607381 </a>
|
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</span>
|
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</td>
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</tr>
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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/19/826?start=-3&limit=10&highlight=826"> 19q13.32 </a>
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|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/258501"> 3-methylglutaconic aciduria, type III </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/258501"> 258501 </a>
|
|
</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/606580"> OPA3 </a>
|
|
</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/606580"> 606580 </a>
|
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</span>
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</td>
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</tr>
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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/X/861?start=-3&limit=10&highlight=861"> Xq28 </a>
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/302060"> Barth syndrome </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="X-linked recessive">XLR</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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<a href="/entry/302060"> 302060 </a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/300394"> TAFAZZIN </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/300394"> 300394 </a>
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Not Mapped
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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/250951"> 3-methylglutaconic aciduria, type IV </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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</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/250951"> 250951 </a>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/250951"> MGCA1 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/250951"> 250951 </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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|
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<div class="text-right small">
|
|
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
|
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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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<br />
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that autosomal recessive 3-methylglutaconic aciduria type VIIB (MGCA7B) is caused by homozygous or compound heterozygous loss-of-function mutations in the CLPB gene (<a href="/entry/616254">616254</a>) on chromosome 11q13.</p><p>Heterozygous dominant-negative mutations in the CLPB gene cause autosomal dominant MGCA7A (<a href="/entry/619835">619835</a>), which shows similar features.</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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</div>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<p>3-Methylglutaconic aciduria (MGCA7) is an inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with variable neurologic deficits and neutropenia. The phenotype is highly variable: most patients have infantile onset of a severe progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common variable features include cataracts, seizures, recurrent infections due to neutropenia, and brain imaging abnormalities (summary by <a href="#4" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al., 2015</a> and <a href="#3" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25597511+25597510" 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 phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (<a href="/entry/250950">250950</a>).</p>
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<p><a href="#4" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> reported 14 individuals from 9 unrelated families with an inborn error of metabolism characterized by increased urinary excretion of 3-MGA. Additional features were highly variable, with some patients having no neurologic involvement or infections and others having neonatal or even prenatal onset of progressive neurologic symptoms and/or severe neutropenia with progression to leukemia and death in the first months of life. Common features included delayed psychomotor development/variable intellectual disability (12 patients), congenital neutropenia (10 patients), brain atrophy (7 patients), microcephaly (7 patients), movement disorder (7 patients), and cataracts (5 patients). The oldest living patient was 18 years old and the youngest was 2; 6 patients died between 24 days and 46 months of age. The least severely affected children were a pair of sibs ascertained due to neutropenia. One sib had congenital nuclear cataracts and the other had attention deficit-hyperactivity disorder, dyslexia, and dysgraphia; however, both showed normal overall growth and development at ages 8 and 10 years, respectively. Most of the other patients showed neonatal hypotonia that progressed to spasticity, suggesting pyramidal tract dysfunction. Patients with a moderate phenotype had hypotonia, feeding difficulties, microcephaly, delayed psychomotor development, ataxia, and dystonia. Four patients had the most severe phenotype, with onset in utero or at birth of increased muscle tension ('stiff babies'), lack of eye contact, complete absence of development, and death in the first months of life. Eleven patients had swallowing difficulties, and 4 had seizures. Results of brain imaging also varied significantly, and included normal findings, isolated cerebellar atrophy, cerebral atrophy, and abnormalities of the basal ganglia. Ten patients had neutropenia, but only some patients had recurrent severe infections. Two sibs developed acute myeloid leukemia and myelodysplastic syndrome, respectively. Less common features, occurring in only a few patients, included facial dysmorphism, cardiomyopathy or hypertrophy, and hypothyroidism. Studies of patient cells did not show defects in mitochondrial oxidative phosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" 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="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a> reported 4 children, including 2 sibs, of Greenlandic descent, and an unrelated child of northern European and Asian descent, with 3-MGCA and neutropenia. The 4 children of Greenlandic origin showed regression of psychomotor development after a few months of normal early development; all died within the first years of life. The fifth child presented at birth with growth retardation, microcephaly, rigidity, contractures, and abnormal facial features, and died from respiratory failure on day 8 of life. Additional variable features among all patients included cataracts, hypotonia, extrapyramidal symptoms such as myoclonus, dystonia, choreoathetosis, opisthotonus, and seizures. Bone marrow biopsies showed maturational arrest of granulopoiesis. Brain imaging was either normal or showed cerebral atrophy; 1 patient had lesions in the basal ganglia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L. <strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong> J. Med. Genet. 