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<title>
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Entry
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- #620940 - METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL
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- OMIM
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<span class="h4">#620940</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/620940"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS277400"> <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="#creationDate"><strong>Creation Date</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(METHYLMALONIC ACIDURIA HOMOCYSTINURIA, cblL TYPE) OR (THAP11)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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</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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</span>
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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>
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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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620940
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
|
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<th>
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Phenotype
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</th>
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<th>
|
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Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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<th>
|
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Gene/Locus
|
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</th>
|
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<th>
|
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Gene/Locus <br /> MIM number
|
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</th>
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</tr>
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</thead>
|
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<tbody>
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/561?start=-3&limit=10&highlight=561">
|
|
16q22.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
?Methylmalonic aciduria and homocystinuria, cblL type
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
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</span>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620940"> 620940 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<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">
|
|
THAP11
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609119"> 609119 </a>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/620940" 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 class="btn-group">
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<a href="/phenotypicSeries/PS277400" class="btn btn-info" role="button"> Phenotypic Series </a>
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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<div class="btn-group">
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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/620940" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/620940" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
|
</div>
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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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> HEAD & NECK </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Eyes </em>
|
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</span>
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</div>
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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|
|
- Esotropia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16596007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16596007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/378.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">378.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/378.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">378.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014877&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014877</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000565" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000565</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000565" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000565</a>]</span><br /> -
|
|
Hyperopia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38101003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38101003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H52.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H52.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/367.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">367.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020490&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020490</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000540" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000540</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000540" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000540</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
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|
|
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|
|
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Global developmental delay, profound <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553450&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553450</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012736" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012736</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012736" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012736</a>]</span> <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><br /> -
|
|
Encephalopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81308009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81308009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G93.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G93.40</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/348.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.30</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/348.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085584</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001298</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001298</a>]</span><br /> -
|
|
Seizures, myoclonic <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1208991001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1208991001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4317123&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4317123</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032794</a>]</span><br /> -
|
|
