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<title>
Entry
- #251000 - METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY; MAMM
- OMIM
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<span class="h4">#251000</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/251000"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS251000"> <strong>Phenotypic Series</strong> </a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#history">History</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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<div><a href="https://clinicaltrials.gov/search?cond=METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY" 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>
<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;">&#9658;</span>EuroGentest</div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=1263&Typ=Pat" title="Vitamin B12-unresponsive methylmalonic acidemia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Vitamin B12-unresponsive m…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20777&Typ=Pat" title="Vitamin B12-unresponsive methylmalonic acidemia type mut0" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Vitamin B12-unresponsive m…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11338&Typ=Pat" title="Vitamin B12-unresponsive methylmalonic acidemia type mut-" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Vitamin B12-unresponsive m…&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1231/" 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>
<div><a href="https://www.diseaseinfosearch.org/x/4721" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=251000[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>
<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;">&#9658;</span>Newborn Screening</div>
<div id="mimNewbornScreeningFold" class="collapse">
<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>
</div>
<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Orphanet</div>
<div id="mimOrphanetFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=27" title="Vitamin B12-unresponsive methylmalonic acidemia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Vitamin B12-unresponsive m…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289916" title="Vitamin B12-unresponsive methylmalonic acidemia type mut0" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Vitamin B12-unresponsive m…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79312" title="Vitamin B12-unresponsive methylmalonic acidemia type mut-" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Vitamin B12-unresponsive m…</a></div>
</div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/18d5e495-76a8-4273-a09a-bfeef97d9380/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0060740" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/251000" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/OMIA002849/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0060740" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:251000" 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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ORPHA:</strong> 27, 289916, 79312<br />
<strong>DO:</strong> 0060740<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
251000
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY; MAMM
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
METHYLMALONIC ACIDEMIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY<br />
MMA DUE TO MCM DEFICIENCY<br />
METHYLMALONIC ACIDURIA, mut TYPE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
METHYLMALONIC ACIDURIA, mut(0) TYPE, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
METHYLMALONIC ACIDURIA, mut(-) TYPE, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/568?start=-3&limit=10&highlight=568">
6p12.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Methylmalonic aciduria, mut(0) type
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/251000"> 251000 </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">
MMUT
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609058"> 609058 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/251000" 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>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS251000" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/251000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/251000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Weight </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cardiomyopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85898001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85898001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/57809008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">57809008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I51.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I51.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/425" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0878544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0878544</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001638" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001638</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001638" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001638</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pancreas </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pancreatitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75694006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75694006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K85.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K85.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030305&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030305</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001733</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001733</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Recurrent episodes of vomiting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855118&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855118</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Interstitial nephritis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/264536006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">264536006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/428255004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">428255004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N10-N16" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N10-N16</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N12" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N12</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N15.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N15.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N16" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N16</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027707&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027707</a>, <a href="https://bioportal.bioontology.org/search?q=C0041349&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041349</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001969" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001969</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001970</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001970</a>]</span><br /> -