52: 303-311, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25650066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25650066</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25650066">Capo-Chichi et al. (2015)</a> reported 4 sibs, born of consanguineous Cambodian parents, with a severe form of MGCA7. They did not move or breathe spontaneously at birth. Appendicular tone was increased, and they showed sustained clonic movements induced by minimal tactile stimulation. EEG showed burst suppression. Brain imaging in 1 patient showed gyral simplification. All were ventilator-dependent and died in the first week of life after removal of respiratory support. Laboratory studies showed increased serum lactate, increased urinary 3-methylglutaconic acid and methylglutaric acid, neutropenia, and coagulation defects. Neuropathologic examination showed neuronal loss in several brain regions, diffuse gliosis, and microvacuolization, which are nonspecific changes consistent with a defect in energy metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25650066" 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="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a> reported a 5-year-old girl who was found to have severe neutropenia in the setting of respiratory distress and fever at 1 year of age. She had severe, persistent neutropenia, and a bone marrow examination showed selective maturation arrest of neutrophil precursors. Laboratory testing showed hypergammaglobulinemia with normal IgA, IgM, and IgE as well as normal response to vaccines. She had increased excretion of urine 3-methylglutaconic acid and 3-methylglutaric acid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" 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 MGCA7B in the families reported by <a href="#4" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> and <a href="#3" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25597511+25597510" 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 14 individuals from 9 unrelated families with MGCA7B, <a href="#4" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> identified 14 different homozygous or compound heterozygous mutations in the CLPB gene (see, e.g., <a href="/entry/616254#0001">616254.0001</a>-<a href="/entry/616254#0007">616254.0007</a>). Mutations in the first 2 unrelated patients were found by exome sequencing; mutations in subsequent patients were found by direct sequencing of the CLPB gene in 16 additional individuals with a similar phenotype. There was no clear correlation between the severity of the disorder and the position and nature of the specific missense mutations, although patients with a more severe phenotype tended to carry mutations resulting in complete absence of the functional protein. Fibroblasts from affected individuals did not show defects in mitochondrial oxidative phosphorylation or phospholipid metabolism. In vitro functional expression studies performed on 1 of the mutations (R408G; <a href="/entry/616254#0006">616254.0006</a>) showed that the mutant protein had decreased ATPase activity at 26% of wildtype. Four missense variants were unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants had little or no residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 patients, including 2 sibs, of Greenlandic descent with MGCA7B, <a href="#3" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a> identified a homozygous missense mutation in the CLPB gene (T268M; <a href="/entry/616254#0008">616254.0008</a>). The mutation was found by homozygosity mapping and candidate gene sequencing. Exome sequencing of an unrelated patient with a similar disorder identified compound heterozygous truncating mutations in the CLPB gene (<a href="/entry/616254#0007">616254.0007</a> and <a href="/entry/616254#0009">616254.0009</a>). Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 sibs, born of consanguineous Cambodian parents, with MGCA7B, <a href="#1" class="mim-tip-reference" title="Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L. <strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong> J. Med. Genet. 52: 303-311, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25650066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25650066</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25650066">Capo-Chichi et al. (2015)</a> identified a homozygous truncating mutation in the CLPB gene (<a href="/entry/616254#0010">616254.0010</a>) that segregated with the disorder in the family. The mutation was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25650066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with MGCA7B, <a href="#2" class="mim-tip-reference" title="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a> identified compound heterozygous mutations in the CLPB gene (<a href="/entry/616254#0018">616254.0018</a>-<a href="/entry/616254#0019">616254.0019</a>). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. <a href="#2" class="mim-tip-reference" title="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a> concluded that biallelic mutations in CLPB can cause a mild phenotype with isolated severe congenital neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" 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="#4" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> found that morpholino knockdown of the clpb ortholog in zebrafish embryos resulted in dose-dependent cerebellar defects, microcephaly, and reduction of the size of the optic tectum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" 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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Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L.
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<strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong>
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J. Med. Genet. 52: 303-311, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25650066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25650066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25650066" 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-2014-102952" target="_blank">Full Text</a>]
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Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A.
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<strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong>
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Pediat. Allergy Immun. 33: e13782, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" 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/10.1111/pai.13782" target="_blank">Full Text</a>]
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Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E.
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<strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong>
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Am. J. Hum. Genet. 96: 258-265, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[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=25597511" 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.ajhg.2014.12.020" target="_blank">Full Text</a>]
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Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others.
