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Entry
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- #277410 - METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE; MAHCD
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- OMIM
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<p>
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<span class="h4">#277410</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/277410"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS277400"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</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="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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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… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3260&Typ=Pat" title="Vitamin B12-responsive methylmalonic acidemia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Vitamin B12-responsive met… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21305&Typ=Pat" title="Methylcobalamin deficiency type cblDv1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Methylcobalamin deficiency… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21312&Typ=Pat" title="Vitamin B12-responsive methylmalonic acidemia, type cblDv2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Vitamin B12-responsive met… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3369&Typ=Pat" title="Homocystinuria without methylmalonic aciduria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Homocystinuria without met… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11309&Typ=Pat" title="Methylmalonic acidemia with homocystinuria, type cblD" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Methylmalonic acidemia wit… </a></div>
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</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><a href="https://www.diseaseinfosearch.org/x/8566" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="#mimMedlinePlusGeneticsFold" id="mimMedlinePlusGeneticsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Consumer-friendly information about the effects of genetic variation on human health."><span id="mimMedlinePlusGeneticsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>MedlinePlus Genetics</div>
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<div id="mimMedlinePlusGeneticsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/homocystinuria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">Homocystinuria </a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/methylmalonic-acidemia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">Methylmalonic acidemia </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=277410[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimNewbornScreeningFold" id="mimNewbornScreeningToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Information and resources for newborn screening and genetics."><span id="mimNewbornScreeningToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Newborn Screening</div>
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<div id="mimNewbornScreeningFold" class="collapse">
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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;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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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=28" title="Vitamin B12-responsive methylmalonic acidemia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Vitamin B12-responsive met…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=308380" title="Methylcobalamin deficiency type cblDv1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Methylcobalamin deficiency…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=308442" title="Vitamin B12-responsive methylmalonic acidemia, type cblDv2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Vitamin B12-responsive met…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=622" title="Homocystinuria without methylmalonic aciduria" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Homocystinuria without met…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79283" title="Methylmalonic acidemia with homocystinuria, type cblD" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Methylmalonic acidemia wit…</a></div>
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</div>
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<span class="small">
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050716" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/277410" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0050716" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:277410" 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>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 26, 28, 308380, 308442, 622, 79283<br />
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<strong>DO:</strong> 0050716<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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277410
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE; MAHCD
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
METHYLMALONIC ACIDEMIA AND HOMOCYSTINURIA, cblD TYPE<br />
|
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METHYLMALONIC ACIDURIA, cblH TYPE, FORMERLY<br />
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METHYLMALONIC ACIDEMIA, cblH TYPE, FORMERLY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
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|
Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
|
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<th>
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Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
|
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
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</th>
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</tr>
|
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</thead>
|
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<tbody>
|
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|
<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/683?start=-3&limit=10&highlight=683">
|
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2q23.2
|
|
</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Methylmalonic aciduria and homocystinuria, cblD type
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/277410"> 277410 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
MMADHC