Chronic renal failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90688005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90688005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/46177005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">46177005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/433146000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">433146000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/709044004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">709044004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N18.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N18.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N18.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N18.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N18.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N18.6</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N18" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N18</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/585" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">585</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/585.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">585.6</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/585.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">585.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1561643&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1561643</a>, <a href="https://bioportal.bioontology.org/search?q=C0022661&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022661</a>, <a href="https://bioportal.bioontology.org/search?q=C2316810&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2316810</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012622" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012622</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0003774" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003774</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003774" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003774</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Lethargy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/214264003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">214264003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R53.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R53.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023380&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023380</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001254" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001254</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
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 /> -
Coma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371632003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371632003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405809000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405809000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0543874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0543874</a>, <a href="https://bioportal.bioontology.org/search?q=C3146279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3146279</a>, <a href="https://bioportal.bioontology.org/search?q=C0009421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009421</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span><br /> -
Severe involvement of globus pallidus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855117&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855117</a>]</span><br /> -
Delay in myelination <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/135810007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">135810007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1277241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1277241</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012448" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012448</a>]</span><br /> -
Cerebellar hemorrhage (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75038005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75038005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149854&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149854</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011695</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011695</a>]</span><br /> -
Ischemic stroke in the basal ganglia (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151505</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> METABOLIC FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Dehydration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34095006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34095006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E86.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E86.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/276.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">276.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011175&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011175</a>, <a href="https://bioportal.bioontology.org/search?q=C2062903&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2062903</a>, <a href="https://bioportal.bioontology.org/search?q=C4284399&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4284399</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001944" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001944</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001944" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001944</a>]</span><br /> -
Neonatal or infantile metabolic ketoacidosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855125&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855125</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Leukopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/419188005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">419188005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84828003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84828003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.819</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.50</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0750394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750394</a>, <a href="https://bioportal.bioontology.org/search?q=C0023530&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023530</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001882" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001882</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001882" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001882</a>]</span><br /> -
Thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415116008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415116008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302215000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302215000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392386</a>, <a href="https://bioportal.bioontology.org/search?q=C0040034&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040034</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span><br />