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<strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong>
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Am. J. Hum. Genet. 96: 245-257, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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=25597510" 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.ajhg.2014.12.013" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 08/11/2022
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Cassandra L. Kniffin - updated : 03/28/2022<br>Cassandra L. Kniffin - updated : 6/16/2015
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Cassandra L. Kniffin : 3/19/2015
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carol : 08/11/2022
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carol : 04/14/2022<br>ckniffin : 04/13/2022<br>carol : 04/12/2022<br>carol : 04/11/2022<br>ckniffin : 03/28/2022<br>carol : 12/17/2019<br>carol : 04/27/2017<br>carol : 06/18/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>carol : 3/20/2015<br>mcolton : 3/20/2015<br>mcolton : 3/20/2015<br>ckniffin : 3/19/2015
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<strong>#</strong> 616271
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3-METHYLGLUTACONIC ACIDURIA, TYPE VIIB; MGCA7B
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MGCA7<br />
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3-METHYLGLUTACONIC ACIDURIA WITH CATARACTS, NEUROLOGIC INVOLVEMENT, AND NEUTROPENIA, AUTOSOMAL RECESSIVE; MEGCANN
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<strong>ORPHA:</strong> 445038;
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<strong>DO:</strong> 0081134, 0110003;
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<strong>Phenotype-Gene Relationships</strong>
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Inheritance
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11q13.4
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3-methylglutaconic aciduria, type VIIB, autosomal recessive
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616271
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Autosomal recessive
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3
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CLPB
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616254
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<p>A number sign (#) is used with this entry because of evidence that autosomal recessive 3-methylglutaconic aciduria type VIIB (MGCA7B) is caused by homozygous or compound heterozygous loss-of-function mutations in the CLPB gene (616254) on chromosome 11q13.</p><p>Heterozygous dominant-negative mutations in the CLPB gene cause autosomal dominant MGCA7A (619835), which shows similar features.</p>
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<p>3-Methylglutaconic aciduria (MGCA7) is an inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with variable neurologic deficits and neutropenia. The phenotype is highly variable: most patients have infantile onset of a severe progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common variable features include cataracts, seizures, recurrent infections due to neutropenia, and brain imaging abnormalities (summary by Wortmann et al., 2015 and Saunders et al., 2015). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (250950).</p>
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<strong>Clinical Features</strong>
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<p>Wortmann et al. (2015) reported 14 individuals from 9 unrelated families with an inborn error of metabolism characterized by increased urinary excretion of 3-MGA. Additional features were highly variable, with some patients having no neurologic involvement or infections and others having neonatal or even prenatal onset of progressive neurologic symptoms and/or severe neutropenia with progression to leukemia and death in the first months of life. Common features included delayed psychomotor development/variable intellectual disability (12 patients), congenital neutropenia (10 patients), brain atrophy (7 patients), microcephaly (7 patients), movement disorder (7 patients), and cataracts (5 patients). The oldest living patient was 18 years old and the youngest was 2; 6 patients died between 24 days and 46 months of age. The least severely affected children were a pair of sibs ascertained due to neutropenia. One sib had congenital nuclear cataracts and the other had attention deficit-hyperactivity disorder, dyslexia, and dysgraphia; however, both showed normal overall growth and development at ages 8 and 10 years, respectively. Most of the other patients showed neonatal hypotonia that progressed to spasticity, suggesting pyramidal tract dysfunction. Patients with a moderate phenotype had hypotonia, feeding difficulties, microcephaly, delayed psychomotor development, ataxia, and dystonia. Four patients had the most severe phenotype, with onset in utero or at birth of increased muscle tension ('stiff babies'), lack of eye contact, complete absence of development, and death in the first months of life. Eleven patients had swallowing difficulties, and 4 had seizures. Results of brain imaging also varied significantly, and included normal findings, isolated cerebellar atrophy, cerebral atrophy, and abnormalities of the basal ganglia. Ten patients had neutropenia, but only some patients had recurrent severe infections. Two sibs developed acute myeloid leukemia and myelodysplastic syndrome, respectively. Less common features, occurring in only a few patients, included facial dysmorphism, cardiomyopathy or hypertrophy, and hypothyroidism. Studies of patient cells did not show defects in mitochondrial oxidative phosphorylation. </p><p>Saunders et al. (2015) reported 4 children, including 2 sibs, of Greenlandic descent, and an unrelated child of northern European and Asian descent, with 3-MGCA and neutropenia. The 4 children of Greenlandic origin showed regression of psychomotor development after a few months of normal early development; all died within the first years of life. The fifth child presented at birth with growth retardation, microcephaly, rigidity, contractures, and abnormal facial features, and died from respiratory failure on day 8 of life. Additional variable features among all patients included cataracts, hypotonia, extrapyramidal symptoms such as