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/611935"> 611935 </a>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/277410" 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>
|
|
</button>
|
|
</div>
|
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|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS277400" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/277410" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/277410" 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>
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<div>
|
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<p />
|
|
</div>
|
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|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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|
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<div>
|
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<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>
|
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<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> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- 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 />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- 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 /> -
|
|
Impaired intellectual development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747273</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
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 /> -
|
|
Encephalopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81308009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81308009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G93.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G93.40</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/348.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.30</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/348.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">348.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085584</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001298</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001298" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001298</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
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|
|
|
</div>
|
|
|
|
</div>
|
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|
<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 /> -
|
|
Increased mean corpuscular volume <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165454002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165454002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0302845&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0302845</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005518</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005518" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005518</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
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|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- 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 /> -
|
|
Decreased methylmalonyl-CoA mutase (MUT) 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) 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 or mildly reduced serum cobalamin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848558&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848558</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in infancy or childhood<br /> -
|
|
Three unrelated families have been reported (last curated September 2024)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the metabolism of cobalamin associated D gene (MMADHC, <a href="/entry/611935#0007">611935.0007</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Methylmalonic aciduria and homocystinuria
|
|
- <a href="/phenotypicSeries/PS277400">PS277400</a>
|
|
- 7 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/557?start=-3&limit=10&highlight=557"> 1p34.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<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>
|
|
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<a href="/entry/277400"> Methylmalonic aciduria and homocystinuria, cblC type, digenic </a>
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<a href="/entry/309541"> Methylmalonic aciduria and homocysteinemia, cblX type </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>A number sign (#) is used with this entry because of evidence that combined methylmalonic aciduria and homocystinuria type cblD (MAHCD) is caused by homozygous mutation in the MMADHC gene (<a href="/entry/611935">611935</a>) on chromosome 2q23.</p><p>Biallelic mutation in the MMADHC gene can also cause homocystinuria-megaloblastic anemia type cblD (HMAD; <a href="/entry/620952">620952</a>) or methylmalonic aciduria type cblD (MACD; <a href="/entry/620953">620953</a>), depending on the location of the mutation within the gene.</p>
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<p>Methylmalonic aciduria (MMA) and homocystinuria type cblD (MAHCD) is an autosomal recessive disorder of cobalamin (cbl; vitamin B12) metabolism. Affected individuals typically present in infancy or early childhood with variable neurologic abnormalities, including developmental delay, encephalopathy, seizures, poor feeding, impaired intellectual development, and nystagmus. Onset of symptoms in the teenage years has also been reported. Most patients also have megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria (<a href="#2" class="mim-tip-reference" title="Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. <strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong> New Eng. J. Med. 358: 1454-1464, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385497</a>] [<a href="https://doi.org/10.1056/NEJMoa072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385497">Coelho et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385497" 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 metabolic 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>) (<a href="#2" class="mim-tip-reference" title="Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. <strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong> New Eng. J. Med. 358: 1454-1464, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385497</a>] [<a href="https://doi.org/10.1056/NEJMoa072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385497">Coelho et al., 2008</a>; review by <a href="#7" class="mim-tip-reference" title="Watkins, D., Rosenblatt, D. S. <strong>Inherited defects of cobalamin metabolism.</strong> Vitam. Horm. 119: 355-376, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35337626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35337626</a>] [<a href="https://doi.org/10.1016/bs.vh.2022.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35337626">Watkins and Rosenblatt, 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=35337626+18385497" 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>Genetic Heterogeneity of Methylmalonic Aciduria and Homocystinuria</em></strong></p><p>