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<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Normal serum cobalamin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848571</a>]</span><br /> -
Metabolic ketoacidosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854704&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854704</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005979" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005979</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005979" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005979</a>]</span><br /> -
Hyperammonemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/9360008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">9360008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5574662&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5574662</a>, <a href="https://bioportal.bioontology.org/search?q=C0220994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220994</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001987" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001987</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001987" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001987</a>]</span><br /> -
Hyperglycinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64654004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64654004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268559&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268559</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002154" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002154</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002154" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002154</a>]</span><br /> -
Methymalonicaciduria <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> 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> <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 /> -
Methylmalonyl-CoA mutase deficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124680001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124680001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2931536&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2931536</a>]</span><br /> -
Low plasma free and total carnitine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855120</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- mut-0 denotes individuals with cultured fibroblast mutase activity that is undetectable secondary to no functional mutase<br /> -
mut- denotes individuals with structurally altered mutase with reduced affinity for adenosylcobalamin (AdoCbl)<br /> -
Incidence of 1/50,000 births<br />
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<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the methylmalonyl-CoA mutase gene (MMUT, <a href="/entry/609058#0001">609058.0001</a>)<br />
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<h5>
Methylmalonic aciduria
- <a href="/phenotypicSeries/PS251000">PS251000</a>
- 4 Entries
</h5>
</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<strong>Location</strong>
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
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<td>
<span class="mim-font">
<a href="/geneMap/2/683?start=-3&limit=10&highlight=683"> 2q23.2 </a>
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</td>
<td>
<span class="mim-font">
<a href="/entry/620953"> Methylmalonic aciduria, cblD type </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
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<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
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<td>
<span class="mim-font">
<a href="/entry/620953"> 620953 </a>
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<td>
<span class="mim-font">
<a href="/entry/611935"> MMADHC </a>
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</td>
<td>
<span class="mim-font">
<a href="/entry/611935"> 611935 </a>
</span>
</td>
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<td>
<span class="mim-font">
<a href="/geneMap/4/589?start=-3&limit=10&highlight=589"> 4q31.21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/251100"> Methylmalonic aciduria, vitamin B12-responsive, cblA 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>
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<span class="mim-font">
<a href="/entry/251100"> 251100 </a>
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<span class="mim-font">
<a href="/entry/607481"> MMAA </a>
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<span class="mim-font">
<a href="/entry/607481"> 607481 </a>
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<td>
<span class="mim-font">
<a href="/geneMap/6/568?start=-3&limit=10&highlight=568"> 6p12.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/251000"> Methylmalonic aciduria, mut(0) type </a>
</span>
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<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>
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<td>
<span class="mim-font">
<a href="/entry/251000"> 251000 </a>
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</td>
<td>
<span class="mim-font">
<a href="/entry/609058"> MMUT </a>
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</td>
<td>
<span class="mim-font">
<a href="/entry/609058"> 609058 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/791?start=-3&limit=10&highlight=791"> 12q24.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/251110"> Methylmalonic aciduria, vitamin B12-responsive, cblB 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>
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<td>
<span class="mim-font">
<a href="/entry/251110"> 251110 </a>
</span>
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<td>
<span class="mim-font">
<a href="/entry/607568"> MMAB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607568"> 607568 </a>
</span>
</td>
</tr>
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</table>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because methylmalonic aciduria (MMA) of the complementation group 'mut' (MAMM) is caused by homozygous or compound heterozygous mutation in the gene encoding methylmalonyl-CoA mutase (MUT; <a href="/entry/609058">609058</a>) on chromosome 6p12.</p>
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<a id="description" class="mim-anchor"></a>
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<strong>Description</strong>
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<p>Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group: cblA (<a href="/entry/251100">251100</a>), caused by mutation in the MMAA gene (<a href="/entry/607481">607481</a>) on chromosome 4q31, cblB (<a href="/entry/251110">251110</a>), caused by mutation in the MMAB gene (<a href="/entry/607568">607568</a>) on 12q24, and cblD (<a href="/entry/620953">620953</a>), caused by mutation in the MMADHC gene (<a href="/entry/611935">611935</a>).</p><p>Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (<a href="/entry/277400">277400</a>), cblD (<a href="/entry/277410">277410</a>), and cblF (<a href="/entry/277380">277380</a>).</p><p>See the comprehensive review of <a href="#17" class="mim-tip-reference" title="Ledley, F. D. &lt;strong&gt;Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl CoA mutase.&lt;/strong&gt; BioEssays 12: 335-340, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1975493/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1975493&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/bies.950120706&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1975493">Ledley (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1975493" 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>Clinical Features</strong>
