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<title>
Entry
- #277400 - METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE; MAHCC
- OMIM
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<span class="h4">#277400</span>
<br />
<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/277400"><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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<li role="presentation" style="margin-left: 1em">
<a href="#heterogeneity">Heterogeneity</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#pathogenesis">Pathogenesis</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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<div><a href="https://clinicaltrials.gov/search?cond=METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=710&Typ=Pat" title="Methylmalonic acidemia with homocystinuria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Methylmalonic acidemia wit…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11308&Typ=Pat" title="Methylmalonic acidemia with homocystinuria, type cblC" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Methylmalonic acidemia wit…&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1328/" 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 style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Elevated%20C3%20Acylcarnitine%20PA%20and%20MA.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG ACT Sheet</a></div><div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/C3-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Orphanet</div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=26" title="Methylmalonic acidemia with homocystinuria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Methylmalonic acidemia wit…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79282" title="Methylmalonic acidemia with homocystinuria, type cblC" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Methylmalonic acidemia wit…</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/984ae53f-d7de-4dd8-90dd-4cd799285689/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0050715" 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>
<div><a href="http://www.informatics.jax.org/disease/277400" 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>
<div><a href="https://wormbase.org/resources/disease/DOID:0050715" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
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</a>
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</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:277400" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
</div>
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<span>
<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.">
&nbsp;
</span>
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</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 74653006<br />
<strong>ORPHA:</strong> 26, 79282<br />
<strong>DO:</strong> 0050715<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
277400
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE; MAHCC
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
METHYLMALONIC ACIDEMIA AND HOMOCYSTINURIA, cblC TYPE<br />
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, VITAMIN B12-RESPONSIVE<br />
VITAMIN B12 METABOLIC DEFECT WITH COMBINED DEFICIENCY OF METHYLMALONYL-CoA MUTASE AND HOMOCYSTEINE:METHYLTETRAHYDROFOLATE METHYLTRANSFERASE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</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>
<td>
<span class="mim-font">
Methylmalonic aciduria and homocystinuria, cblC type
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277400"> 277400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
MMACHC
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609831"> 609831 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/558?start=-3&limit=10&highlight=558">
1p34.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Methylmalonic aciduria and homocystinuria, cblC type, digenic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277400"> 277400 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
PRDX1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176763"> 176763 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/277400" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS277400" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/277400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/277400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> 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="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Hydrocephalus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230745008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230745008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G91</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G91.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020255</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000238" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000238</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000238" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000238</a>]</span><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">
- Long face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836047&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836047</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000276</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000276</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=729bf273c6a346c2f07ab0965824ffb2" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Face,Long-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=729bf273c6a346c2f07ab0965824ffb2&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
High forehead <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239676&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239676</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000348" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000348</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000348" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000348</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1ed202dc7ca7d5b2c5e34a787d713dec" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Hairline,High_Anterior-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=1ed202dc7ca7d5b2c5e34a787d713dec&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Flat philtrum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1142533&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1142533</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000319</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=64d497514ce8c2250bd637c9cb83892d" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Philtrum,Smooth-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=64d497514ce8c2250bd637c9cb83892d&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Low-set ears <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95515009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95515009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q17.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q17.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239234&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239234</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000369</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000369</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9f0956aaa4fd45c34f94336afbbdc931" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Ear,Low-Set-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9f0956aaa4fd45c34f94336afbbdc931&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Large, floppy ears <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848570&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848570</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">
- Pigmentary retinopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28835009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28835009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.52</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551715&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551715</a>, <a href="https://bioportal.bioontology.org/search?q=C0035334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035334</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000580" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000580</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000580" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000580</a>]</span><br /> -
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br /> -
Decreased visual acuity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13164000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234632&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234632</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007663" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007663</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007663" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007663</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Vascular lesions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1402315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1402315</a>]</span><br /> -
Thrombotic microangiopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/126729006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">126729006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M31.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M31.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/446.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">446.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2717961&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2717961</a>]</span><br /> -
Thromboembolism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13713005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13713005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371039008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371039008</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/453.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">453.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001907" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001907</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001907" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001907</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035078</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br /> -
Hemolytic-uremic syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111407006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111407006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D59.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D59.30</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D59.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D59.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/283.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">283.11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019061&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019061</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005575" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005575</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005575" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005575</a>]</span><br /> -
Thrombotic microangiopathic nephropathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848569&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848569</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">
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Lethargy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/214264003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">214264003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R53.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R53.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023380&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023380</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span><br /> -
Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <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">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</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>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</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 /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> 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> <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 /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Cortical 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=C4551583&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551583</a>, <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:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>, <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:0002120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002120</a>]</span><br /> -
Acute neurologic decompensation (in later-onset cases) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5195097&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5195097</a>]</span><br /> -
Decreased cognition (later-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848563</a>]</span><br /> -
Confusion (later-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848564&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848564</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40917007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40917007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/286933003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">286933003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R41.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R41.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001289" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001289</a>]</span><br /> -
Dementia (later-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848565</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52448006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52448006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12348006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12348006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F03.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/290.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/294.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">294.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000726</a>]</span><br /> -
Delirium (later-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848566&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848566</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2776000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2776000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/419567006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">419567006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R41.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R41.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031258" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031258</a>]</span><br /> -
Extrapyramidal symptoms (later-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848567&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848567</a>]</span> <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">[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 /> -
Tremor (later-onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848568&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848568</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26079004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26079004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R25.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001337</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">
- Metabolic acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59455009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59455009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220981</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001942</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001942</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Megaloblastic anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53165003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53165003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D53.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D53.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001889" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001889</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001889" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001889</a>]</span><br /> -
Thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415116008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415116008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302215000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302215000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392386</a>, <a href="https://bioportal.bioontology.org/search?q=C0040034&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040034</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span><br /> -
Anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271737000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271737000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D64.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D64.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/285.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">285.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002871</a>, <a href="https://bioportal.bioontology.org/search?q=C1000483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1000483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span><br /> -
Neutropenia <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 />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Homocystinuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11282001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11282001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019880&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019880</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002156</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002156</a>]</span><br /> -
Homocysteinemia <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R79.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R79.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3495426&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3495426</a>]</span><br /> -
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 /> -