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Different forms of combined methylmalonic aciduria and homocystinuria have been classified historically according to complementation groups of cells in vitro: cblC (MAHCC; <a href="/entry/277400">277400</a>), cblD, cblF (MAHCF; <a href="/entry/277380">277380</a>), cblJ (MAHCJ; <a href="/entry/614857">614857</a>), and cblL (MAHCL; <a href="/entry/620940">620940</a>).</p>
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<p><a href="#4" class="mim-tip-reference" title="Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W. <strong>Homocystinuria with methylmalonic aciduria: two cases in a sibship.</strong> Biochem. Med. 4: 500-515, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5524089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5524089</a>] [<a href="https://doi.org/10.1016/0006-2944(70)90080-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5524089">Goodman et al. (1970)</a> reported 2 brothers, from a consanguineous Spanish-American family, with combined homocystinuria and methylmalonic aciduria. The older boy presented at 14 years of age during an acute psychotic episode. Examination showed moderately impaired intellectual development (IQ of 50), a somewhat marfanoid appearance, and neurologic signs, including horizontal nystagmus increased by lateral gaze, hyperreflexia, and mildly impaired finger to nose movement. Laboratory studies showed methylmalonic aciduria and homocystinuria. After the acute psychotic episode, he remained in good health except for intellectual disability. His 2.5-year-old younger brother had normal physical and neurologic development. Laboratory studies at at 1 year showed methylmalonic aciduria, but no homocystinuria. However, repeat studies at age 2 showed homocystinuria. Plasma B12 was normal in both patients. Complementation studies on cell lines of these patients (<a href="#8" class="mim-tip-reference" title="Willard, H. F., Mellman, I. S., Rosenberg, L. E. <strong>Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity: evidence for a new class of human cobalamin mutant.</strong> Am. J. Hum. Genet. 30: 1-13, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23678</a>]" pmid="23678">Willard et al., 1978</a>) indicated a fifth Cbl complementation group, designated CblD. Patient cells showed an abnormally low cobalamin content and deficient activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate-homocysteine S-methyltransferase, as well as decreased levels of their respective cofactors, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). There was complementation with cblC, indicating that the 2 groups were genetically distinct. <a href="#3" class="mim-tip-reference" title="Fenton, W. A., Rosenberg, L. E. <strong>Genetic and biochemical analysis of human cobalamin mutants in cell culture.</strong> Annu. Rev. Genet. 12: 223-248, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/371525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">371525</a>] [<a href="https://doi.org/10.1146/annurev.ge.12.120178.001255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="371525">Fenton and Rosenberg (1978)</a> suggested that the defect in cblD may involve cobalamin reductase (<a href="/entry/602568">602568</a>), which reduces the charge of the cobalt of cobalamin from +3 to +2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=371525+23678+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="#2" class="mim-tip-reference" title="Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. <strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong> New Eng. J. Med. 358: 1454-1464, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385497</a>] [<a href="https://doi.org/10.1056/NEJMoa072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385497">Coelho et al. (2008)</a> reported 2 additional unrelated patients with MAHCD. P6, a Scandinavian girl, presented at 3 months of age with developmental delay, seizures, and megaloblastic anemia. P7, a boy born of consanguineous Italian parents, presented at 22 days of age with poor feeding, encephalopathy, seizures, and increased red cell MCV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of MAHCD in the family reported by <a href="#4" class="mim-tip-reference" title="Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W. <strong>Homocystinuria with methylmalonic aciduria: two cases in a sibship.</strong> Biochem. Med. 4: 500-515, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5524089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5524089</a>] [<a href="https://doi.org/10.1016/0006-2944(70)90080-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5524089">Goodman et al. (1970)</a> was consistent with autosomal recessive inheritance. <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>
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<p>By complementation of cblD patient cells with somatic cell hybrids, <a href="#2" class="mim-tip-reference" title="Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. <strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong> New Eng. J. Med. 358: 1454-1464, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385497</a>] [<a href="https://doi.org/10.1056/NEJMoa072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385497">Coelho et al. (2008)</a> localized the defect to human chromosome 2. Fine mapping identified a 10.2-Mb regions on 2q22.1-2q23.3 between markers D2S150 and D2S2324. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 unrelated patients with MAHCD, <a href="#2" class="mim-tip-reference" title="Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B. <strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong> New Eng. J. Med. 358: 1454-1464, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385497</a>] [<a href="https://doi.org/10.1056/NEJMoa072200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385497">Coelho et al. (2008)</a> identified homozygous mutations in the MMADHC gene: P5 (previously reported by <a href="#4" class="mim-tip-reference" title="Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W. <strong>Homocystinuria with methylmalonic aciduria: two cases in a sibship.