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<p>The clinical spectrum of methylmalonic aciduria is wide, ranging from a benign condition (<a href="#16" class="mim-tip-reference" title="Ledley, F. D., Levy, H. L., Shih, V. E., Benjamin, R., Mahoney, M. J. &lt;strong&gt;Benign methylmalonic aciduria.&lt;/strong&gt; New Eng. J. Med. 311: 1015-1018, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6148691/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6148691&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198410183111604&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6148691">Ledley et al., 1984</a>) to fatal neonatal disease (<a href="#18" class="mim-tip-reference" title="Matsui, S. M., Mahoney, M. J., Rosenberg, L. E. &lt;strong&gt;The natural history of the inherited methylmalonic acidemias.&lt;/strong&gt; New Eng. J. Med. 308: 857-861, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6132336/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6132336&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198304143081501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6132336">Matsui et al., 1983</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6132336+6148691" 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="#21" class="mim-tip-reference" title="Oberholzer, V. G., Levin, B., Burgess, E. A., Young, W. F. &lt;strong&gt;Methylmalonic aciduria: an inborn error of metabolism leading to chronic metabolic acidosis.&lt;/strong&gt; Arch. Dis. Child. 42: 492-504, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6061291/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6061291&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.42.225.492&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6061291">Oberholzer et al. (1967)</a> reported an inborn error of metabolism characterized by methylmalonic aciduria associated with developmental retardation and chronic metabolic acidosis. Treatment with cobalamin was ineffective. <a href="#3" class="mim-tip-reference" title="Barness, L. A., Morrow, G., III. &lt;strong&gt;Methylmalonic aciduria--a newly discovered inborn error.&lt;/strong&gt; Ann. Intern. Med. 69: 633-635, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5673182/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5673182&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-69-3-633_2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5673182">Barness and Morrow (1968)</a> noted that some cases of methylmalonic aciduria responded to vitamin B12. Of those not responsive to B12, only a subset had hyperglycinemia. <a href="#19" class="mim-tip-reference" title="Morrow, G., III, Barness, L. A., Cardinale, G. J., Abeles, R. H., Flaks, J. G. &lt;strong&gt;Congenital methylmalonic acidemia: enzymatic evidence for two forms of the disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 63: 191-197, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5257962/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5257962&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.63.1.191&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5257962">Morrow et al. (1969)</a> provided enzymatic proof of 2 forms of the disease with regard to response to cobalamin treatment: methylmalonyl-CoA mutase activity was essentially absent from the liver in a vitamin B12-unresponsive case, whereas residual enzyme activity increased to normal with added coenzyme in a vitamin B12-responsive case. The latter case was interpreted as having a defect in AdoCbl synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5673182+6061291+5257962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Gravel, R. A., Mahoney, M. J., Ruddle, F. H., Rosenberg, L. E. &lt;strong&gt;Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism.&lt;/strong&gt; Proc. Nat. Acad. Sci. 72: 3181-3185, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1059104/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1059104&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.72.8.3181&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1059104">Gravel et al. (1975)</a> confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1059104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Willard, H. F., Rosenberg, L. E. &lt;strong&gt;Inherited deficiencies of human methylmalonyl CaA (sic) mutase activity: reduced affinity of mutant apoenzyme for adenosylcobalamin.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 78: 927-934, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20894/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20894&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0006-291x(77)90511-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20894">Willard and Rosenberg (1977)</a> found that the mutase enzyme in cells from some MMA patients showed decreased affinity for AdoCbl with abnormally high Km for the coenzyme. These cases were considered to represent a structurally abnormal enzyme and were characteristic of the mut(-) phenotype. By immunohistochemical analysis of the mutase enzyme, <a href="#13" class="mim-tip-reference" title="Kolhouse, J. F., Utley, C., Fenton, W. A., Rosenberg, L. E. &lt;strong&gt;Immunochemical studies on cultured fibroblasts from patients with inherited methylmalonic acidemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 78: 7737-7741, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6121323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6121323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.78.12.7737&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6121323">Kolhouse et al. (1981)</a> found that cell lines from mut(-) patients had detectable crossreacting material (CRM) ranging from 20 to 100% of control, whereas cells from mut(0) patients had CRM ranging from no detectable protein to 40% of controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6121323+20894" 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="#18" class="mim-tip-reference" title="Matsui, S. M., Mahoney, M. J., Rosenberg, L. E. &lt;strong&gt;The natural history of the inherited methylmalonic acidemias.