Methylmalonic acidemia <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=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: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:0002912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002912</a>]</span><br /> -
Decreased serum methionine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848555&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848555</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003658</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003658</a>]</span><br /> -
Cystathioninemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/6669004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">6669004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268618&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268618</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003286</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003286</a>]</span><br /> -
Cystathioninuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/6885006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">6885006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13003007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13003007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.19</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268616&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268616</a>, <a href="https://bioportal.bioontology.org/search?q=C0220993&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220993</a>, <a href="https://bioportal.bioontology.org/search?q=C1963708&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1963708</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003153" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003153</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003153" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003153</a>]</span><br /> -
Uremia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44730006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44730006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1112699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1112699</a>, <a href="https://bioportal.bioontology.org/search?q=C0041948&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041948</a>]</span><br /> -
Hematuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53298000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53298000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34436003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34436003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R31.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R31.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/599.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">599.7</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/599.70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">599.70</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018965&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018965</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000790" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000790</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000790" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000790</a>]</span><br /> -
Proteinuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29738008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29738008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/231860006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">231860006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R80.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R80.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R80</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/791.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">791.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1279888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279888</a>, <a href="https://bioportal.bioontology.org/search?q=C0033687&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033687</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000093</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000093</a>]</span><br /> -
Decreased methylmalonyl-CoA mutase (MUT, <a href="/entry/609058">609058</a>) activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848579&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848579</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003210" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003210</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003210" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003210</a>]</span><br /> -
Decreased methionine synthase (MTR, <a href="/entry/156570">156570</a>) activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848580&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848580</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003524" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003524</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003524" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003524</a>]</span><br /> -
Decreased adenosylcobalamin (AdoCbl) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848556&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848556</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003145" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003145</a>]</span><br /> -
Decreased methylcobalamin (MeCbl) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848557</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003223" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003223</a>]</span><br /> -
Normal serum cobalamin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848571</a>]</span><br /> -
Decreased cobalamin in liver, kidney, and cultured fibroblasts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848572</a>]</span><br />
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<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset usually in first year of life<br /> -
Early-onset associated with more severe course and early death<br /> -
Adolescent or adult onset associated with neuropsychiatric symptoms<br /> -
Patients with later onset do not have dysmorphic features<br /> -
Variable response to vitamin B12 therapy<br /> -
See also CblD (<a href="/entry/277410">277410</a>)<br />
</span>
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<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the MMACHC gene (MMACHC gene <a href="/entry/609831#0001">609831.0001</a>)<br />
</span>
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</div>
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<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>
<td>
<span class="mim-font">
<a href="/entry/277400"> Methylmalonic aciduria and homocystinuria, cblC type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277400"> 277400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609831"> MMACHC </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609831"> 609831 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/558?start=-3&limit=10&highlight=558"> 1p34.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277400"> Methylmalonic aciduria and homocystinuria, cblC type, digenic </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277400"> 277400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176763"> PRDX1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176763"> 176763 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/683?start=-3&limit=10&highlight=683"> 2q23.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277410"> Methylmalonic aciduria and homocystinuria, cblD type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277410"> 277410 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611935"> MMADHC </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611935"> 611935 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/630?start=-3&limit=10&highlight=630"> 6q13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277380"> Methylmalonic aciduria and homocystinuria, cblF type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277380"> 277380 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612625"> LMBRD1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612625"> 612625 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/383?start=-3&limit=10&highlight=383"> 14q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614857"> Methylmalonic aciduria and homocystinuria, cblJ type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614857"> 614857 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603214"> ABCD4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603214"> 603214 </a>
</span>
</td>
</tr>
<tr>
<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">
<a href="/entry/620940"> ?Methylmalonic aciduria and homocystinuria, cblL type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/620940"> 620940 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609119"> THAP11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609119"> 609119 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/847?start=-3&limit=10&highlight=847"> Xq28 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/309541"> Methylmalonic aciduria and homocysteinemia, cblX type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/309541"> 309541 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300019"> HCFC1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300019"> 300019 </a>
</span>
</td>
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<p>A number sign (#) is used with this entry because of evidence that combined methylmalonic aciduria and homocystinuria type cblC (MAHCC) is caused by homozygous or compound heterozygous mutation in the MMACHC gene (<a href="/entry/609831">609831</a>) on chromosome 1p34.</p><p>There is also evidence that MAHCC is caused by digenic mutations: one caused by a coding MAHCC mutation, and the other, a secondary epimutation, triggered by a mutation in the PRDX1 gene (<a href="/entry/176763">176763</a>).</p>
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<strong>Description</strong>
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<p>Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; <a href="/entry/609058">609058</a>) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; <a href="/entry/156570">156570</a>). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (<a href="/entry/277410">277410</a>), cblF (<a href="/entry/277380">277380</a>), and cblJ (<a href="/entry/614857">614857</a>).</p><p>Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (<a href="/entry/251000">251000</a>) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (<a href="/entry/251100">251100</a>) is caused by mutation in the MMAA gene (<a href="/entry/607481">607481</a>) on 4q31; and MMA cblB (<a href="/entry/251110">251110</a>) is caused by mutation in the MMAB gene (<a href="/entry/607568">607568</a>) on 12q24.</p><p>Methylmalonic aciduria and homocystinuria of cblC type is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (<a href="#22" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. &lt;strong&gt;Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.&lt;/strong&gt; Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16311595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16311595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1683&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16311595">Lerner-Ellis et al., 2006</a>). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (<a href="#33" class="mim-tip-reference" title="Rosenblatt, D. S., Aspler, A. L., Shevell, M. I., Pletcher, B. A., Fenton, W. A., Seashore, M. R. &lt;strong&gt;Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).&lt;/strong&gt; J. Inherit. Metab. Dis. 20: 528-538, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9266389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9266389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005353530303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9266389">Rosenblatt et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9266389+16311595" 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="#24" class="mim-tip-reference" title="Mahoney, M. J., Hart, A. C., Steen, V. D., Rosenberg, L. E. &lt;strong&gt;Methylmalonicacidemia: biochemical heterogeneity in defects of 5-prime-deoxyadenosylcobalamin synthesis.&lt;/strong&gt; Proc. Nat. Acad. Sci. 72: 2799-2803, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1058495/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1058495&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.72.7.2799&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1058495">Mahoney et al. (1975)</a> identified 4 forms of methylmalonic aciduria as defined by ability to synthesize the coenzyme AdoCbl: patients with deficiency of the mutase apoenzyme retained the ability to synthesize both AdoCbl and MeCbl ('mut'); a second group had a deficiency in synthesis of both AdoCbl and MeCbl ('cblC'); and 2 others had isolated AdoCbl deficiency ('cblA' and 'cblB'). The authors concluded that the defect in cblC was proximal to the separation of the pathways for AdoCbl and MeCbl synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1058495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Gravel, R. A., Mahoney, M. J., Ruddle, F. H., Rosenberg, L. E. &lt;strong&gt;Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism.&lt;/strong&gt; Proc. Nat. Acad. Sci. 72: 3181-3185, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1059104/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1059104&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.72.8.3181&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1059104">Gravel et al. (1975)</a> confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1059104" 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="#30" class="mim-tip-reference" title="Mudd, S. H., Levy, H. L., Abeles, R. H. &lt;strong&gt;A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 35: 121-126, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5779140/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5779140&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-291x(69)90491-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5779140">Mudd et al. (1969)</a> reported an infant with homocysteinemia, methylmalonic aciduria, cystathioninemia, and a decrease in blood methionine. He died at 7.5 weeks of age. In vitro analysis identified a defect in the 2 reactions in which vitamin B12 derivatives function as coenzymes: methionine formation from 5-methylfolate-H(4) (MTR) and homocysteine, and isomerization of methylmalonyl-CoA to succinyl-CoA (MUT). Since vitamin B12 was present in normal concentrations in the liver, <a href="#30" class="mim-tip-reference" title="Mudd, S. H., Levy, H. L., Abeles, R. H. &lt;strong&gt;A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 35: 121-126, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5779140/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5779140&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-291x(69)90491-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5779140">Mudd et al. (1969)</a> concluded that the gene-determined defect involved the conversion of B12 to the active coenzymes. <a href="#26" class="mim-tip-reference" title="McCully, K. S. &lt;strong&gt;Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.&lt;/strong&gt; Am. J. Path. 56: 111-128, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5792556/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5792556&lt;/a&gt;]" pmid="5792556">McCully (1969)</a> studied the same patient as that reported by <a href="#31" class="mim-tip-reference" title="Mudd, S. H., Levy, H. L., Morrow, G., III. &lt;strong&gt;Deranged B12 metabolism: effects on sulfur amino acid metabolism.&lt;/strong&gt; Biochem. Med. 4: 193-214, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5524064/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5524064&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-2944(70)90049-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5524064">Mudd et al. (1970)</a> and noted arterial changes and atherosclerosis on pathologic examination. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5524064+5792556+5779140" 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 patient described by <a href="#13" class="mim-tip-reference" title="Dillon, M. J., England, J. M., Gompertz, D., Goodey, P. A., Grant, D. B., Hussein, H. A.-A., Linnell, J. C., Matthews, D. M., Mudd, S. H., Newns, G. H., Seakins, J. W. T., Uhlendorf, B. W., Wise, U. K. &lt;strong&gt;Mental retardation, megaloblastic anaemia, methylmalonicaciduria, and abnormal homocysteine metabolism due to an error in vitamin B12 metabolism.&lt;/strong&gt; Clin. Sci. Molec. Med. 47: 43-61, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4853163/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4853163&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1042/cs0470043&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4853163">Dillon et al. (1974)</a> differed from the others in that in addition to severe mental retardation and megaloblastosis, clinical and pathologic changes typical of subacute degeneration of the spinal cord were present. <a href="#5" class="mim-tip-reference" title="Baumgartner, E. R., Wick, H., Linnell, J. C., Gaull, G. E., Bachmann, C., Steinmann, B. &lt;strong&gt;Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. II. Biochemical investigations.&lt;/strong&gt; Helv. Paediat. Acta 34: 483-496, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/43301/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;43301&lt;/a&gt;]" pmid="43301">Baumgartner et al. (1979)</a> reported a male infant who died at 4 months of age after 2 episodes of acute heart failure. He had hemolytic and megaloblastic anemia, hematuria, proteinuria, and mild uremia. Plasma and urine levels of methionine were low, whereas levels of cystathionine were increased. Vitamin B12 deficiency, malabsorption, and transport defect were excluded by normal serum cobalamin and transcobalamins. Autopsy showed severe vascular lesions with changes of thrombotic thrombocytopenia in the kidney, suggesting the hemolytic-uremic syndrome. Elevated plasma homocysteine was presumed to be responsible for the vascular lesions. Analysis of postmortem liver showed deficiency of both cobalamin-dependent enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=43301+4853163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Brandstetter, Y., Weinhouse, E., Splaingard, M. L., Tang, T. T. &lt;strong&gt;Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (cbl-C type).&lt;/strong&gt; Am. J. Med. Genet. 