Tetraplegia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11538006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11538006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G82.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G82.50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G82.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G82.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/344.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">344.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034372&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034372</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002445" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002445</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002445" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002445</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Mild methylmalonic aciduria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42393006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42393006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E71.120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E71.120</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855119&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855119</a>, <a href="https://bioportal.bioontology.org/search?q=C0268583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268583</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012120</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002912</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012120</a>]</span><br /> -
|
|
Low-normal plasma methionine<br /> -
|
|
High-normal plasma homocysteine<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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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> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Impaired function of cobalamin-dependent enzymes MUT (<a href="/entry/609058">609058</a>) and MTR (<a href="/entry/156570">156570</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in early infancy<br /> -
|
|
One patient has been reported (last curated September 2024)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the THAP domain-containing protein 11 gene (THAP11, <a href="/entry/609119#0001">609119.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Methylmalonic aciduria and homocystinuria
|
|
- <a href="/phenotypicSeries/PS277400">PS277400</a>
|
|
- 7 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/557?start=-3&limit=10&highlight=557"> 1p34.1 </a>
|
|
|
|
</span>
|
|
</td>
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<a href="/entry/277400"> Methylmalonic aciduria and homocystinuria, cblC type </a>
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<a href="/entry/277400"> Methylmalonic aciduria and homocystinuria, cblC type, digenic </a>
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<a href="/entry/309541"> Methylmalonic aciduria and homocysteinemia, cblX type </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>A number sign (#) is used with this entry because of evidence that methylmalonic aciduria and homocystinuria of the cblL type (MAHCL) is caused by homozygous mutation in the THAP11 gene (<a href="/entry/609119">609119</a>) on chromosome 16q11. One such patient has been reported.</p>
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<p>Methylmalonic aciduria and homocystinuria of the cblL type (MAHCL) is an autosomal recessive metabolic disorder with onset of symptoms in infancy. The disorder is characterized by neurologic features, including seizures and profoundly impaired neurodevelopment. In the single reported patient, metabolic workup showed mild methylmalonicaciduria without homocystinuria, but complementation studies were consistent with a biochemical diagnosis of cblC (<a href="/entry/277400">277400</a>) and cblX (<a href="/entry/309541">309541</a>). Mutations in the MMACHC gene (<a href="/entry/609831">609831</a>) and HCFC1 (<a href="/entry/300019">300019</a>) were excluded before identification of mutation in the THAP11 gene (<a href="#2" class="mim-tip-reference" title="Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. <strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong> Hum. Molec. Genet. 26: 2838-2849, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28449119">Quintana et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28449119" 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>The biochemical abnormalities in cblC and cblX tend to be mild, and some patients with cblX without homocystinuria have been reported (<a href="#4" class="mim-tip-reference" title="Yu, H.-C., Sloan, J. L., Scharer, G., Brebner, A., Quintana, A. M., Achilly, N. P., Manoli, I., Coughlin, C. R., II, Geiger, E. A., Schneck, U., Watkins, D., Suormala, T., Van Hove, J. L. K., Fowler, B., Baumgartner, M. R., Rosenblatt, D. S., Venditti, C. P., Shaikh, T. H. <strong>An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.</strong> Am. J. Hum. Genet. 93: 506-514, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24011988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24011988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24011988[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.2013.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24011988">Yu et al., 2013</a>). Since THAP11 forms a functional complex with HCFC1, it is possible that future reported patients with THAP11 mutations may have homocystinuria (see review by <a href="#3" class="mim-tip-reference" title="Watkins, D., Rosenblatt, D. S. <strong>Inherited defects of cobalamin metabolism.</strong> Vitam. Horm. 119: 355-376, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35337626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35337626</a>] [<a href="https://doi.org/10.1016/bs.vh.2022.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35337626">Watkins and Rosenblatt, 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24011988+35337626" 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="#2" class="mim-tip-reference" title="Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. <strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong> Hum. Molec. Genet. 26: 2838-2849, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28449119">Quintana et al. (2017)</a> reported a boy, born of unrelated Moroccan parents, who presented at 2 months of age with myoclonic seizures followed by severely impaired global development. Metabolic workup showed mild methylmalonic aciduria and low-normal plasma methionine; homocysteine could not be detected in the urine. Later studies showed plasma homocysteine at the high end of normal. Standard treatment (protein restriction, hydroxocobalamin injection, pyridoxine, folic acid, and betaine) was ineffective. He gradually developed encephalopathy, tetraplegia, and profoundly impaired intellectual development. Eye examination showed esotropia and hyperopia. Brain imaging was not performed. The patient died from pneumonia at 10 years of age. Studies of patient fibroblasts showed impaired function of the cobalamin-dependent enzymes MUT (<a href="/entry/609058">609058</a>) and MTR (<a href="/entry/156570">156570</a>) and decreased synthesis of both adenosylcobalamin and methylcobalamin. Complementation studies were consistent with a biochemical diagnosis of cblC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28449119" 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 MAHCL in the family reported by <a href="#2" class="mim-tip-reference" title="Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. <strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong> Hum. Molec. Genet. 