myoclonus, dystonia, choreoathetosis, opisthotonus, and seizures. Bone marrow biopsies showed maturational arrest of granulopoiesis. Brain imaging was either normal or showed cerebral atrophy; 1 patient had lesions in the basal ganglia. </p><p>Capo-Chichi et al. (2015) reported 4 sibs, born of consanguineous Cambodian parents, with a severe form of MGCA7. They did not move or breathe spontaneously at birth. Appendicular tone was increased, and they showed sustained clonic movements induced by minimal tactile stimulation. EEG showed burst suppression. Brain imaging in 1 patient showed gyral simplification. All were ventilator-dependent and died in the first week of life after removal of respiratory support. Laboratory studies showed increased serum lactate, increased urinary 3-methylglutaconic acid and methylglutaric acid, neutropenia, and coagulation defects. Neuropathologic examination showed neuronal loss in several brain regions, diffuse gliosis, and microvacuolization, which are nonspecific changes consistent with a defect in energy metabolism. </p><p>Rivalta et al. (2022) reported a 5-year-old girl who was found to have severe neutropenia in the setting of respiratory distress and fever at 1 year of age. She had severe, persistent neutropenia, and a bone marrow examination showed selective maturation arrest of neutrophil precursors. Laboratory testing showed hypergammaglobulinemia with normal IgA, IgM, and IgE as well as normal response to vaccines. She had increased excretion of urine 3-methylglutaconic acid and 3-methylglutaric acid. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of MGCA7B in the families reported by Wortmann et al. (2015) and Saunders et al. (2015) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>In 14 individuals from 9 unrelated families with MGCA7B, Wortmann et al. (2015) identified 14 different homozygous or compound heterozygous mutations in the CLPB gene (see, e.g., 616254.0001-616254.0007). Mutations in the first 2 unrelated patients were found by exome sequencing; mutations in subsequent patients were found by direct sequencing of the CLPB gene in 16 additional individuals with a similar phenotype. There was no clear correlation between the severity of the disorder and the position and nature of the specific missense mutations, although patients with a more severe phenotype tended to carry mutations resulting in complete absence of the functional protein. Fibroblasts from affected individuals did not show defects in mitochondrial oxidative phosphorylation or phospholipid metabolism. In vitro functional expression studies performed on 1 of the mutations (R408G; 616254.0006) showed that the mutant protein had decreased ATPase activity at 26% of wildtype. Four missense variants were unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants had little or no residual activity. </p><p>In 4 patients, including 2 sibs, of Greenlandic descent with MGCA7B, Saunders et al. (2015) identified a homozygous missense mutation in the CLPB gene (T268M; 616254.0008). The mutation was found by homozygosity mapping and candidate gene sequencing. Exome sequencing of an unrelated patient with a similar disorder identified compound heterozygous truncating mutations in the CLPB gene (616254.0007 and 616254.0009). Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. </p><p>In 4 sibs, born of consanguineous Cambodian parents, with MGCA7B, Capo-Chichi et al. (2015) identified a homozygous truncating mutation in the CLPB gene (616254.0010) that segregated with the disorder in the family. The mutation was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. </p><p>In a patient with MGCA7B, Rivalta et al. (2022) identified compound heterozygous mutations in the CLPB gene (616254.0018-616254.0019). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Rivalta et al. (2022) concluded that biallelic mutations in CLPB can cause a mild phenotype with isolated severe congenital neutropenia. </p>
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<p>Wortmann et al. (2015) found that morpholino knockdown of the clpb ortholog in zebrafish embryos resulted in dose-dependent cerebellar defects, microcephaly, and reduction of the size of the optic tectum. </p>
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Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L.
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<strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong>
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J. Med. Genet. 52: 303-311, 2015.
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[PubMed: 25650066]
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[Full Text: https://doi.org/10.1136/jmedgenet-2014-102952]
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Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A.
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<strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong>
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Pediat. Allergy Immun. 33: e13782, 2022.
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[PubMed: 35616898]
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[Full Text: https://doi.org/10.1111/pai.13782]
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Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E.
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<strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong>
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Am. J. Hum. Genet. 96: 258-265, 2015.
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[PubMed: 25597511]
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[Full Text: https://doi.org/10.1016/j.ajhg.2014.12.020]
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Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others.
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<strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong>
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Am. J. Hum. Genet. 96: 245-257, 2015.
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[PubMed: 25597510]
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[Full Text: https://doi.org/10.1016/j.ajhg.2014.12.013]
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Hilary J. Vernon - updated : 08/11/2022<br>Cassandra L. Kniffin - updated : 03/28/2022<br>Cassandra L. Kniffin - updated : 6/16/2015
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