36: 167-171, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2368803/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2368803&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320360208&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2368803">Brandstetter et al. (1990)</a> reported a 16-week-old infant with cblC who died from cor pulmonale due to thromboemboli in the pulmonary circulation. They suggested that the pathogenesis was the same as that of thromboembolic disease in homocystinuria due to cystathionine beta-synthase deficiency (<a href="/entry/236200">236200</a>). <a href="#10" class="mim-tip-reference" title="Brandstetter, Y., Weinhouse, E., Splaingard, M. L., Tang, T. T. &lt;strong&gt;Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (cbl-C type).&lt;/strong&gt; Am. J. Med. Genet. 36: 167-171, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2368803/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2368803&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320360208&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2368803">Brandstetter et al. (1990)</a> emphasized the frequent finding of pigmentary retinopathy and abnormality in the macular area of the ocular fundus. <a href="#34" class="mim-tip-reference" title="Russo, P., Doyon, J., Sonsino, E., Ogier, H., Saudubray, J.-M. &lt;strong&gt;A congenital anomaly of vitamin B12 metabolism: a study of three cases.&lt;/strong&gt; Hum. Path. 23: 504-512, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1568746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1568746&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0046-8177(92)90127-o&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1568746">Russo et al. (1992)</a> described 3 infants with cblC disease characterized by metabolic acidosis, methylmalonic aciduria, and homocystinuria. In the first weeks of life, all showed failure to thrive, hypotonia, and lethargy associated with pancytopenia and hepatic dysfunction, which progressed to severe respiratory insufficiency and renal failure consistent with hemolytic-uremic syndrome. The infants died at 40, 45, and 75 days of age. Postmortem findings were dominated by thrombotic microangiopathy of the kidneys and lungs, diffuse hepatic steatosis, and megaloblastic changes in the bone marrow. Severe gastritis with striking cystic dysplastic mucosal changes and total absence of parietal and chief cells was found in all 3 patients, with the rest of the gastrointestinal tract being essentially normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2368803+1568746" 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="#33" class="mim-tip-reference" title="Rosenblatt, D. S., Aspler, A. L., Shevell, M. I., Pletcher, B. A., Fenton, W. A., Seashore, M. R. &lt;strong&gt;Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).&lt;/strong&gt; J. Inherit. Metab. Dis. 20: 528-538, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9266389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9266389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005353530303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9266389">Rosenblatt et al. (1997)</a> reviewed 50 cblC patients who could be classified into 2 broad phenotypes: 44 had early onset and 6 had later onset. The 44 patients presented in the first year of life with feeding difficulties, hypotonia, developmental delay, seizures, pigmentary retinopathy, and anemia. About one-fourth of the patients died, and those who survived had neurologic impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9266389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Cerone, R., Schiaffino, M. C., Caruso, U., Lupino, S., Gatti, R. &lt;strong&gt;Minor facial anomalies in combined methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism.&lt;/strong&gt; J. Inherit. Metab. Dis. 22: 247-250, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10384379/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10384379&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005521702298&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10384379">Cerone et al. (1999)</a> described mild facial anomalies in combined methylmalonic aciduria and homocystinuria of the cblC form. Features included a long face, high forehead, large, floppy, and low-set ears, and flat philtrum. The morphologic characteristics became more evident after 3 years of age, and were noted separately by physicians of 2 different departments. A female patient showed high forehead and low-set ears when first observed at the age of 2 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10384379" 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="Andersson, H. C., Marble, M., Shapira, E. &lt;strong&gt;Long-term outcome in treated combined methylmalonic acidemia and homocystinemia.&lt;/strong&gt; Genet. Med. 1: 146-150, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11258350/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11258350&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00125817-199905000-00006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11258350">Andersson et al. (1999)</a> described the clinical and biochemical features of 8 cblC patients who were treated for an average of 5.7 years. Treatment consisted of daily oral carnitine and intramuscular hydroxocobalamin. The patients had congenital malformations including microcephaly at birth (2 of 8), congenital heart disease (2 of 8), dysmorphic facial features (1 of 8), and thyroglossal duct cyst (1 of 8). Postnatal hydrocephalus (2 of 8) and hip dislocation caused by ligament laxity (1 of 8) were also noted. One patient had profound visual impairment before 6 months of age secondary to cblC retinopathy, and 2 patients had abnormal retinal pigmentation with normal visual function. All patients presented with poor growth, feeding problems, and/or seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258350" 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="#38" class="mim-tip-reference" title="Van Hove, J. L. K., Van Damme-Lombaerts, R., Grunewald, S., Peters, H., Van Damme, B., Fryns, J.-P., Arnout, J., Wevers, R., Baumgartner, E. R., Fowler, B. &lt;strong&gt;Cobalamin disorder cbl-C presenting with late-onset thrombotic microangiopathy.&lt;/strong&gt; Am. J. Med. Genet. 111: 195-201, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12210350/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12210350&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10499&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12210350">Van Hove et al. (2002)</a> described a 12-year-old boy and his 4-year-old sister who presented with proteinuria, hematuria, hypertension, and chronic hemolytic anemia. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Hyperhomocysteinemia and mild methylmalonic aciduria were also found. Fibroblast studies were compatible with a mild cblC complementation group. The children had no neurologic symptoms and minimal pigmentary retinal abnormalities. Both children and their father carried a balanced reciprocal translocation, t(8;19)(q23.2;q13.3). Treatment with higher than usual doses of parenteral hydroxycobalamin and oral betaine stopped the thrombotic microangiopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210350" 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="#35" class="mim-tip-reference" title="Schimel, A. M., Mets, M. B. &lt;strong&gt;The natural history of retinal degeneration in association with cobalamin C (cbl C) disease.&lt;/strong&gt; Ophthalmic Genet. 27: 9-14, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16543196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16543196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1080/13816810500481758&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16543196">Schimel and Mets (2006)</a> reported the ocular findings in 3 patients with cblC disease. All 3 presented with macular pigmentary changes and showed attenuation of electroretinographic (ERG) responses. Based on the findings in these patients and a literature review, <a href="#35" class="mim-tip-reference" title="Schimel, A. M., Mets, M. B. &lt;strong&gt;The natural history of retinal degeneration in association with cobalamin C (cbl C) disease.&lt;/strong&gt; Ophthalmic Genet. 27: 9-14, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16543196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16543196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1080/13816810500481758&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16543196">Schimel and Mets (2006)</a> concluded that cblC disease results in progressive retinal degeneration beginning in the first few months of life and progressing rapidly over the first few years of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16543196" 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="#20" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. &lt;strong&gt;Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.&lt;/strong&gt; Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23837176/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23837176&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.2012-2581&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23837176">Komhoff et al. (2013)</a> studied 4 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy, who were identified from the Dutch national referral center for pediatric pulmonary hypertension. A fifth patient with this combination was contacted to collect clinical data. All 5 had cobalamin C (cblC) deficiency, diagnosed postmortem in 2 patients. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, pulmonary arterial hypertension was preceded by renal thrombotic microangiopathy from age 2.5 to 7 years. Three patients presenting at 3 years of age or younger died of right ventricular failure secondary to progressive pulmonary arterial hypertension. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 exhibited progressive pulmonary vasculopathy, and 1 patient was in stable condition at the time of the study. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. <a href="#20" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. &lt;strong&gt;Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.&lt;/strong&gt; Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23837176/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23837176&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.2012-2581&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23837176">Komhoff et al. (2013)</a> identified cblC deficiency as the cause of the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy in these patients. The authors proposed that early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may ameliorate the devastating course of this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" 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="Ahrens-Nicklas, R. C., Whitaker, A. M., Kaplan, P., Cuddapah, S., Burfield, J., Blair, J., Brochi, L., Yudkoff, M., Ficicioglu, C. &lt;strong&gt;Efficacy of early treatment in patients with cobalamin C disease identified by newborn screening: a 16-year experience.&lt;/strong&gt; Genet. Med. 19: 926-935, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28151490/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28151490&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2016.214&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28151490">Ahrens-Nicklas et al. (2017)</a> completed a retrospective analysis of 12 patients with cblC referred for abnormal newborn screening results and followed at the Children's Hospital of Pennsylvania between 1999 and 2015. Of the patients, 87.5% had intellectual disability and 75% had retinopathy; 16.7% had 1 episode of mild acidosis. However, no patients manifested major metabolic decompensation. Developmental outcomes correlated more closely with initial metabolic abnormalities than with long-term metabolic control. Increased intake of medical foods resulted in better control but also perturbations in the ratios of essential amino acids and lower z-scores for head circumference. <a href="#1" class="mim-tip-reference" title="Ahrens-Nicklas, R. C., Whitaker, A. M., Kaplan, P., Cuddapah, S., Burfield, J., Blair, J., Brochi, L., Yudkoff, M., Ficicioglu, C. &lt;strong&gt;Efficacy of early treatment in patients with cobalamin C disease identified by newborn screening: a 16-year experience.&lt;/strong&gt; Genet. Med. 19: 926-935, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28151490/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28151490&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2016.214&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28151490">Ahrens-Nicklas et al. (2017)</a> found no relationship between diet and cognitive outcomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28151490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others. &lt;strong&gt;Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.&lt;/strong&gt; Neurology 95: e3129-e3137, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32943488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32943488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0000000000010912&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32943488">He et al. (2020)</a> reported 70 Chinese patients with early-onset MAHCC and hydrocephalus. In the 68 cases with available clinical information, the median age of diagnosis of hydrocephalus was 3 months (range, 0.3-96 months). The hydrocephalus presented before metabolic treatment in 60 cases and after metabolic treatment in 8 cases. Signs of intracranial hypertension were uncommon and included vomiting in 7 cases, 'sunset eyes' in 7 cases, and enlarged head circumference in 6 cases. Brain imaging by CT and/or MRI showed bilateral ventricular dilatation and cortical atrophy in all 70 patients and subdural collections in 13 cases. A ventriculoperitoneal shunt was performed in 36 cases for indications including progressive aggravation of intracranial hypertension and moderate to severe bilateral ventriculomegaly. In 30 patients, the hydrocephalus improved after metabolic treatment only. Other clinical manifestations in the patients included psychomotor retardation in 68, visual impairments in 68, seizures in 42, anemia in 27, and lethargy/coma in 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32943488" 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="#25" class="mim-tip-reference" title="Matmat, K., Gueant-Rodriguez, R. M., Oussalah, A., Wiedemann-Fode, A., Dionisi-Vici, C., Coelho, D., Gueant, J. L., Conart, J. B. &lt;strong&gt;Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review.&lt;/strong&gt; Hum. Genet. 141: 1239-1251, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34652574/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34652574&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-021-02350-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34652574">Matmat et al. (2022)</a> provided a systematic review of ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism from a literature review of 52 studies reporting 163 cbl and 24 mut patients. Ocular manifestations were identified in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder, affecting 137 patients (84%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34652574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Late-Onset cblC Disease</em></strong></p><p>
<a href="#15" class="mim-tip-reference" title="Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W. &lt;strong&gt;Homocystinuria with methylmalonic aciduria: two cases in a sibship.&lt;/strong&gt; Biochem. Med. 4: 500-515, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5524089/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5524089&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-2944(70)90080-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5524089">Goodman et al. (1970)</a> reported 2 brothers with a milder, possibly allelic form of the disorder. The elder, a 14-year-old Mexican American, was first admitted to the hospital in an acute psychotic episode. He had an IQ of about 50, a somewhat marfanoid habitus, and mild abnormalities on neurologic examination. Ectopia lentis and chest deformity were lacking. The parents were first cousins once removed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5524089" 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="#36" class="mim-tip-reference" title="Shinnar, S., Singer, H. S. &lt;strong&gt;Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence: a treatable cause of dementia and myelopathy.&lt;/strong&gt; New Eng. J. Med. 311: 451-454, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6749192/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6749192&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198408163110707&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6749192">Shinnar and Singer (1984)</a> described a clinically atypical patient with the cblC defect. An adolescent girl had been a straight-A student and in excellent health until age 12. Over the period of a year, her grades deteriorated markedly and her work became equivalent to that of a first-grader. She developed apathy, unsteady gait, and impaired speech. Examination showed broad-based gait, impaired vibration and position sense, and extensor Babinski response. IQ was 40 to 50. Hemoglobin was 12.6 gm%, mean corpuscular volume 96, serum B12 level normal, and red cell folate level 88 ng per ml red cells (mildly decreased). Blood showed elevated homocysteine and only a trace of methionine. The urine contained large amounts of homocysteine and methylmalonic acid. On parenteral hydroxycobalamin (1,000 micrograms per day), the patient improved markedly. A 12-year-old sister and an 8-week-old brother were found to have the same cblC defect, confirmed by fibroblast studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6749192" 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="#33" class="mim-tip-reference" title="Rosenblatt, D. S., Aspler, A. L., Shevell, M. I., Pletcher, B. A., Fenton, W. A., Seashore, M. R. &lt;strong&gt;Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).