26: 2838-2849, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28449119">Quintana et al. (2017)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28449119" 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 a boy, born of Moroccan parents, with MAHCL, <a href="#2" class="mim-tip-reference" title="Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. <strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong> Hum. Molec. Genet. 26: 2838-2849, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28449119">Quintana et al. (2017)</a> identified a homozygous missense mutation in the THAP11 gene (F80L; <a href="/entry/609119#0001">609119.0001</a>). The mutation, which was found by direct sequencing of the THAP11 gene in patient cells, was not present in public databases, including gnomAD. Parental DNA was not available, so familial segregation studies could not be performed. <a href="#2" class="mim-tip-reference" title="Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. <strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong> Hum. Molec. Genet. 26: 2838-2849, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28449119">Quintana et al. (2017)</a> studied the THAP11 gene based on the known interaction between THAP11 and HCFC1 (<a href="/entry/300019">300019</a>), which is mutated in MAHCX (<a href="/entry/309541">309541</a>). Complementation studies were consistent with a biochemical diagnosis of cblC (<a href="/entry/277400">277400</a>); however, mutation in the MMACHC gene (<a href="/entry/609831">609831</a>) was excluded. RNA-seq analysis of patient fibroblasts showed downregulation of several genes, including TMOD2 (<a href="/entry/602928">602928</a>) and MMACHC, the latter of which most likely caused the aberrant cobalamin metabolism. The transcriptome clustered in the same clade found in patients with mutations in the HCFC1 gene. Retroviral transduction of MMACHC into patient THAP11 mutant fibroblasts corrected the cobalamin-related biochemical abnormalities. The findings, including results of studies in zebrafish (see ANIMAL MODEL), indicated that THAP11 and HCFC1 coregulate an overlapping set of genes which play a role in the phenotype of both MAHCL and MAHCX (<a href="/entry/309541">309541</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28449119" 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="#2" class="mim-tip-reference" title="Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. <strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong> Hum. Molec. Genet. 26: 2838-2849, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28449119">Quintana et al. (2017)</a> found that thap11-null zebrafish embryos had severe craniofacial abnormalities, including defective development of Meckel cartilage. These defects were restored with wildtype THAP11. Thap11-null zebrafish also showed structural brain anomalies associated with abnormal acetylated tubulin and reduced axons, as well as increased numbers of SOX2 (<a href="/entry/184429">184429</a>) neural progenitor cells, suggesting impaired neuronal differentiation. Overexpression of THAP11 mRNA also increased the number of SOX2-positive cells in certain brain regions. The results indicated that changes in the level of thap11 expression during brain development can alter the fate of neural precursors. In contrast, expression of the human F80L mutation (<a href="/entry/609119#0001">609119.0001</a>) significantly decreased the number of SOX2-positive neural precursor cells in the developing brain, with a bias toward neuronal differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28449119" 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="Chern, T., Achilleos, A., Tong, X., Hill, M. C., Saltzman, A. B., Reineke, L. C., Chaudhury, A., Dasgupta, S. K., Redhead, Y., Watkins, D., Neilson, J. R., Thiagarajan, P., Green, J. B. A., Malovannaya, A., Martin, J. F., Rosenblatt, D. S., Poche, R. A. <strong>Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.</strong> Nature Commun. 13: 134, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35013307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35013307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35013307[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-021-27759-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35013307">Chern et al. (2022)</a> found that almost all mutant mice that were homozygous for the F80L mutation (<a href="/entry/609118#0001">609118.0001</a>) died prior to weaning. Out of 260 mutant mice, only 1 survived to about 1 month of age and was runted. Studies of pregnant dams indicated that the homozygous mutant pups died from an inability to breathe, without brainstem, lung, or diaphragm defects. Mutant mice showed developmental brain defects and disrupted astrogliogenesis. Additional features included myocardial abnormalities, anemia, and craniofacial defects. F80L Thap11 mutant transcripts were increased in mutant mouse brain, but protein levels were decreased, suggesting instability of the mutant protein. Although mutant F80L Thap11 was still able to bind to Hcfc1, it likely was unable to bind to DNA, caused impaired function. There was a dramatic reduction in Mmachc RNA and protein expression associated with decreased cobalamin coenzymes MeCbl and AdoCbl and decreased functional activity of MTR and MUT. Similar findings were observed in hemizygous male mice carrying the HCFC1 mutation A115V (<a href="/entry/300019#0003">300019.0003</a>). RNA-seq analysis showed dysregulation of genes involved in ribosome biogenesis and there was abnormal protein translation; the authors concluded that THAP11 and HCFC1 mutations cause a ribosomopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35013307" 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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Chern, T., Achilleos, A., Tong, X., Hill, M. C., Saltzman, A. B., Reineke, L. C., Chaudhury, A., Dasgupta, S. K., Redhead, Y., Watkins, D., Neilson, J. R., Thiagarajan, P., Green, J. B. A., Malovannaya, A., Martin, J. F., Rosenblatt, D. S., Poche, R. A.
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<strong>Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.</strong>
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Nature Commun. 13: 134, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35013307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35013307</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35013307[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=35013307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41467-021-27759-7" target="_blank">Full Text</a>]
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Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H.
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<strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong>
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Hum. Molec. Genet. 26: 2838-2849, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28449119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28449119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28449119[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=28449119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddx157" target="_blank">Full Text</a>]
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Watkins, D., Rosenblatt, D. S.