</strong> Biochem. Med. 4: 500-515, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5524089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5524089</a>] [<a href="https://doi.org/10.1016/0006-2944(70)90080-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5524089">Goodman et al., 1970</a>) was a Spanish-American boy with a homozygous nonsense mutation (R250X; <a href="/entry/611935#0007">611935.0007</a>); P6 was a Scandinavian girl with a homozygous frameshift (c.419dupA; <a href="/entry/611935#0008">611935.0008</a>); and P7 was an Italian boy with a homozygous splice site mutation resulting in the skipping of exon 7 and an in-frame deletion (<a href="/entry/611935#0009">611935.0009</a>). All mutations occurred close to the C terminus. In vitro functional expression studies showed that wildtype MMADHC could rescue the biochemical abnormalities of cells carrying these mutations. Additional studies of patient cells were not performed, but all 3 mutations were predicted to result in a defective protein that lacks both functional domains or is subject to nonsense-mediated mRNA decay and a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5524089+18385497" 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="#6" class="mim-tip-reference" title="Stucki, M., Coelho, D., Suormala, T., Burda, P., Fowler, B., Baumgartner, M. R. <strong>Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism.</strong> Hum. Molec. Genet. 21: 1410-1418, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22156578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22156578</a>] [<a href="https://doi.org/10.1093/hmg/ddr579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22156578">Stucki et al. (2012)</a> studied the effect of various MMADHC constructs on protein function in cell lines. For example, mutant alleles associated with the cblD-homocystinuria (HMAD) phenotype were unable to rescue MeCbl synthesis, whereas mutant alleles associated with the cblD-methylmalonic aciduria (MMAICD) phenotype could restore MeCbl synthesis. In combined cblD-MAHCD cells, improving mitochondrial targeting of MMADHC increased the formation of AdoCbl with a concomitant decrease in MeCbl formation. In cblD-MMA cells, this effect was dependent on the mutation and showed a negative correlation with endogenous MMADHC mRNA levels. The findings supported the hypothesis that the MMADHC protein contains various domains for targeting the protein towards the mitochondria, MeCbl synthesis, and AdoCbl synthesis. There is a delicate balance between cytosolic MeCbl and mitochondrial AdoCbl synthesis, suggesting that the cblD protein is a branch point in intracellular cobalamin trafficking. Detailed data analysis indicated that the sequence after met116 is sufficient for MeCbl synthesis, whereas the additional sequence between met62 and met116 is required for AdoCbl synthesis. The nature and location of mutations within the protein thus determines 1 of the 3 biochemical phenotypes, combined MMA/HC, isolated MMA, or isolated HC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22156578" 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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<strong>See Also:</strong>
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<a href="#Carmel1980" class="mim-tip-reference" title="Carmel, R., Bedros, A. A., Mace, J. W., Goodman, S. I. <strong>Congenital methylmalonic aciduria-homocystinuria with megaloblastic anemia: observations on response to hydroxycobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test.</strong> Blood 55: 570-579, 1980.">Carmel et al. (1980)</a>; <a href="#Mellman1978" class="mim-tip-reference" title="Mellman, I., Willard, H. F., Rosenberg, L. E. <strong>Cobalamin binding and cobalamin-dependent enzyme activity in normal and mutant human fibroblasts.</strong> J. Clin. Invest. 62: 952-960, 1978.">Mellman et al. (1978)</a>
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<strong>REFERENCES</strong>
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Carmel, R., Bedros, A. A., Mace, J. W., Goodman, S. I.
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<strong>Congenital methylmalonic aciduria-homocystinuria with megaloblastic anemia: observations on response to hydroxycobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test.</strong>
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Blood 55: 570-579, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7357085</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Coelho2008" class="mim-anchor"></a>
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Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B.
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<strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong>
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New Eng. J. Med. 358: 1454-1464, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385497</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa072200" target="_blank">Full Text</a>]
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<a id="Fenton1978" class="mim-anchor"></a>
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Fenton, W. A., Rosenberg, L. E.
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<strong>Genetic and biochemical analysis of human cobalamin mutants in cell culture.</strong>
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Annu. Rev. Genet. 12: 223-248, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/371525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">371525</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=371525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1146/annurev.ge.12.120178.001255" target="_blank">Full Text</a>]
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<a id="Goodman1970" class="mim-anchor"></a>
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Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W.
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<strong>Homocystinuria with methylmalonic aciduria: two cases in a sibship.</strong>
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Biochem. Med. 4: 500-515, 1970.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5524089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5524089</a>, <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'})">related citations</a>]
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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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<a id="Mellman1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mellman, I., Willard, H. F., Rosenberg, L. E.