&lt;/strong&gt; J. Inherit. Metab. Dis. 20: 528-538, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9266389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9266389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005353530303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9266389">Rosenblatt et al. (1997)</a> found that 6 of 50 cblC patients had later onset, after age 4 years. These patients presented with acute neurologic dysfunction, including cognitive decline, confusion, psychosis, dementia, and extrapyramidal signs. Later-onset patients had better survival, better response to treatment, and less neurologic sequelae compared to the early-onset patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9266389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Bodamer, O. A. F., Rosenblatt, D. S., Appel, S. H., Beaudet, A. L. &lt;strong&gt;Adult-onset combined methylmalonic aciduria and homocystinuria (cblC)&lt;/strong&gt; Neurology 56: 1113 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11320193/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11320193&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.56.8.1113&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11320193">Bodamer et al. (2001)</a> reported what they believed to be the first case of adult-onset cblC. The patient was a 20-year-old man who presented with slowly progressive leg weakness, loss of bowel and bladder function, episodes of forgetfulness, slurred speech, and deep venous thromboses. He later became unresponsive and required mechanical ventilation. A diagnosis of cobalamin defect was suggested after he was determined to have elevated plasma homocysteine and methylmalonic aciduria. Treatment with hydroxycobalamin and carnitine proved effective. The authors suggested that the patient may have had a mild mutation resulting in significant residual enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11320193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A. &lt;strong&gt;Late-onset cobalamin-C disorder: a challenging diagnosis.&lt;/strong&gt; Am. J. Med. Genet. 143A: 979-984, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17431913/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17431913&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31671&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17431913">Ben-Omran et al. (2007)</a> reported 2 unrelated patients with late-onset cblC disease. The first patient was a 14-year old girl, born of first-cousin Pakistani parents, who developed progressive neurologic decline, including dementia, depression, ataxia, lethargy, incontinence, and seizures over a period of 2 years. After visits to several physicians without a correct diagnosis, analysis of plasma and urine showed increased homocysteine and methylmalonate consistent with a defect in cobalamin synthesis. Appropriate treatment resulted in clinical improvement with residual mild gait ataxia. The second patient was a 10-year-old girl of Bengali descent who presented with acute dementia, anorexia, extreme weight loss, and 'catatonic psychotic behavior.' She had a mild learning disability with an IQ of 72 and seizures. Brain MRI performed at ages 4 and 10 years showed progressive volume loss. Laboratory analysis detected cblC disease, and appropriate treatment resulted in clinical improvement. Both patients were found to be homozygous for the R132X mutation in the MMACHC gene (<a href="/entry/609831#0003">609831.0003</a>). <a href="#7" class="mim-tip-reference" title="Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A. &lt;strong&gt;Late-onset cobalamin-C disorder: a challenging diagnosis.&lt;/strong&gt; Am. J. Med. Genet. 143A: 979-984, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17431913/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17431913&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31671&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17431913">Ben-Omran et al. (2007)</a> noted the diagnostic difficulty in late-onset cblC disease and emphasized the utility of plasma and urine analysis, as patients may have normal red blood cell indices. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431913" 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="#37" class="mim-tip-reference" title="Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A. &lt;strong&gt;Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.&lt;/strong&gt; Am. J. Med. Genet. 143A: 2430-2434, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17853453/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17853453&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31932&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17853453">Tsai et al. (2007)</a> described a 36-year-old woman with a spinal cord infarct who was subsequently diagnosed with methylmalonic aciduria and homocystinuria, cblC type. Her past medical history was significant for joint hypermobility, arthritis, bilateral cataracts, unilateral hearing loss, chronic anemia, and frequent urinary tract infections secondary to a urogenital fistula. She reported emotional difficulties beginning in her teens and was diagnosed with depression and psychosis requiring hospitalization in her thirties. One to 2 years prior to the spinal cord infarct, the patient experienced increasing muscular weakness, leg paresthesias, and difficulty walking. The woman sought help in the emergency department for her weakness and paresthesia but was misdiagnosed with malingering because of her psychiatric history. One week later, she experienced lower extremity hemiplegia, and bladder incontinence and diagnosed with a spinal cord infarct. Laboratory evaluation revealed elevated homocysteine and methylmalonic acid consistent with cblC disease. Molecular analysis of the MMACHC gene revealed the 271dupA (<a href="/entry/609831#0001">609831.0001</a>) and R161Q (<a href="/entry/609831#0005">609831.0005</a>) mutations. <a href="#37" class="mim-tip-reference" title="Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A. &lt;strong&gt;Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.&lt;/strong&gt; Am. J. Med. Genet. 143A: 2430-2434, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17853453/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17853453&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31932&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17853453">Tsai et al. (2007)</a> recommended that all patients with psychiatric disease complicated by dementia and myelopathy be screened with plasma amino acids and urine organic acids allowing cblC disease to be preliminarily diagnosed or effectively excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853453" 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="#12" class="mim-tip-reference" title="Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R. &lt;strong&gt;Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (clbC) with non-syndromic bull&#x27;s eye maculopathy.&lt;/strong&gt; Ophthal. Genet. 36: 270-275, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25687216/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25687216&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/13816810.2015.1010736&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25687216">Collison et al. (2015)</a> reported a 28-year-old woman who presented with decreased central vision and mild photoaversion for 2 years. She had a past medical history of iron deficiency anemia and kidney and urinary tract infections. Visual field testing demonstrated a bilateral pericentral scotoma, and funduscopy showed bilateral bull's eye-appearing macular lesions. Repeat ophthalmologic evaluation at age 35 years showed the bull's eye-appearing macular dystrophy with extension of retinal peripheral atrophy. Laboratory testing showed elevated urine methylmalonic acid and homocysteine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25687216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Bonafede, L., Ficicioglu, C. H., Serrano, L., Han, G., Morgan, J. I. W., Mills, M. D., Forbes, B. J., Davidson, S. L., Binenbaum, G., Kaplan, P. B., Nichols, C. W., Verloo, P., Leroy, B. P., Maguire, A. M., Aleman, T. S. &lt;strong&gt;Cobalamin C deficiency shows a rapidly progressing maculopathy with severe photoreceptor and ganglion cell loss.&lt;/strong&gt; Invest. Ophthal. Vis. Sci. 56: 7875-7887, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26658511/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26658511&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26658511[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1167/iovs.15-17857&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26658511">Bonafede et al. (2015)</a> reported retinal abnormalities in 11 patients, aged 4 months to 15 years, with cblC. The patients with early-onset cblC demonstrated rapidly progressive maculopathy with severe loss of outer nuclear and ganglion cell layers, generally before 1 year of age. The 4 patients with later-onset cblC disease (older than 7 years of age) had a retina-wide degeneration, suggesting a different rate of disease progression in the extramacular retina in these patients. Other ophthalmologic findings included pseudocolobomas in 3 patients and nystagmus in 8 patients. Of the 6 patients who had electroretinograms, 5 were normal and 1 showed reduced rod-mediated responses. The most common refractive error was myopia. <a href="#9" class="mim-tip-reference" title="Bonafede, L., Ficicioglu, C. H., Serrano, L., Han, G., Morgan, J. I. W., Mills, M. D., Forbes, B. J., Davidson, S. L., Binenbaum, G., Kaplan, P. B., Nichols, C. W., Verloo, P., Leroy, B. P., Maguire, A. M., Aleman, T. S. &lt;strong&gt;Cobalamin C deficiency shows a rapidly progressing maculopathy with severe photoreceptor and ganglion cell loss.&lt;/strong&gt; Invest. Ophthal. Vis. Sci. 56: 7875-7887, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26658511/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26658511&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26658511[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1167/iovs.15-17857&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26658511">Bonafede et al. (2015)</a> noted that there was no obvious association between the degree of metabolic control of cblC disease (plasma methionine, homocysteine and methylmalonic acid levels) and the severity of ocular abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26658511" 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="#3" class="mim-tip-reference" title="Atkinson, J. L., Paterson, A., Renaud, D., Clarke, J. T. R., Wilcken, B., Bulman, D., Rommens, J. M. &lt;strong&gt;Genetic mapping of cobalamin C deficiency: putative linkage to chromosome 1q. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. (suppl.) 71: 452 only, 2002."None>Atkinson et al. (2002)</a> mapped the locus for cobalamin C deficiency to chromosome 1q by linkage analysis. <a href="#22" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. &lt;strong&gt;Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.&lt;/strong&gt; Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16311595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16311595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1683&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16311595">Lerner-Ellis et al. (2006)</a> refined the assignment using homozygosity mapping and haplotype analyses and identified the MMACHC gene on 1p34.1 as the site of disease-causing mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others. &lt;strong&gt;Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.&lt;/strong&gt; Nature Genet. 38: 93-100, 2006. Note: Erratum: Nature Genet. 38: 957 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16311595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16311595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1683&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16311595">Lerner-Ellis et al. (2006)</a> refined the chromosomal map interval containing the mutation for methylmalonic aciduria and homocystinuria, cblC type, to a region of the short arm of chromosome 1 containing the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA (<a href="/entry/609831#0001">609831.0001</a>), accounted for 40% of all disease alleles. Transduction of wildtype MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311595" 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>Among 79 unrelated Chinese patients with combined methylmalonic aciduria and homocystinuria of the cblC type, <a href="#23" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. &lt;strong&gt;Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.&lt;/strong&gt; J. Hum. Genet. 55: 621-626, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20631720/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20631720&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/jhg.2010.81&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20631720">Liu et al. (2010)</a> identified 24 different mutations in the MMACHC gene, including 7 novel mutations. All patients had 2 mutations, except for 3 patients in whom only 1 mutation was identified. The 2 most common alleles were W203X (<a href="/entry/609831#0006">609831.0006</a>) and 658delAAG (<a href="/entry/609831#0007">609831.0007</a>), which accounted for 48.1% and 13.9% of mutant alleles, respectively. Haplotype analysis indicated a different founder effect for each mutation, but the major mutation profile did not differ between patients from northern and southern China. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631720" 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 3 affected members of unrelated families with autosomal recessive cblC vitamin B12 deficiency, <a href="#18" class="mim-tip-reference" title="Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others. &lt;strong&gt;A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.&lt;/strong&gt; Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29302025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29302025&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29302025[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41467-017-02306-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29302025">Gueant et al. (2018)</a> identified compound heterozygous mutations in the MMACHC gene: a different coding mutation on 1 allele in all 3 (<a href="/entry/609831#0011">609831.0011</a>-<a href="/entry/609831#0013">609831.0013</a>), combined with the same 'secondary epimutation' on the other allele. The epimutation, 32 hypermethylated CpG sites detected by bisulfite sequencing, was a consequence of a heterozygous mutation in the adjacent, reverse-oriented, PRDX1 gene: c.515-1G-T (<a href="/entry/176763#0001">176763.0001</a>) or c.515-2A-T (<a href="/entry/176763#0002">176763.0002</a>). The PRDX1 mutations were also found in unaffected relatives who carried the secondary epimutation. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. The resulting read-through transcript extended through the adjacent MMACHC locus in the antisense orientation. The authors proposed that the antisense transcript leads to the formation of triplexes in the promoter of MMACHC and generates CpG methylation resulting in reduced expression of the normal message. This was confirmed experimentally by growing fibroblasts from an affected proband in 5-azacytidine, which reduced promoter methylation, and by silencing PRDX1 with an siRNA, both of which increased expression of MMACHC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29302025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Sanger or next-generation sequencing in 70 Chinese individuals with MAHCC and hydrocephalus, <a href="#19" class="mim-tip-reference" title="He, R., Zhang, H., Kang, L., Li, H., Shen, M., Zhang, Y., Mo, R., Liu, Y., Song, J., Chen, Z., Liu, Y., Jin, Y., and 11 others. &lt;strong&gt;Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.&lt;/strong&gt; Neurology 95: e3129-e3137, 2020. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32943488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32943488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/WNL.0000000000010912&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32943488">He et al. (2020)</a> identified homozygous or compound heterozygous mutations in the MMACHC gene. The parents in each case were carriers of one mutation. Eighteen individual mutations were identified, including 4 novel mutations (Q143X, W200X, Y205X, and c.568insT) that were predicted to cause loss of function and were not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. The most frequent mutation was W209X (<a href="/entry/609831#0006">609831.0006</a>), accounting for 62.9% of the mutations, followed by c.658delAAG (<a href="/entry/609831#0007">609831.0007</a>), R73X, and c.567dupT, seen at a frequency of 12.1%, 5%, and 5%, respectively. The findings were consistent with a previous study in the Chinese population by <a href="#23" class="mim-tip-reference" title="Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T. &lt;strong&gt;Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria.&lt;/strong&gt; J. Hum. Genet. 55: 621-626, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20631720/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20631720&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/jhg.2010.81&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20631720">Liu et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20631720+32943488" 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 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, <a href="#12" class="mim-tip-reference" title="Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R. &lt;strong&gt;Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (clbC) with non-syndromic bull&#x27;s eye maculopathy.&lt;/strong&gt; Ophthal. Genet. 36: 270-275, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25687216/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25687216&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/13816810.2015.1010736&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25687216">Collison et al. (2015)</a> identified compound heterozygous mutations in the MMACHC gene (<a href="/entry/609831#0005">609831.0005</a> and <a href="/entry/609831#0011">609831.0011</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25687216" 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 review of epimutation mechanisms in metabolic disorders including MAHCC, <a href="#17" class="mim-tip-reference" title="Gueant, J. L., Siblini, Y., Chery, C., Schmitt, G., Gueant-Rodriguez, R. M., Coelho, D., Watkins, D., Rosenblatt, D. S., Oussalah, A. &lt;strong&gt;Epimutation in inherited metabolic disorders: the influence of aberrant transcription in adjacent genes.&lt;/strong&gt; Hum. Genet. 141: 1309-1325, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35190856/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35190856&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-021-02414-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35190856">Gueant et al. (2022)</a> discussed that the epimutation in MMACHC due to PRDX1 mutations was likely to be constitutional because it was detected in DNA pre- and postzygotic tissue including sperm, blood cells, and fibroblasts. However, they also suggested that the high frequency of hypermethylation in the MMACHC promoter across the general population compared to epigenetic modification of other disease-causing genes indicated that methylation effects on the MMACHC promoter are influenced by both secondary epimutation (PRDX1 mutations affecting methylation) and primary epimutations (such as postzygotic environmental exposures). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35190856" 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="#29" class="mim-tip-reference" title="Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S. &lt;strong&gt;Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.&lt;/strong&gt; Molec. Genet. Metab. 88: 315-321, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16714133/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16714133&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2006.04.001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16714133">Morel et al. (2006)</a> reported genotype-phenotype correlations in 37 patients from published case reports, representing most of the landmark descriptions of cobalamin C deficiency. Twenty-five of 37 had early-onset disease, presenting in the first 6 months of life; 17 of these 25 were found to be homozygous for the 271dupA mutation (<a href="/entry/609831#0001">609831.0001</a>) (9 patients) or for the 331C-T (R111X; <a href="/entry/609831#0004">609831.0004</a>) mutation (3 patients) or compound heterozygous for these 2 mutations (5 patients). Nine of 12 late-onset cases presented with acute neurologic symptoms: 4 of 9 were homozygous for the 347T-C mutation (L116P; <a href="/entry/609831#0002">609831.0002</a>), 2 of 9 were compound heterozygous for the 271dupA and 394C-T (R132X; <a href="/entry/609831#0003">609831.0003</a>) mutations, and 3 of 9 for the 271dupA mutation and a missense mutation. The 394C-T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714133" 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>Among 118 patients with cblC, <a href="#21" class="mim-tip-reference" title="Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B. &lt;strong&gt;Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.&lt;/strong&gt; Hum. Mutat. 30: 1072-1081, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19370762/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19370762&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.21001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19370762">Lerner-Ellis et al. (2009)</a> identified 34 different MMACHC mutations, including 11 novel mutations. The 271dupA mutation was the most common, accounting for 42% of pathogenic alleles, followed by the R132X (20%) and R111X (5%) mutations. Six variants defined specific haplotypes that varied with ethnicity. Genotype/phenotype correlations were apparent. Individuals with the R132X and R161Q (<a href="/entry/609831#0005">609831.0005</a>) mutations tended to present with late-onset disease, whereas patients with the R111X and 271dupA mutations tended to present in infancy. Functional expression analysis on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and the late-onset R132X and R161Q mutations. The early-onset R111X mutation was also underexpressed when compared to control alleles and the R132X mutation. Quantitative RT-PCR studies showed that the late-onset R132X mutation had significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19370762" 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 with a rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency, <a href="#20" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. &lt;strong&gt;Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.&lt;/strong&gt; Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23837176/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23837176&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.2012-2581&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23837176">Komhoff et al. (2013)</a> detected 1 of 2 basepair substitutions (G-to-A or G-to-T) at nucleotide 276 of the MMACHC gene (<a href="/entry/609831#0008">609831.0008</a>, <a href="/entry/609831#0009">609831.0009</a>). These mutations were not found in approximately 500 patients with cblC deficiency and other phenotypes, or in 200 control individuals. <a href="#20" class="mim-tip-reference" title="Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F. &lt;strong&gt;Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.&lt;/strong&gt; Pediatrics 132: e540-e544, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23837176/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23837176&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.2012-2581&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23837176">Komhoff et al. (2013)</a> concluded that these mutations hold specific vascular pathogenicity in addition to compromising enzyme function. These patients were additionally heterozygous for various frameshift mutations on the other MMACHC allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23837176" 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="Bartholomew, D. W., Batshaw, M. L., Allen, R. H., Roe, C. R., Rosenblatt, D., Valle, D. L., Francomano, C. A. &lt;strong&gt;Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria.&lt;/strong&gt; J. Pediat. 112: 32-39, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3257264/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3257264&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(88)80114-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3257264">Bartholomew et al. (1988)</a> reported variable results with vitamin B12 therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3257264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Enns, G. M., Barkovich, A. J., Rosenblatt, D. S., Fredrick, D. R., Weisiger, K., Ohnstad, C., Packman, S. &lt;strong&gt;Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin.&lt;/strong&gt; J. Inherit. Metab. Dis. 22: 599-607, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10399092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10399092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005517727451&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10399092">Enns et al. (1999)</a> reported a 4-year-old Hispanic girl with cblC methylmalonic acidemia who had undergone intramuscular hydroxocobalamin therapy starting at 3 weeks of age. Despite treatment, she showed progressive neurologic deterioration and worsening head MRI changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10399092" 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="Andersson, H. C., Marble, M., Shapira, E. &lt;strong&gt;Long-term outcome in treated combined methylmalonic acidemia and homocystinemia.&lt;/strong&gt; Genet. Med. 1: 146-150, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11258350/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11258350&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00125817-199905000-00006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11258350">Andersson et al. (1999)</a> reported successful treatment of 8 patients with cblC. All patients had dramatic reduction of plasma free homocystine and urine methylmalonic acid excretion after initiation of treatment with carnitine, intramuscular hydroxocobalamin and, in 2 cases, oral betaine. Growth was significantly improved in most cases after the initiation of therapy, and microcephaly resolved in 1 patient. All patients were developmentally delayed regardless of the age at which treatment began, although 2 patients had relatively mild developmental delay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p><a href="#28" class="mim-tip-reference" title="Mellman, I., Willard, H. F., Youngdahl-Turner, P., Rosenberg, L. E. &lt;strong&gt;Cobalamin coenzyme synthesis in normal and mutant human fibroblasts. Evidence for a processing enzyme activity deficient in cblC cells.&lt;/strong&gt; J. Biol. Chem. 254: 11847-11853, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/500677/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;500677&lt;/a&gt;]" pmid="500677">Mellman et al. (1979)</a> found that cells from a cblC patient were unable to associate newly taken up (57)Co-cobalamin with the methyltransferase, whereas hybrids of mouse cells and cblC cells showed human (57)Co-cobalamin-methyltransferase whenever human chromosome 1 was present (<a href="#27" class="mim-tip-reference" title="Mellman, I. S., Lin, P. F., Ruddle, F. H., Rosenberg, L. E. &lt;strong&gt;Genetic control of cobalamin binding in normal and mutant cells: assignment of the gene for 5-methyltetrahydrofolate:L-homocysteine S-methyltransferase to human chromosome 1.&lt;/strong&gt; Proc. Nat. Acad. Sci. 76: 405-409, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/284356/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;284356&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.76.1.405&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="284356">Mellman et al., 1979</a>). The authors concluded that the cblC mutation did not affect the methyltransferase apoprotein, but rather a metabolic step that converts cobalamin to the coenzyme capable of attaching to the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=500677+284356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span class="mim-font">
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<strong>See Also:</strong>
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<span class="mim-text-font">
<a href="#Baumgartner1979" class="mim-tip-reference" title="Baumgartner, E. R., Wick, H., Maurer, R., Egli, N., Steinmann, B. &lt;strong&gt;Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. I. Case report and histopathology.&lt;/strong&gt; Helv. Paediat. Acta 34: 465-482, 1979.">Baumgartner et al. (1979)</a>; <a href="#Mudd1970" class="mim-tip-reference" title="Mudd, S. H., Uhlendorf, B. W., Hinde, K. R., Levy, H. L. &lt;strong&gt;Deranged B12 metabolism: studies of fibroblasts grown in tissue culture.&lt;/strong&gt; Biochem. Med. 4: 215-239, 1970.">Mudd et al. (1970)</a>
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<a id="references"class="mim-anchor"></a>
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
</span>
</h4>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="1" class="mim-anchor"></a>
<a id="Ahrens-Nicklas2017" class="mim-anchor"></a>
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<p class="mim-text-font">
Ahrens-Nicklas, R. C., Whitaker, A. M., Kaplan, P., Cuddapah, S., Burfield, J., Blair, J., Brochi, L., Yudkoff, M., Ficicioglu, C.
<strong>Efficacy of early treatment in patients with cobalamin C disease identified by newborn screening: a 16-year experience.</strong>
Genet. Med. 19: 926-935, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28151490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28151490</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28151490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2016.214" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Andersson1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Andersson, H. C., Marble, M., Shapira, E.
<strong>Long-term outcome in treated combined methylmalonic acidemia and homocystinemia.</strong>
Genet. Med. 1: 146-150, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11258350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11258350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/00125817-199905000-00006" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="Atkinson2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Atkinson, J. L., Paterson, A., Renaud, D., Clarke, J. T. R., Wilcken, B., Bulman, D., Rommens, J. M.
<strong>Genetic mapping of cobalamin C deficiency: putative linkage to chromosome 1q. (Abstract)</strong>
Am. J. Hum. Genet. (suppl.) 71: 452 only, 2002.
</p>
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</li>
<li>
<a id="4" class="mim-anchor"></a>
<a id="Bartholomew1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bartholomew, D. W., Batshaw, M. L., Allen, R. H., Roe, C. R., Rosenblatt, D., Valle, D. L., Francomano, C. A.
<strong>Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria.</strong>
J. Pediat. 112: 32-39, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3257264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3257264</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3257264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(88)80114-8" target="_blank">Full Text</a>]
</p>
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<a id="5" class="mim-anchor"></a>
<a id="Baumgartner1979" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Baumgartner, E. R., Wick, H., Linnell, J. C., Gaull, G. E., Bachmann, C., Steinmann, B.
<strong>Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. II. Biochemical investigations.</strong>
Helv. Paediat. Acta 34: 483-496, 1979.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/43301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">43301</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=43301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="6" class="mim-anchor"></a>
<a id="Baumgartner1979" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Baumgartner, E. R., Wick, H., Maurer, R., Egli, N., Steinmann, B.
<strong>Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. I. Case report and histopathology.</strong>
Helv. Paediat. Acta 34: 465-482, 1979.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/528229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">528229</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=528229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="7" class="mim-anchor"></a>
<a id="Ben-Omran2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A.
<strong>Late-onset cobalamin-C disorder: a challenging diagnosis.</strong>
Am. J. Med. Genet. 143A: 979-984, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.31671" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Bodamer2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bodamer, O. A. F., Rosenblatt, D. S., Appel, S. H., Beaudet, A. L.
<strong>Adult-onset combined methylmalonic aciduria and homocystinuria (cblC)</strong>
Neurology 56: 1113 only, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11320193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11320193</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11320193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/wnl.56.8.1113" target="_blank">Full Text</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Bonafede2015" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bonafede, L., Ficicioglu, C. H., Serrano, L., Han, G., Morgan, J. I. W., Mills, M. D., Forbes, B. J., Davidson, S. L., Binenbaum, G., Kaplan, P. B., Nichols, C. W., Verloo, P., Leroy, B. P., Maguire, A. M., Aleman, T. S.
<strong>Cobalamin C deficiency shows a rapidly progressing maculopathy with severe photoreceptor and ganglion cell loss.</strong>
Invest. Ophthal. Vis. Sci. 56: 7875-7887, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26658511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26658511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26658511[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=26658511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1167/iovs.15-17857" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Brandstetter1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Brandstetter, Y., Weinhouse, E., Splaingard, M. L., Tang, T. T.
<strong>Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (cbl-C type).</strong>
Am. J. Med. Genet. 36: 167-171, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2368803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2368803</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2368803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320360208" target="_blank">Full Text</a>]
</p>
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<a id="11" class="mim-anchor"></a>
<a id="Cerone1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Cerone, R., Schiaffino, M. C., Caruso, U., Lupino, S., Gatti, R.
<strong>Minor facial anomalies in combined methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism.</strong>
J. Inherit. Metab. Dis. 22: 247-250, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10384379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10384379</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10384379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1023/a:1005521702298" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Collison2015" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Collison, F. T., Xie, Y., Gambin, T., Jhangiani, S., Muzny, D., Gibbs, R., Lupski, J. R., Fishman, G. A., Allikmets, R.
<strong>Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (clbC) with non-syndromic bull's eye maculopathy.</strong>
Ophthal. Genet. 36: 270-275, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25687216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25687216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25687216[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=25687216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.3109/13816810.2015.1010736" target="_blank">Full Text</a>]
</p>
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<a id="13" class="mim-anchor"></a>
<a id="Dillon1974" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Dillon, M. J., England, J. M., Gompertz, D., Goodey, P. A., Grant, D. B., Hussein, H. A.-A., Linnell, J. C., Matthews, D. M., Mudd, S. H., Newns, G. H., Seakins, J. W. T., Uhlendorf, B. W., Wise, U. K.
<strong>Mental retardation, megaloblastic anaemia, methylmalonicaciduria, and abnormal homocysteine metabolism due to an error in vitamin B12 metabolism.</strong>
Clin. Sci. Molec. Med. 47: 43-61, 1974.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4853163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4853163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4853163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1042/cs0470043" target="_blank">Full Text</a>]
</p>
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<a id="14" class="mim-anchor"></a>
<a id="Enns1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Enns, G. M., Barkovich, A. J., Rosenblatt, D. S., Fredrick, D. R., Weisiger, K., Ohnstad, C., Packman, S.
<strong>Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin.</strong>
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[<a href="https://doi.org/10.1023/a:1005517727451" target="_blank">Full Text</a>]
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<strong>Homocystinuria with methylmalonic aciduria: two cases in a sibship.</strong>
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[<a href="https://doi.org/10.1016/0006-2944(70)90080-3" target="_blank">Full Text</a>]
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<strong>Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism.</strong>
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[<a href="https://doi.org/10.1073/pnas.72.8.3181" target="_blank">Full Text</a>]
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Gueant, J. L., Siblini, Y., Chery, C., Schmitt, G., Gueant-Rodriguez, R. M., Coelho, D., Watkins, D., Rosenblatt, D. S., Oussalah, A.