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<strong>Inherited defects of cobalamin metabolism.</strong>
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Vitam. Horm. 119: 355-376, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35337626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35337626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35337626" 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/bs.vh.2022.01.010" target="_blank">Full Text</a>]
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Yu, H.-C., Sloan, J. L., Scharer, G., Brebner, A., Quintana, A. M., Achilly, N. P., Manoli, I., Coughlin, C. R., II, Geiger, E. A., Schneck, U., Watkins, D., Suormala, T., Van Hove, J. L. K., Fowler, B., Baumgartner, M. R., Rosenblatt, D. S., Venditti, C. P., Shaikh, T. H.
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<strong>An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.</strong>
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Am. J. Hum. Genet. 93: 506-514, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24011988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24011988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24011988[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=24011988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cassandra L. Kniffin : 09/10/2024
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ckniffin : 09/18/2024<br>alopez : 09/16/2024<br>alopez : 09/16/2024<br>ckniffin : 09/12/2024
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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<th>
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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16q22.1
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<span class="mim-font">
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?Methylmalonic aciduria and homocystinuria, cblL type
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</td>
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<span class="mim-font">
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620940
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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THAP11
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<span class="mim-font">
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609119
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that methylmalonic aciduria and homocystinuria of the cblL type (MAHCL) is caused by homozygous mutation in the THAP11 gene (609119) on chromosome 16q11. One such patient has been reported.</p>
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<strong>Description</strong>
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<p>Methylmalonic aciduria and homocystinuria of the cblL type (MAHCL) is an autosomal recessive metabolic disorder with onset of symptoms in infancy. The disorder is characterized by neurologic features, including seizures and profoundly impaired neurodevelopment. In the single reported patient, metabolic workup showed mild methylmalonicaciduria without homocystinuria, but complementation studies were consistent with a biochemical diagnosis of cblC (277400) and cblX (309541). Mutations in the MMACHC gene (609831) and HCFC1 (300019) were excluded before identification of mutation in the THAP11 gene (Quintana et al., 2017). </p><p>The biochemical abnormalities in cblC and cblX tend to be mild, and some patients with cblX without homocystinuria have been reported (Yu et al., 2013). Since THAP11 forms a functional complex with HCFC1, it is possible that future reported patients with THAP11 mutations may have homocystinuria (see review by Watkins and Rosenblatt, 2022). </p>
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<strong>Clinical Features</strong>
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<span class="mim-text-font">
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<p>Quintana et al. (2017) reported a boy, born of unrelated Moroccan parents, who presented at 2 months of age with myoclonic seizures followed by severely impaired global development. Metabolic workup showed mild methylmalonic aciduria and low-normal plasma methionine; homocysteine could not be detected in the urine. Later studies showed plasma homocysteine at the high end of normal. Standard treatment (protein restriction, hydroxocobalamin injection, pyridoxine, folic acid, and betaine) was ineffective. He gradually developed encephalopathy, tetraplegia, and profoundly impaired intellectual development. Eye examination showed esotropia and hyperopia. Brain imaging was not performed. The patient died from pneumonia at 10 years of age. Studies of patient fibroblasts showed impaired function of the cobalamin-dependent enzymes MUT (609058) and MTR (156570) and decreased synthesis of both adenosylcobalamin and methylcobalamin. Complementation studies were consistent with a biochemical diagnosis of cblC. </p>
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</span>
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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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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The transmission pattern of MAHCL in the family reported by Quintana et al. (2017) was consistent with autosomal recessive inheritance. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a boy, born of Moroccan parents, with MAHCL, Quintana et al. (2017) identified a homozygous missense mutation in the THAP11 gene (F80L; 609119.0001). The mutation, which was found by direct sequencing of the THAP11 gene in patient cells, was not present in public databases, including gnomAD. Parental DNA was not available, so familial segregation studies could not be performed. Quintana et al. (2017) studied the THAP11 gene based on the known interaction between THAP11 and HCFC1 (300019), which is mutated in MAHCX (309541). Complementation studies were consistent with a biochemical diagnosis of cblC (277400); however, mutation in the MMACHC gene (609831) was excluded. RNA-seq analysis of patient fibroblasts showed downregulation of several genes, including TMOD2 (602928) and MMACHC, the latter of which most likely caused the aberrant cobalamin metabolism. The transcriptome clustered in the same clade found in patients with mutations in the HCFC1 gene. Retroviral transduction of MMACHC into patient THAP11 mutant fibroblasts corrected the cobalamin-related biochemical abnormalities. The findings, including results of studies in zebrafish (see ANIMAL MODEL), indicated that THAP11 and HCFC1 coregulate an overlapping set of genes which play a role in the phenotype of both MAHCL and MAHCX (309541). </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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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Quintana et al. (2017) found that thap11-null zebrafish embryos had severe craniofacial abnormalities, including defective development of Meckel cartilage. These defects were restored with wildtype THAP11. Thap11-null zebrafish also showed structural brain anomalies associated with abnormal acetylated tubulin and reduced axons, as well as increased numbers of SOX2 (184429) neural progenitor cells, suggesting impaired neuronal differentiation. Overexpression of THAP11 mRNA also increased the number of SOX2-positive cells in certain brain regions. The results indicated that changes in the level of thap11 expression during brain development can alter the fate of neural precursors. In contrast, expression of the human F80L mutation (609119.0001) significantly decreased the number of SOX2-positive neural precursor cells in the developing brain, with a bias toward neuronal differentiation. </p><p>Chern et al. (2022) found that almost all mutant mice that were homozygous for the F80L mutation (609118.0001) died prior to weaning. Out of 260 mutant mice, only 1 survived to about 1 month of age and was runted. Studies of pregnant dams indicated that the homozygous mutant pups died from an inability to breathe, without brainstem, lung, or diaphragm defects. Mutant mice showed developmental brain defects and disrupted astrogliogenesis. Additional features included myocardial abnormalities, anemia, and craniofacial defects. F80L Thap11 mutant transcripts were increased in mutant mouse brain, but protein levels were decreased, suggesting instability of the mutant protein. Although mutant F80L Thap11 was still able to bind to Hcfc1, it likely was unable to bind to DNA, caused impaired function. There was a dramatic reduction in Mmachc RNA and protein expression associated with decreased cobalamin coenzymes MeCbl and AdoCbl and decreased functional activity of MTR and MUT. Similar findings were observed in hemizygous male mice carrying the HCFC1 mutation A115V (300019.0003). RNA-seq analysis showed dysregulation of genes involved in ribosome biogenesis and there was abnormal protein translation; the authors concluded that THAP11 and HCFC1 mutations cause a ribosomopathy. </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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<h4>
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<span class="mim-font">
|
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<strong>REFERENCES</strong>
|
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Chern, T., Achilleos, A., Tong, X., Hill, M. C., Saltzman, A. B., Reineke, L. C., Chaudhury, A., Dasgupta, S. K., Redhead, Y., Watkins, D., Neilson, J. R., Thiagarajan, P., Green, J. B. A., Malovannaya, A., Martin, J. F., Rosenblatt, D. S., Poche, R. A.
|
|
<strong>Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.</strong>
|
|
Nature Commun. 13: 134, 2022.
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[PubMed: 35013307]
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[Full Text: https://doi.org/10.1038/s41467-021-27759-7]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H.
|
|
<strong>Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.</strong>
|
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Hum. Molec. Genet. 26: 2838-2849, 2017.
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[PubMed: 28449119]
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[Full Text: https://doi.org/10.1093/hmg/ddx157]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Watkins, D., Rosenblatt, D. S.
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<strong>Inherited defects of cobalamin metabolism.</strong>
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Vitam. Horm. 119: 355-376, 2022.
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[PubMed: 35337626]
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[Full Text: https://doi.org/10.1016/bs.vh.2022.01.010]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Yu, H.-C., Sloan, J. L., Scharer, G., Brebner, A., Quintana, A. M., Achilly, N. P., Manoli, I., Coughlin, C. R., II, Geiger, E. A., Schneck, U., Watkins, D., Suormala, T., Van Hove, J. L. K., Fowler, B., Baumgartner, M. R., Rosenblatt, D. S., Venditti, C. P., Shaikh, T. H.
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<strong>An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.</strong>
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Am. J. Hum. Genet. 93: 506-514, 2013.
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[PubMed: 24011988]
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.07.022]
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</ol>
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<div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 09/10/2024
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Edit History:
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<span class="mim-text-font">
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carol : 09/18/2024<br>ckniffin : 09/18/2024<br>alopez : 09/16/2024<br>alopez : 09/16/2024<br>ckniffin : 09/12/2024
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