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<strong>Cobalamin binding and cobalamin-dependent enzyme activity in normal and mutant human fibroblasts.</strong>
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J. Clin. Invest. 62: 952-960, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI109224" target="_blank">Full Text</a>]
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<a id="Stucki2012" class="mim-anchor"></a>
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Stucki, M., Coelho, D., Suormala, T., Burda, P., Fowler, B., Baumgartner, M. R.
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<strong>Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism.</strong>
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Hum. Molec. Genet. 21: 1410-1418, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22156578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22156578</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22156578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr579" target="_blank">Full Text</a>]
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<a id="Watkins2022" class="mim-anchor"></a>
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<p class="mim-text-font">
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Watkins, D., Rosenblatt, D. S.
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<strong>Inherited defects of cobalamin metabolism.</strong>
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Vitam. Horm. 119: 355-376, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35337626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35337626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35337626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/bs.vh.2022.01.010" target="_blank">Full Text</a>]
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<a id="Willard1978" class="mim-anchor"></a>
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<p class="mim-text-font">
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Willard, H. F., Mellman, I. S., Rosenberg, L. E.
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<strong>Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity: evidence for a new class of human cobalamin mutant.</strong>
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Am. J. Hum. Genet. 30: 1-13, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23678</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 09/23/2024
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/24/2013<br>Cassandra L. Kniffin - updated : 4/7/2008<br>Cassandra L. Kniffin - updated : 12/7/2004
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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carol : 09/25/2024
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ckniffin : 09/23/2024<br>carol : 09/17/2024<br>carol : 01/12/2018<br>carol : 09/09/2016<br>carol : 04/25/2016<br>carol : 7/1/2013<br>ckniffin : 6/24/2013<br>wwang : 11/18/2010<br>ckniffin : 11/18/2010<br>wwang : 4/7/2008<br>ckniffin : 4/7/2008<br>carol : 12/10/2004<br>ckniffin : 12/10/2004<br>ckniffin : 12/7/2004<br>mgross : 3/18/2004<br>mgross : 1/14/2003<br>ckniffin : 7/9/2002<br>mimadm : 3/12/1994<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>reenie : 6/25/1986
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<span class="mim-font">
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<strong>#</strong> 277410
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<h3>
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblD TYPE; MAHCD
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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METHYLMALONIC ACIDEMIA AND HOMOCYSTINURIA, cblD TYPE<br />
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METHYLMALONIC ACIDURIA, cblH TYPE, FORMERLY<br />
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METHYLMALONIC ACIDEMIA, cblH TYPE, FORMERLY
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<strong>ORPHA:</strong> 26, 28, 308380, 308442, 622, 79283;
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<strong>DO:</strong> 0050716;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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<th>
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<tbody>
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<span class="mim-font">
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2q23.2
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<span class="mim-font">
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Methylmalonic aciduria and homocystinuria, cblD type
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<span class="mim-font">
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277410
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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MMADHC
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<span class="mim-font">
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611935
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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 cblD (MAHCD) is caused by homozygous mutation in the MMADHC gene (611935) on chromosome 2q23.</p><p>Biallelic mutation in the MMADHC gene can also cause homocystinuria-megaloblastic anemia type cblD (HMAD; 620952) or methylmalonic aciduria type cblD (MACD; 620953), depending on the location of the mutation within the gene.</p>
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<span class="mim-font">
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<strong>Description</strong>