<strong>Epimutation in inherited metabolic disorders: the influence of aberrant transcription in adjacent genes.</strong>
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[<a href="https://doi.org/10.1007/s00439-021-02414-9" target="_blank">Full Text</a>]
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Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others.
<strong>A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients.</strong>
Nature Commun. 9: 67, 2018. Note: Electronic Article. Erratum: Nature Commun. 9: 554, 2018.
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[<a href="https://doi.org/10.1038/s41467-017-02306-5" target="_blank">Full Text</a>]
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<strong>Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency.</strong>
Neurology 95: e3129-e3137, 2020. Note: Electronic Article.
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[<a href="https://doi.org/10.1212/WNL.0000000000010912" target="_blank">Full Text</a>]
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<strong>Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.</strong>
Pediatrics 132: e540-e544, 2013. Note: Electronic Article.
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Lerner-Ellis, J. P., Anastasio, N., Liu, J., Coelho, D., Suormala, T., Stucki, M., Loewy, A. D., Gurd, S., Grundberg, E., Morel, C. F., Watkins, D., Baumgartner, M. R., Pastinen, T., Rosenblatt, D. S., Fowler, B.
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[<a href="https://doi.org/10.1002/humu.21001" target="_blank">Full Text</a>]
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Lerner-Ellis, J. P., Tirone, J. C., Pawelek, P. D., Dore, C., Atkinson, J. L., Watkins, D., Morel, C. F., Fujiwara, T. M., Moras, E., Hosack, A. R., Dunbar, G. V., Antonicka, H., and 10 others.
<strong>Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.</strong>
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[<a href="https://doi.org/10.1038/ng1683" target="_blank">Full Text</a>]
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Liu, M.-Y., Yang, Y.-L., Chang, Y.-C., Chiang, S.-H., Lin, S.-P., Han, L.-S., Qi, Y., Hsiao, K.-J., Liu, T.-T.
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[<a href="https://doi.org/10.1038/jhg.2010.81" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.72.7.2799" target="_blank">Full Text</a>]
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Matmat, K., Gueant-Rodriguez, R. M., Oussalah, A., Wiedemann-Fode, A., Dionisi-Vici, C., Coelho, D., Gueant, J. L., Conart, J. B.
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[<a href="https://doi.org/10.1007/s00439-021-02350-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.76.1.405" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2006.04.001" target="_blank">Full Text</a>]
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<a id="Mudd1969" class="mim-anchor"></a>
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Mudd, S. H., Levy, H. L., Abeles, R. H.
<strong>A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria.</strong>
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[<a href="https://doi.org/10.1016/0006-291x(69)90491-4" target="_blank">Full Text</a>]
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<strong>Deranged B12 metabolism: effects on sulfur amino acid metabolism.</strong>
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[<a href="https://doi.org/10.1016/0006-2944(70)90049-9" target="_blank">Full Text</a>]
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Mudd, S. H., Uhlendorf, B. W., Hinde, K. R., Levy, H. L.
<strong>Deranged B12 metabolism: studies of fibroblasts grown in tissue culture.</strong>
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[<a href="https://doi.org/10.1016/0006-2944(70)90050-5" target="_blank">Full Text</a>]
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Rosenblatt, D. S., Aspler, A. L., Shevell, M. I., Pletcher, B. A., Fenton, W. A., Seashore, M. R.
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[<a href="https://doi.org/10.1023/a:1005353530303" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0046-8177(92)90127-o" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1080/13816810500481758" target="_blank">Full Text</a>]
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<strong>Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence: a treatable cause of dementia and myelopathy.</strong>
New Eng. J. Med. 311: 451-454, 1984.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6749192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6749192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6749192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM198408163110707" target="_blank">Full Text</a>]
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<a id="Tsai2007" class="mim-anchor"></a>
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Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A.
<strong>Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.</strong>
Am. J. Med. Genet. 143A: 2430-2434, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17853453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17853453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.31932" target="_blank">Full Text</a>]
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Van Hove, J. L. K., Van Damme-Lombaerts, R., Grunewald, S., Peters, H., Van Damme, B., Fryns, J.-P., Arnout, J., Wevers, R., Baumgartner, E. R., Fowler, B.
<strong>Cobalamin disorder cbl-C presenting with late-onset thrombotic microangiopathy.</strong>
Am. J. Med. Genet. 111: 195-201, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.10499" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 11/03/2022
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Carol A. Bocchini - updated : 10/18/2022<br>Hilary J. Vernon - updated : 11/19/2021<br>Hilary J. Vernon - updated : 04/06/2021<br>Ada Hamosh - updated : 06/15/2018<br>Alan F. Scott - updated : 03/06/2018<br>Ada Hamosh - updated : 12/1/2014<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - updated : 11/10/2009<br>Kelly A. Przylepa - updated : 4/1/2008<br>Jane Kelly - updated : 11/20/2007<br>Cassandra L. Kniffin - updated : 7/17/2007<br>Ada Hamosh - updated : 6/28/2007<br>Victor A. McKusick - updated : 1/18/2006<br>Cassandra L. Kniffin - reorganized : 12/10/2004<br>Cassandra L. Kniffin - updated : 12/7/2004<br>Deborah L. Stone - updated : 1/6/2003<br>Cassandra L. Kniffin - updated : 5/24/2002<br>Victor A. McKusick - updated : 9/15/1999<br>Ada Hamosh - updated : 8/9/1999<br>Victor A. McKusick - updated : 7/16/1999
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Victor A. McKusick : 6/4/1986
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carol : 11/04/2022
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<strong>#</strong> 277400
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE; MAHCC
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<em>Alternative titles; symbols</em>
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METHYLMALONIC ACIDEMIA AND HOMOCYSTINURIA, cblC TYPE<br />
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, VITAMIN B12-RESPONSIVE<br />
VITAMIN B12 METABOLIC DEFECT WITH COMBINED DEFICIENCY OF METHYLMALONYL-CoA MUTASE AND HOMOCYSTEINE:METHYLTETRAHYDROFOLATE METHYLTRANSFERASE
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Other entities represented in this entry:
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC, INCLUDED
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<strong>SNOMEDCT:</strong> 74653006; &nbsp;
<strong>ORPHA:</strong> 26, 79282; &nbsp;
<strong>DO:</strong> 0050715; &nbsp;
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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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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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1p34.1
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Methylmalonic aciduria and homocystinuria, cblC type
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277400
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Autosomal recessive
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3
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MMACHC
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609831
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1p34.1
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Methylmalonic aciduria and homocystinuria, cblC type, digenic
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277400
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Autosomal recessive
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3
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PRDX1
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176763
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that combined methylmalonic aciduria and homocystinuria type cblC (MAHCC) is caused by homozygous or compound heterozygous mutation in the MMACHC gene (609831) on chromosome 1p34.</p><p>There is also evidence that MAHCC is caused by digenic mutations: one caused by a coding MAHCC mutation, and the other, a secondary epimutation, triggered by a mutation in the PRDX1 gene (176763).</p>
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<strong>Description</strong>
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<p>Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (277410), cblF (277380), and cblJ (614857).</p><p>Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (251000) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (251100) is caused by mutation in the MMAA gene (607481) on 4q31; and MMA cblB (251110) is caused by mutation in the MMAB gene (607568) on 12q24.</p><p>Methylmalonic aciduria and homocystinuria of cblC type is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (Lerner-Ellis et al., 2006). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (Rosenblatt et al., 1997). </p>
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<strong>Heterogeneity</strong>
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<p>Mahoney et al. (1975) identified 4 forms of methylmalonic aciduria as defined by ability to synthesize the coenzyme AdoCbl: patients with deficiency of the mutase apoenzyme retained the ability to synthesize both AdoCbl and MeCbl ('mut'); a second group had a deficiency in synthesis of both AdoCbl and MeCbl ('cblC'); and 2 others had isolated AdoCbl deficiency ('cblA' and 'cblB'). The authors concluded that the defect in cblC was proximal to the separation of the pathways for AdoCbl and MeCbl synthesis. </p><p>Gravel et al. (1975) confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls. </p>
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<strong>Clinical Features</strong>
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<p>Mudd et al. (1969) reported an infant with homocysteinemia, methylmalonic aciduria, cystathioninemia, and a decrease in blood methionine. He died at 7.5 weeks of age. In vitro analysis identified a defect in the 2 reactions in which vitamin B12 derivatives function as coenzymes: methionine formation from 5-methylfolate-H(4) (MTR) and homocysteine, and isomerization of methylmalonyl-CoA to succinyl-CoA (MUT). Since vitamin B12 was present in normal concentrations in the liver, Mudd et al. (1969) concluded that the gene-determined defect involved the conversion of B12 to the active coenzymes. McCully (1969) studied the same patient as that reported by Mudd et al. (1970) and noted arterial changes and atherosclerosis on pathologic examination. </p><p>The patient described by Dillon et al. (1974) differed from the others in that in addition to severe mental retardation and megaloblastosis, clinical and pathologic changes typical of subacute degeneration of the spinal cord were present. Baumgartner et al. (1979) reported a male infant who died at 4 months of age after 2 episodes of acute heart failure. He had hemolytic and megaloblastic anemia, hematuria, proteinuria, and mild uremia. Plasma and urine levels of methionine were low, whereas levels of cystathionine were increased. Vitamin B12 deficiency, malabsorption, and transport defect were excluded by normal serum cobalamin and transcobalamins. Autopsy showed severe vascular lesions with changes of thrombotic thrombocytopenia in the kidney, suggesting the hemolytic-uremic syndrome. Elevated plasma homocysteine was presumed to be responsible for the vascular lesions. Analysis of postmortem liver showed deficiency of both cobalamin-dependent enzymes. </p><p>Brandstetter et al. (1990) reported a 16-week-old infant with cblC who died from cor pulmonale due to thromboemboli in the pulmonary circulation. They suggested that the pathogenesis was the same as that of thromboembolic disease in homocystinuria due to cystathionine beta-synthase deficiency (236200). Brandstetter et al. (1990) emphasized the frequent finding of pigmentary retinopathy and abnormality in the macular area of the ocular fundus. Russo et al. (1992) described 3 infants with cblC disease characterized by metabolic acidosis, methylmalonic aciduria, and homocystinuria. In the first weeks of life, all showed failure to thrive, hypotonia, and lethargy associated with pancytopenia and hepatic dysfunction, which progressed to severe respiratory insufficiency and renal failure consistent with hemolytic-uremic syndrome. The infants died at 40, 45, and 75 days of age. Postmortem