&lt;/strong&gt; New Eng. J. Med. 308: 857-861, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6132336/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6132336&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198304143081501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6132336">Matsui et al. (1983)</a> collected detailed information on 45 patients with MMA: 15 with mut(0) type, 5 with mut(-), 14 with cblA, and 11 with cblB. The most common presenting symptoms at onset were lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and hypotonia. Other common features included hepatomegaly, developmental delay, and coma. Mut(0) patients presented earlier in infancy than the 3 other groups. All patients had methylmalonic acidemia and normal serum cobalamin, and most had metabolic acidosis, ketonuria, hyperammonemia, and hyperglycinemia. Approximately half of all the patients had pancytopenia. Most cblA and nearly half of cblB patients showed a decrease in urine and blood concentrations of methylmalonic acid in response to vitamin B12 supplementation, whereas none of the mut(0) or mut(-) responded. Most cblA, cblB, and mut(-) patients were still living at the time of the report; most mut(0) patients died during the first few months of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6132336" 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="#27" class="mim-tip-reference" title="Shevell, M. I., Matiaszuk, N., Ledley, F. D., Rosenblatt, D. S. &lt;strong&gt;Varying neurological phenotypes among mut-0 and mut- patients with methylmalonyl CoA mutase deficiency.&lt;/strong&gt; Am. J. Med. Genet. 45: 619-624, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7681251/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7681251&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320450521&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7681251">Shevell et al. (1993)</a> compared the clinical features in 11 mut(0) patients with those in 9 mut(-) patients. All 11 mut(0) patients had an early neonatal presentation; 6 of these patients died in infancy and 3 of 5 survivors had a poor neurologic outcome as evidenced by severe developmental delay or spastic quadriparesis with dystonia. The 2 other survivors included a 27-month-old child with mild delay in verbal and fine motor skills and an adolescent with low normal intelligence. Of the 9 mut(-) patients, 7 became symptomatic in late infancy or childhood and 2 were found on screening. No episode of metabolic decompensation had occurred in 2 of the 9, yet both were neurologically compromised, one being severely retarded and autistic and the other mildly delayed. Four mut(-) patients had had episodic acidosis and were neurologically moderately affected, while 3 had had episodic acidosis but were neurologically intact. Although a broad correlation was found between mutase class and phenotype, survival with good outcome was possible among mut(0) patients and, conversely, significant morbidity occurred among mut(-) patients. Acidosis and metabolic imbalance were not necessary preconditions for significant morbidity. <a href="#31" class="mim-tip-reference" title="van den Bergh, F. A. J. T. M., del Canho, H., Duran, M. &lt;strong&gt;Methylmalonic aciduria and sudden child death.&lt;/strong&gt; J. Inherit. Metab. Dis. 15: 897-898, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1293386/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1293386&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01800229&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1293386">van den Bergh et al. (1992)</a> reported sudden death in a child with MMA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7681251+1293386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Giorgio, A. J., Trowbridge, M., Boone, A. W., Patten, R. S. &lt;strong&gt;Methylmalonic aciduria without vitamin B12 deficiency in an adult sibship.&lt;/strong&gt; New Eng. J. Med. 295: 310-313, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6909/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6909&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197608052950604&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6909">Giorgio et al. (1976)</a> reported 2 French-Canadian brothers, aged 62 and 70 years, who had a benign form of MMA due to methylmalonyl-CoA mutase deficiency. Neither had anemia or hepatic dysfunction. Serum vitamin B12 was normal and the methylmalonic aciduria was unaffected by administration of vitamin B12 in large dosage. The brothers had presented with adult-onset diabetes mellitus. <a href="#16" class="mim-tip-reference" title="Ledley, F. D., Levy, H. L., Shih, V. E., Benjamin, R., Mahoney, M. J. &lt;strong&gt;Benign methylmalonic aciduria.&lt;/strong&gt; New Eng. J. Med. 311: 1015-1018, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6148691/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6148691&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198410183111604&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6148691">Ledley et al. (1984)</a> reported a benign form of MMA due to deficiency of methylmalonyl-CoA mutase in 8 children identified through routine neonatal screening or screening of infants with affected sibs. Despite lack of dietary or vitamin therapy, the children had normal growth and development (age range, 18 months to 13 years) and performed as well as their unaffected sibs on psychometric tests. None responded to vitamin B12 treatment and there was no other evidence of a cofactor defect. In 2 sibs, complementation studies showed a defect in the mutase apoenzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6148691+6909" 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>Renal insufficiency is frequently reported in mutase-deficient methylmalonic acidemia. <a href="#30" class="mim-tip-reference" title="Van Calcar, S. C., Harding, C. O., Lyne, P., Hogan, K., Banerjee, R., Sollinger, H., Rieselbach, R. E., Wolff, J. A. &lt;strong&gt;Renal transplantation in a patient with methylmalonic acidaemia.&lt;/strong&gt; J. Inherit. Metab. Dis. 21: 729-737, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9819702/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9819702&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005493015489&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9819702">Van Calcar et al. (1998)</a> reported a patient with mut(-) MMA who developed chronic tubulointerstitial nephropathy during adolescence. After 24 years of age, she developed end-stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9819702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of inherited metabolic disorders and stroke, <a href="#29" class="mim-tip-reference" title="Testai, F. D., Gorelick, P. B. &lt;strong&gt;Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.&lt;/strong&gt; Arch. Neurol. 67: 148-153, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20142522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20142522&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneurol.2009.333&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20142522">Testai and Gorelick (2010)</a> noted that patients with branched-chain organic aciduria, including isovaleric aciduria (<a href="/entry/243500">243500</a>), propionic aciduria (<a href="/entry/606054">606054</a>), and methylmalonic aciduria can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Kruszka, P. S., Manoli, I., Sloan, J. L., Kopp, J. B., Venditti, C. P. &lt;strong&gt;Renal growth in isolated methylmalonic acidemia.