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<p>Methylmalonic aciduria (MMA) and homocystinuria type cblD (MAHCD) is an autosomal recessive disorder of cobalamin (cbl; vitamin B12) metabolism. Affected individuals typically present in infancy or early childhood with variable neurologic abnormalities, including developmental delay, encephalopathy, seizures, poor feeding, impaired intellectual development, and nystagmus. Onset of symptoms in the teenage years has also been reported. Most patients also have megaloblastic anemia. Laboratory studies show methylmalonic aciduria and homocystinuria (Coelho et al., 2008). </p><p>The metabolic 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) (Coelho et al., 2008; review by Watkins and Rosenblatt, 2022). </p><p><strong><em>Genetic Heterogeneity of Methylmalonic Aciduria and Homocystinuria</em></strong></p><p>
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Different forms of combined methylmalonic aciduria and homocystinuria have been classified historically according to complementation groups of cells in vitro: cblC (MAHCC; 277400), cblD, cblF (MAHCF; 277380), cblJ (MAHCJ; 614857), and cblL (MAHCL; 620940).</p>
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<h4>
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<strong>Clinical Features</strong>
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<p>Goodman et al. (1970) reported 2 brothers, from a consanguineous Spanish-American family, with combined homocystinuria and methylmalonic aciduria. The older boy presented at 14 years of age during an acute psychotic episode. Examination showed moderately impaired intellectual development (IQ of 50), a somewhat marfanoid appearance, and neurologic signs, including horizontal nystagmus increased by lateral gaze, hyperreflexia, and mildly impaired finger to nose movement. Laboratory studies showed methylmalonic aciduria and homocystinuria. After the acute psychotic episode, he remained in good health except for intellectual disability. His 2.5-year-old younger brother had normal physical and neurologic development. Laboratory studies at at 1 year showed methylmalonic aciduria, but no homocystinuria. However, repeat studies at age 2 showed homocystinuria. Plasma B12 was normal in both patients. Complementation studies on cell lines of these patients (Willard et al., 1978) indicated a fifth Cbl complementation group, designated CblD. Patient cells showed an abnormally low cobalamin content and deficient activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate-homocysteine S-methyltransferase, as well as decreased levels of their respective cofactors, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). There was complementation with cblC, indicating that the 2 groups were genetically distinct. Fenton and Rosenberg (1978) suggested that the defect in cblD may involve cobalamin reductase (602568), which reduces the charge of the cobalt of cobalamin from +3 to +2. </p><p>Coelho et al. (2008) reported 2 additional unrelated patients with MAHCD. P6, a Scandinavian girl, presented at 3 months of age with developmental delay, seizures, and megaloblastic anemia. P7, a boy born of consanguineous Italian parents, presented at 22 days of age with poor feeding, encephalopathy, seizures, and increased red cell MCV. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The transmission pattern of MAHCD in the family reported by Goodman et al. (1970) was consistent with autosomal recessive inheritance. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By complementation of cblD patient cells with somatic cell hybrids, Coelho et al. (2008) localized the defect to human chromosome 2. Fine mapping identified a 10.2-Mb regions on 2q22.1-2q23.3 between markers D2S150 and D2S2324. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 3 unrelated patients with MAHCD, Coelho et al. (2008) identified homozygous mutations in the MMADHC gene: P5 (previously reported by Goodman et al., 1970) was a Spanish-American boy with a homozygous nonsense mutation (R250X; 611935.0007); P6 was a Scandinavian girl with a homozygous frameshift (c.419dupA; 611935.0008); and P7 was an Italian boy with a homozygous splice site mutation resulting in the skipping of exon 7 and an in-frame deletion (611935.0009). All mutations occurred close to the C terminus. In vitro functional expression studies showed that wildtype MMADHC could rescue the biochemical abnormalities of cells carrying these mutations. Additional studies of patient cells were not performed, but all 3 mutations were predicted to result in a defective protein that lacks both functional domains or is subject to nonsense-mediated mRNA decay and a loss of function. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stucki et al. (2012) studied the effect of various MMADHC constructs on protein function in cell lines. For example, mutant alleles associated with the cblD-homocystinuria (HMAD) phenotype were unable to rescue MeCbl synthesis, whereas mutant alleles associated with the cblD-methylmalonic aciduria (MMAICD) phenotype could restore MeCbl synthesis. In combined cblD-MAHCD cells, improving mitochondrial targeting of MMADHC increased the formation of AdoCbl with a concomitant decrease in MeCbl formation. In cblD-MMA cells, this effect was dependent on the mutation and showed a negative correlation with endogenous MMADHC mRNA levels. The findings supported the hypothesis that the MMADHC protein contains various domains for targeting the protein towards the mitochondria, MeCbl synthesis, and AdoCbl synthesis. There is a delicate balance between cytosolic MeCbl and mitochondrial AdoCbl synthesis, suggesting that the cblD protein is a branch point in intracellular cobalamin trafficking. Detailed data analysis indicated that the sequence after met116 is sufficient for MeCbl synthesis, whereas the additional sequence between met62 and met116 is required for AdoCbl synthesis. The nature and location of mutations within the protein thus determines 1 of the 3 biochemical phenotypes, combined MMA/HC, isolated MMA, or isolated HC. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Carmel et al. (1980); Mellman et al. (1978)
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Carmel, R., Bedros, A. A., Mace, J. W., Goodman, S. I.