findings were dominated by thrombotic microangiopathy of the kidneys and lungs, diffuse hepatic steatosis, and megaloblastic changes in the bone marrow. Severe gastritis with striking cystic dysplastic mucosal changes and total absence of parietal and chief cells was found in all 3 patients, with the rest of the gastrointestinal tract being essentially normal. </p><p>Rosenblatt et al. (1997) reviewed 50 cblC patients who could be classified into 2 broad phenotypes: 44 had early onset and 6 had later onset. The 44 patients presented in the first year of life with feeding difficulties, hypotonia, developmental delay, seizures, pigmentary retinopathy, and anemia. About one-fourth of the patients died, and those who survived had neurologic impairment. </p><p>Cerone et al. (1999) described mild facial anomalies in combined methylmalonic aciduria and homocystinuria of the cblC form. Features included a long face, high forehead, large, floppy, and low-set ears, and flat philtrum. The morphologic characteristics became more evident after 3 years of age, and were noted separately by physicians of 2 different departments. A female patient showed high forehead and low-set ears when first observed at the age of 2 months. </p><p>Andersson et al. (1999) described the clinical and biochemical features of 8 cblC patients who were treated for an average of 5.7 years. Treatment consisted of daily oral carnitine and intramuscular hydroxocobalamin. The patients had congenital malformations including microcephaly at birth (2 of 8), congenital heart disease (2 of 8), dysmorphic facial features (1 of 8), and thyroglossal duct cyst (1 of 8). Postnatal hydrocephalus (2 of 8) and hip dislocation caused by ligament laxity (1 of 8) were also noted. One patient had profound visual impairment before 6 months of age secondary to cblC retinopathy, and 2 patients had abnormal retinal pigmentation with normal visual function. All patients presented with poor growth, feeding problems, and/or seizures. </p><p>Van Hove et al. (2002) described a 12-year-old boy and his 4-year-old sister who presented with proteinuria, hematuria, hypertension, and chronic hemolytic anemia. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Hyperhomocysteinemia and mild methylmalonic aciduria were also found. Fibroblast studies were compatible with a mild cblC complementation group. The children had no neurologic symptoms and minimal pigmentary retinal abnormalities. Both children and their father carried a balanced reciprocal translocation, t(8;19)(q23.2;q13.3). Treatment with higher than usual doses of parenteral hydroxycobalamin and oral betaine stopped the thrombotic microangiopathy. </p><p>Schimel and Mets (2006) reported the ocular findings in 3 patients with cblC disease. All 3 presented with macular pigmentary changes and showed attenuation of electroretinographic (ERG) responses. Based on the findings in these patients and a literature review, Schimel and Mets (2006) concluded that cblC disease results in progressive retinal degeneration beginning in the first few months of life and progressing rapidly over the first few years of life. </p><p>Komhoff et al. (2013) studied 4 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy, who were identified from the Dutch national referral center for pediatric pulmonary hypertension. A fifth patient with this combination was contacted to collect clinical data. All 5 had cobalamin C (cblC) deficiency, diagnosed postmortem in 2 patients. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, pulmonary arterial hypertension was preceded by renal thrombotic microangiopathy from age 2.5 to 7 years. Three patients presenting at 3 years of age or younger died of right ventricular failure secondary to progressive pulmonary arterial hypertension. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 exhibited progressive pulmonary vasculopathy, and 1 patient was in stable condition at the time of the study. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Komhoff et al. (2013) identified cblC deficiency as the cause of the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy in these patients. The authors proposed that early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may ameliorate the devastating course of this condition. </p><p>Ahrens-Nicklas et al. (2017) completed a retrospective analysis of 12 patients with cblC referred for abnormal newborn screening results and followed at the Children's Hospital of Pennsylvania between 1999 and 2015. Of the patients, 87.5% had intellectual disability and 75% had retinopathy; 16.7% had 1 episode of mild acidosis. However, no patients manifested major metabolic decompensation. Developmental outcomes correlated more closely with initial metabolic abnormalities than with long-term metabolic control. Increased intake of medical foods resulted in better control but also perturbations in the ratios of essential amino acids and lower z-scores for head circumference. Ahrens-Nicklas et al. (2017) found no relationship between diet and cognitive outcomes. </p><p>He et al. (2020) reported 70 Chinese patients with early-onset MAHCC and hydrocephalus. In the 68 cases with available clinical information, the median age of diagnosis of hydrocephalus was 3 months (range, 0.3-96 months). The hydrocephalus presented before metabolic treatment in 60 cases and after metabolic treatment in 8 cases. Signs of intracranial hypertension were uncommon and included vomiting in 7 cases, 'sunset eyes' in 7 cases, and enlarged head circumference in 6 cases. Brain imaging by CT and/or MRI showed bilateral ventricular dilatation and cortical atrophy in all 70 patients and subdural collections in 13 cases. A ventriculoperitoneal shunt was performed in 36 cases for indications including progressive aggravation of intracranial hypertension and moderate to severe bilateral ventriculomegaly. In 30 patients, the hydrocephalus improved after metabolic treatment only. Other clinical manifestations in the patients included psychomotor retardation in 68, visual impairments in 68, seizures in 42, anemia in 27, and lethargy/coma in 17. </p><p>Matmat et al. (2022) provided a systematic review of ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism from a literature review of 52 studies reporting 163 cbl and 24 mut patients. Ocular manifestations were identified in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder, affecting 137 patients (84%). </p><p><strong><em>Late-Onset cblC Disease</em></strong></p><p>
Goodman et al. (1970) reported 2 brothers with a milder, possibly allelic form of the disorder. The elder, a 14-year-old Mexican American, was first admitted to the hospital in an acute psychotic episode. He had an IQ of about 50, a somewhat marfanoid habitus, and mild abnormalities on neurologic examination. Ectopia lentis and chest deformity were lacking. The parents were first cousins once removed. </p><p>Shinnar and Singer (1984) described a clinically atypical patient with the cblC defect. An adolescent girl had been a straight-A student and in excellent health until age 12. Over the period of a year, her grades deteriorated markedly and her work became equivalent to that of a first-grader. She developed apathy, unsteady gait, and impaired speech. Examination showed broad-based gait, impaired vibration and position sense, and extensor Babinski response. IQ was 40 to 50. Hemoglobin was 12.6 gm%, mean corpuscular volume 96, serum B12 level normal, and red cell folate level 88 ng per ml red cells (mildly decreased). Blood showed elevated homocysteine and only a trace of methionine. The urine contained large amounts of homocysteine and methylmalonic acid. On parenteral hydroxycobalamin (1,000 micrograms per day), the patient improved markedly. A 12-year-old sister and an 8-week-old brother were found to have the same cblC defect, confirmed by fibroblast studies. </p><p>Rosenblatt et al. (1997) found that 6 of 50 cblC patients had later onset, after age 4 years. These patients presented with acute neurologic dysfunction, including cognitive decline, confusion, psychosis, dementia, and extrapyramidal signs. Later-onset patients had better survival, better response to treatment, and less neurologic sequelae compared to the early-onset patients. </p><p>Bodamer et al. (2001) reported what they believed to be the first case of adult-onset cblC. The patient was a 20-year-old man who presented with slowly progressive leg weakness, loss of bowel and bladder function, episodes of forgetfulness, slurred speech, and deep venous thromboses. He later became unresponsive and required mechanical ventilation. A diagnosis of cobalamin defect was suggested after he was determined to have elevated plasma homocysteine and methylmalonic aciduria. Treatment with hydroxycobalamin and carnitine proved effective. The authors suggested that the patient may have had a mild mutation resulting in significant residual enzyme activity. </p><p>Ben-Omran et al. (2007) reported 2 unrelated patients with late-onset cblC disease. The first patient was a 14-year old girl, born of first-cousin Pakistani parents, who developed progressive neurologic decline, including dementia, depression, ataxia, lethargy, incontinence, and seizures over a period of 2 years. After visits to several physicians without a correct diagnosis, analysis of plasma and urine showed increased homocysteine and methylmalonate consistent with a defect in cobalamin synthesis. Appropriate treatment resulted in clinical improvement with residual mild gait ataxia. The second patient was a 10-year-old girl of Bengali descent who presented with acute dementia, anorexia, extreme weight loss, and 'catatonic psychotic behavior.' She had a mild learning disability with an IQ of 72 and seizures. Brain MRI performed at ages 4 and 10 years showed progressive volume loss. Laboratory analysis detected cblC disease, and appropriate treatment resulted in clinical improvement. Both patients were found to be homozygous for the R132X mutation in the MMACHC gene (609831.0003). Ben-Omran et al. (2007) noted the diagnostic difficulty in late-onset cblC disease and emphasized the utility of plasma and urine analysis, as patients may have normal red blood cell indices. </p><p>Tsai et al. (2007) described a 36-year-old woman with a spinal cord infarct who was subsequently diagnosed with methylmalonic aciduria and homocystinuria, cblC type. Her past medical history was significant for joint hypermobility, arthritis, bilateral cataracts, unilateral hearing loss, chronic anemia, and frequent urinary tract infections secondary to a urogenital fistula. She reported emotional difficulties beginning in her teens and was diagnosed with depression and psychosis requiring hospitalization in her thirties. One to 2 years prior to the spinal cord infarct, the patient experienced increasing muscular weakness, leg paresthesias, and difficulty walking. The woman sought help in the emergency department for her weakness and paresthesia but was misdiagnosed with malingering because of her psychiatric history. One week later, she experienced lower extremity hemiplegia, and bladder incontinence and diagnosed with a spinal cord infarct. Laboratory evaluation revealed elevated homocysteine and methylmalonic acid consistent with cblC disease. Molecular analysis of the MMACHC gene revealed the 271dupA (609831.0001) and R161Q (609831.0005) mutations. Tsai et al. (2007) recommended that all patients with psychiatric disease complicated by dementia and myelopathy be screened with plasma amino acids and urine organic acids allowing cblC disease to be preliminarily diagnosed or effectively excluded. </p><p>Collison et al. (2015) reported a 28-year-old woman who presented with decreased central vision and mild photoaversion for 2 years. She had a past medical history of iron deficiency anemia and kidney and urinary tract infections. Visual field testing demonstrated a bilateral pericentral scotoma, and funduscopy showed bilateral bull's eye-appearing macular lesions. Repeat ophthalmologic evaluation at age 35 years showed the bull's eye-appearing macular dystrophy with extension of retinal peripheral atrophy. Laboratory testing showed elevated urine methylmalonic acid and homocysteine. </p><p>Bonafede et al. (2015) reported retinal abnormalities in 11 patients, aged 4 months to 15 years, with cblC. The patients with early-onset cblC demonstrated rapidly progressive maculopathy with severe loss of outer nuclear and ganglion cell layers, generally before 1 year of age. The 4 patients with later-onset cblC disease (older than 7 years of age) had a retina-wide degeneration, suggesting a different rate of disease progression in the extramacular retina in these patients. Other ophthalmologic findings included pseudocolobomas in 3 patients and nystagmus in 8 patients. Of the 6 patients who had electroretinograms, 5 were normal and 1 showed reduced rod-mediated responses. The most common refractive error was myopia. Bonafede et al. (2015) noted that there was no obvious association between the degree of metabolic control of cblC disease (plasma methionine, homocysteine and methylmalonic acid levels) and the severity of ocular abnormalities. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Atkinson et al. (2002) mapped the locus for cobalamin C deficiency to chromosome 1q by linkage analysis. Lerner-Ellis et al. (2006) refined the assignment using homozygosity mapping and haplotype analyses and identified the MMACHC gene on 1p34.1 as the site of disease-causing mutations. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Lerner-Ellis et al. (2006) refined the chromosomal map interval containing the mutation for methylmalonic aciduria and homocystinuria, cblC type, to a region of the short arm of chromosome 1 containing the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA (609831.0001), accounted for 40% of all disease alleles. Transduction of wildtype MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. </p><p>Among 79 unrelated Chinese patients with combined methylmalonic aciduria and homocystinuria of the cblC type, Liu et al. (2010) identified 24 different mutations in the MMACHC gene, including 7 novel mutations. All patients had 2 mutations, except for 3 patients in whom only 1 mutation was identified. The 2 most common alleles were W203X (609831.0006) and 658delAAG (609831.0007), which accounted for 48.1% and 13.9% of mutant alleles, respectively. Haplotype analysis indicated a different founder effect for each mutation, but the major mutation profile did not differ between patients from northern and southern China. </p><p>In 3 affected members of unrelated families with autosomal recessive cblC vitamin B12 deficiency, Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a different coding mutation on 1 allele in all 3 (609831.0011-609831.0013), combined with the same 'secondary epimutation' on the other allele. The epimutation, 32 hypermethylated CpG sites detected by bisulfite sequencing, was a consequence of a heterozygous mutation in the adjacent, reverse-oriented, PRDX1 gene: c.515-1G-T (176763.0001) or c.515-2A-T (176763.0002). The PRDX1 mutations were also found in unaffected relatives who carried the secondary epimutation. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. The resulting read-through transcript extended through the adjacent MMACHC locus in the antisense orientation. The authors proposed that the antisense transcript leads to the formation of triplexes in the promoter of MMACHC and generates CpG methylation resulting in reduced expression of the normal message. This was confirmed experimentally by growing fibroblasts from an affected proband in 5-azacytidine, which reduced promoter methylation, and by silencing PRDX1 with an siRNA, both of which increased expression of MMACHC. </p><p>By Sanger or next-generation sequencing in 70 Chinese individuals with MAHCC and hydrocephalus, He et al. (2020) identified homozygous or compound heterozygous mutations in the MMACHC gene. The parents in each case were carriers of one mutation. Eighteen individual mutations were identified, including 4 novel mutations (Q143X, W200X, Y205X, and c.568insT) that were predicted to cause loss of function and were not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. The most frequent mutation was W209X (609831.0006), accounting for 62.9% of the mutations, followed by c.658delAAG (609831.0007), R73X, and c.567dupT, seen at a frequency of 12.1%, 5%, and 5%, respectively. The findings were consistent with a previous study in the Chinese population by Liu et al. (2010). </p><p>In a 28-year-old woman with nonsyndromic bull's eye maculopathy who was subsequently diagnosed with cblC, Collison et al. (2015) identified compound heterozygous mutations in the MMACHC gene (609831.0005 and 609831.0011). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. </p><p>In a review of epimutation mechanisms in metabolic disorders including MAHCC, Gueant et al. (2022) discussed that the epimutation in MMACHC due to PRDX1 mutations was likely to be constitutional because it was detected in DNA pre- and postzygotic tissue including sperm, blood cells, and fibroblasts. However, they also suggested that the high frequency of hypermethylation in the MMACHC promoter across the general population compared to epigenetic modification of other disease-causing genes indicated that methylation effects on the MMACHC promoter are influenced by both secondary epimutation (PRDX1 mutations affecting methylation) and primary epimutations (such as postzygotic environmental exposures). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Morel et al. (2006) reported genotype-phenotype correlations in 37 patients from published case reports, representing most of the landmark descriptions of cobalamin C deficiency. Twenty-five of 37 had early-onset disease, presenting in the first 6 months of life; 17 of these 25 were found to be homozygous for the 271dupA mutation (609831.0001) (9 patients) or for the 331C-T (R111X; 609831.0004) mutation (3 patients) or compound heterozygous for these 2 mutations (5 patients). Nine of 12 late-onset cases presented with acute neurologic symptoms: 4 of 9 were homozygous for the 347T-C mutation (L116P; 609831.0002), 2 of 9 were compound heterozygous for the 271dupA and 394C-T (R132X; 609831.0003) mutations, and 3 of 9 for the 271dupA mutation and a missense mutation. The 394C-T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. </p><p>Among 118 patients with cblC, Lerner-Ellis et al. (2009) identified 34 different MMACHC mutations, including 11 novel mutations. The 271dupA mutation was the most common, accounting for 42% of pathogenic alleles, followed by the R132X (20%) and R111X (5%) mutations. Six variants defined specific haplotypes that varied with ethnicity. Genotype/phenotype correlations were apparent. Individuals with the R132X and R161Q (609831.0005) mutations tended to present with late-onset disease, whereas patients with the R111X and 271dupA mutations tended to present in infancy. Functional expression analysis on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and the late-onset R132X and R161Q mutations. The early-onset R111X mutation was also underexpressed when compared to control alleles and the R132X mutation. Quantitative RT-PCR studies showed that the late-onset R132X mutation had significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations. </p><p>In 4 patients with a rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency, Komhoff et al. (2013) detected 1 of 2 basepair substitutions (G-to-A or G-to-T) at nucleotide 276 of the MMACHC gene (609831.0008, 609831.0009). These mutations were not found in approximately 500 patients with cblC deficiency and other phenotypes, or in 200 control individuals. Komhoff et al. (2013) concluded that these mutations hold specific vascular pathogenicity in addition to compromising enzyme function. These patients were additionally heterozygous for various frameshift mutations on the other MMACHC allele. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bartholomew et al. (1988) reported variable results with vitamin B12 therapy. </p><p>Enns et al. (1999) reported a 4-year-old Hispanic girl with cblC methylmalonic acidemia who had undergone intramuscular hydroxocobalamin therapy starting at 3 weeks of age. Despite treatment, she showed progressive neurologic deterioration and worsening head MRI changes. </p><p>Andersson et al. (1999) reported successful treatment of 8 patients with cblC. All patients had dramatic reduction of plasma free homocystine and urine methylmalonic acid excretion after initiation of treatment with carnitine, intramuscular hydroxocobalamin and, in 2 cases, oral betaine. Growth was significantly improved in most cases after the initiation of therapy, and microcephaly resolved in 1 patient. All patients were developmentally delayed regardless of the age at which treatment began, although 2 patients had relatively mild developmental delay. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Mellman et al. (1979) found that cells from a cblC patient were unable to associate newly taken up (57)Co-cobalamin with the methyltransferase, whereas hybrids of mouse cells and cblC cells showed human (57)Co-cobalamin-methyltransferase whenever human chromosome 1 was present (Mellman et al., 1979). The authors concluded that the cblC mutation did not affect the methyltransferase apoprotein, but rather a metabolic step that converts cobalamin to the coenzyme capable of attaching to the enzyme. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Baumgartner et al. (1979); Mudd et al. (1970)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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Ben-Omran, T. I., Wong, H., Blaser, S., Feigenbaum, A.
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Gravel, R. A., Mahoney, M. J., Ruddle, F. H., Rosenberg, L. E.
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Gueant, J.-L., Chery, C., Oussalah, A., Nadaf, J., Coelho, D., Josse, T., Flayac, J., Robert, A., Koscinski, I., Gastin, I., Filhine-Tresarrieu, P., Pupavac, M., and 19 others.
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Komhoff, M., Roofthooft, M. T., Westra, D., Teertstra, T. K., Losito, A., van de Kar, N. C. A. J., Berger, R. M. F.
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Mellman, I., Willard, H. F., Youngdahl-Turner, P., Rosenberg, L. E.
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<p class="mim-text-font">
Morel, C. F., Lerner-Ellis, J. P., Rosenblatt, D. S.
<strong>Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.</strong>
Molec. Genet. Metab. 88: 315-321, 2006.
[PubMed: 16714133]
[Full Text: https://doi.org/10.1016/j.ymgme.2006.04.001]
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</li>
<li>
<p class="mim-text-font">
Mudd, S. H., Levy, H. L., Abeles, R. H.
<strong>A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria.</strong>
Biochem. Biophys. Res. Commun. 35: 121-126, 1969.
[PubMed: 5779140]
[Full Text: https://doi.org/10.1016/0006-291x(69)90491-4]
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</li>
<li>
<p class="mim-text-font">
Mudd, S. H., Levy, H. L., Morrow, G., III.
<strong>Deranged B12 metabolism: effects on sulfur amino acid metabolism.</strong>
Biochem. Med. 4: 193-214, 1970.
[PubMed: 5524064]
[Full Text: https://doi.org/10.1016/0006-2944(70)90049-9]
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</li>
<li>
<p class="mim-text-font">
Mudd, S. H., Uhlendorf, B. W., Hinde, K. R., Levy, H. L.
<strong>Deranged B12 metabolism: studies of fibroblasts grown in tissue culture.</strong>
Biochem. Med. 4: 215-239, 1970.
[PubMed: 5524065]
[Full Text: https://doi.org/10.1016/0006-2944(70)90050-5]
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</li>
<li>
<p class="mim-text-font">
Rosenblatt, D. S., Aspler, A. L., Shevell, M. I., Pletcher, B. A., Fenton, W. A., Seashore, M. R.
<strong>Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).</strong>
J. Inherit. Metab. Dis. 20: 528-538, 1997.
[PubMed: 9266389]
[Full Text: https://doi.org/10.1023/a:1005353530303]
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</li>
<li>
<p class="mim-text-font">
Russo, P., Doyon, J., Sonsino, E., Ogier, H., Saudubray, J.-M.
<strong>A congenital anomaly of vitamin B12 metabolism: a study of three cases.</strong>
Hum. Path. 23: 504-512, 1992.
[PubMed: 1568746]
[Full Text: https://doi.org/10.1016/0046-8177(92)90127-o]
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</li>
<li>
<p class="mim-text-font">
Schimel, A. M., Mets, M. B.
<strong>The natural history of retinal degeneration in association with cobalamin C (cbl C) disease.</strong>
Ophthalmic Genet. 27: 9-14, 2006.
[PubMed: 16543196]
[Full Text: https://doi.org/10.1080/13816810500481758]
</p>
</li>
<li>
<p class="mim-text-font">
Shinnar, S., Singer, H. S.
<strong>Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence: a treatable cause of dementia and myelopathy.</strong>
New Eng. J. Med. 311: 451-454, 1984.
[PubMed: 6749192]
[Full Text: https://doi.org/10.1056/NEJM198408163110707]
</p>
</li>
<li>
<p class="mim-text-font">
Tsai, A. C.-H., Morel, C. F., Scharer, G., Yang, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Thomas, J. A.
<strong>Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance.</strong>
Am. J. Med. Genet. 143A: 2430-2434, 2007.
[PubMed: 17853453]
[Full Text: https://doi.org/10.1002/ajmg.a.31932]
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<li>
<p class="mim-text-font">
Van Hove, J. L. K., Van Damme-Lombaerts, R., Grunewald, S., Peters, H., Van Damme, B., Fryns, J.-P., Arnout, J., Wevers, R., Baumgartner, E. R., Fowler, B.
<strong>Cobalamin disorder cbl-C presenting with late-onset thrombotic microangiopathy.</strong>
Am. J. Med. Genet. 111: 195-201, 2002.
[PubMed: 12210350]
[Full Text: https://doi.org/10.1002/ajmg.10499]
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Hilary J. Vernon - updated : 11/03/2022<br>Carol A. Bocchini - updated : 10/18/2022<br>Hilary J. Vernon - updated : 11/19/2021<br>Hilary J. Vernon - updated : 04/06/2021<br>Ada Hamosh - updated : 06/15/2018<br>Alan F. Scott - updated : 03/06/2018<br>Ada Hamosh - updated : 12/1/2014<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Cassandra L. Kniffin - updated : 11/10/2009<br>Kelly A. Przylepa - updated : 4/1/2008<br>Jane Kelly - updated : 11/20/2007<br>Cassandra L. Kniffin - updated : 7/17/2007<br>Ada Hamosh - updated : 6/28/2007<br>Victor A. McKusick - updated : 1/18/2006<br>Cassandra L. Kniffin - reorganized : 12/10/2004<br>Cassandra L. Kniffin - updated : 12/7/2004<br>Deborah L. Stone - updated : 1/6/2003<br>Cassandra L. Kniffin - updated : 5/24/2002<br>Victor A. McKusick - updated : 9/15/1999<br>Ada Hamosh - updated : 8/9/1999<br>Victor A. McKusick - updated : 7/16/1999
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Victor A. McKusick : 6/4/1986
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