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<strong>Congenital methylmalonic aciduria-homocystinuria with megaloblastic anemia: observations on response to hydroxycobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test.</strong>
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Blood 55: 570-579, 1980.
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[PubMed: 7357085]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Coelho, D., Suormala, T., Stucki, M., Lerner-Ellis, J. P., Rosenblatt, D. S., Newbold, R. F., Baumgartner, M. R., Fowler, B.
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<strong>Gene identification for the cblD defect of vitamin B12 metabolism.</strong>
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New Eng. J. Med. 358: 1454-1464, 2008.
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[PubMed: 18385497]
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[Full Text: https://doi.org/10.1056/NEJMoa072200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fenton, W. A., Rosenberg, L. E.
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<strong>Genetic and biochemical analysis of human cobalamin mutants in cell culture.</strong>
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Annu. Rev. Genet. 12: 223-248, 1978.
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[PubMed: 371525]
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[Full Text: https://doi.org/10.1146/annurev.ge.12.120178.001255]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Goodman, S. I., Moe, P. G., Hammond, K. B., Mudd, S. H., Uhlendorf, B. W.
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<strong>Homocystinuria with methylmalonic aciduria: two cases in a sibship.</strong>
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Biochem. Med. 4: 500-515, 1970.
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[PubMed: 5524089]
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[Full Text: https://doi.org/10.1016/0006-2944(70)90080-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Mellman, I., Willard, H. F., Rosenberg, L. E.
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<strong>Cobalamin binding and cobalamin-dependent enzyme activity in normal and mutant human fibroblasts.</strong>
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J. Clin. Invest. 62: 952-960, 1978.
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[PubMed: 30783]
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[Full Text: https://doi.org/10.1172/JCI109224]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Stucki, M., Coelho, D., Suormala, T., Burda, P., Fowler, B., Baumgartner, M. R.
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<strong>Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism.</strong>
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Hum. Molec. Genet. 21: 1410-1418, 2012.
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[PubMed: 22156578]
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[Full Text: https://doi.org/10.1093/hmg/ddr579]
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Watkins, D., Rosenblatt, D. S.
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<strong>Inherited defects of cobalamin metabolism.</strong>
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Vitam. Horm. 119: 355-376, 2022.
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[PubMed: 35337626]
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[Full Text: https://doi.org/10.1016/bs.vh.2022.01.010]
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Willard, H. F., Mellman, I. S., Rosenberg, L. E.
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<strong>Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity: evidence for a new class of human cobalamin mutant.</strong>
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Am. J. Hum. Genet. 30: 1-13, 1978.
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[PubMed: 23678]
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Cassandra L. Kniffin - updated : 09/23/2024<br>Cassandra L. Kniffin - updated : 6/24/2013<br>Cassandra L. Kniffin - updated : 4/7/2008<br>Cassandra L. Kniffin - updated : 12/7/2004
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Victor A. McKusick : 6/4/1986
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