&lt;/strong&gt; Genet. Med. 15: 990-996, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23639900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23639900&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23639900[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.42&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23639900">Kruszka et al. (2013)</a> studied renal growth in isolated MMA. Fifty patients with MMA (35 mut subtype, 9 cblA subtype, and 6 cblB subtype), followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple regression analyses. Comparisons with age-matched controls showed that renal length in subjects with MMA was significantly decreased (p less than 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C (<a href="/entry/604312">604312</a>), and serum methylmalonic acid concentrations best predicted kidney size. <a href="#14" class="mim-tip-reference" title="Kruszka, P. S., Manoli, I., Sloan, J. L., Kopp, J. B., Venditti, C. P. &lt;strong&gt;Renal growth in isolated methylmalonic acidemia.&lt;/strong&gt; Genet. Med. 15: 990-996, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23639900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23639900&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23639900[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.42&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23639900">Kruszka et al. (2013)</a> concluded that renal length, reflective of kidney growth, significantly decreased in patients with MMA over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23639900" 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="#12" class="mim-tip-reference" title="Kaplan, P., Ficicioglu, C., Mazur, A. T., Palmieri, M. J., Berry, G. T. &lt;strong&gt;Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency.&lt;/strong&gt; Molec. Genet. Metab. 88: 322-326, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16750411/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16750411&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2006.04.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16750411">Kaplan et al. (2006)</a> reported the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the United States and provided new biochemical data that indicated why transplanted patients remain susceptible to 'metabolic strokes.' In their 10-year-old male patient, there was clear evidence that the de novo synthesis of propionyl-CoA within the central nervous system led to brain methylmalonate accumulation that was largely unaffected by transplantation. <a href="#12" class="mim-tip-reference" title="Kaplan, P., Ficicioglu, C., Mazur, A. T., Palmieri, M. J., Berry, G. T. &lt;strong&gt;Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency.&lt;/strong&gt; Molec. Genet. Metab. 88: 322-326, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16750411/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16750411&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2006.04.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16750411">Kaplan et al. (2006)</a> concluded that liver transplantation is not a cure for methylmalonic acidopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16750411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Niemi, A.-K., Kim, I. K., Krueger, C. E., Cowan, T. M., Baugh, N., Farrell, R., Bonham, C. A., Concepcion, W., Esquivel, C. O., Enns, G. M. &lt;strong&gt;Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation.&lt;/strong&gt; J. Pediat. 166: 1455-1461, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25771389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25771389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.jpeds.2015.01.051&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25771389">Niemi et al. (2015)</a> reported the outcome of 14 MMA patients who underwent liver transplantation (6 patients) or liver-kidney transplantation (8 patients) at a mean age of 8.2 years (range 0.8 to 20.7 years). At mean follow-up of 3.25 years, survival was 100%, liver allograft survival was 93% (1 patient required retransplantation due to hepatic artery thrombosis) and renal allograft survival was 100%. Following transplantation, there were no metabolic decompensations, and neurodevelopmental abilities were maintained or improved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25771389" 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>Using 3D organotypic brain cell cultures derived from embryos of a brain-specific Mut -/- mouse, <a href="#22" class="mim-tip-reference" title="Remacle, N., Forny, P., Cudre-Cung, H.-P., Gonzalez-Melo, M., do Vale-Pereira, S., Henry, H., Teav, T., Gallart-Ayala, H., Braissant, O., Baumgartner, M., Ballhausen, D. &lt;strong&gt;New in vitro model derived from brain-specific Mut-/- mice confirms cerebral ammonium accumulation in methylmalonic aciduria.&lt;/strong&gt; Molec. Genet. Metab. 124: 266-277, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29934063/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29934063&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2018.06.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29934063">Remacle et al. (2018)</a> investigated mechanisms leading to brain damage in methylmalonic aciduria. The in vitro model was challenged with the catabolic stress of temperature shift. <a href="#22" class="mim-tip-reference" title="Remacle, N., Forny, P., Cudre-Cung, H.-P., Gonzalez-Melo, M., do Vale-Pereira, S., Henry, H., Teav, T., Gallart-Ayala, H., Braissant, O., Baumgartner, M., Ballhausen, D. &lt;strong&gt;New in vitro model derived from brain-specific Mut-/- mice confirms cerebral ammonium accumulation in methylmalonic aciduria.&lt;/strong&gt; Molec. Genet. Metab. 124: 266-277, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29934063/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29934063&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2018.06.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29934063">Remacle et al. (2018)</a> found typical metabolites for methylmalonic aciduria as well as a massive ammonia increase in the media of mutant mouse brain cultures. Investigation of pathways involved in intracerebral ammonia production revealed increased expression of glutaminase-2 (GLS2; <a href="/entry/606365">606365</a>) and diminished expression of glutamate dehydrogenase-1 (GLUD1; <a href="/entry/138130">138130</a>) in Mut -/- aggregates. Astrocytes showed swollen fibers and cell bodies, and oligodendrocytes showed inhibited axonal elongation and delayed myelination. Most effects were even more pronounced after 48 hours at 39 degrees C. Microglia activation and an increased apoptosis rate suggested degeneration of Mut -/- brain cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29934063" 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>Because of improvements in therapy, many patients with MMA reach childbearing age. <a href="#32" class="mim-tip-reference" title="Wasserstein, M. P., Gaddipati, S., Snyderman, S. E., Eddleman, K., Desnick, R. J., Sansaricq, C. &lt;strong&gt;Successful pregnancy in severe methylmalonic acidaemia.&lt;/strong&gt; J. Inherit. Metab. Dis. 22: 788-794, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10518278/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10518278&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1005597722237&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10518278">Wasserstein et al. (1999)</a> reported a successful pregnancy and delivery of a healthy baby to a 20-year-old woman with vitamin B12-unresponsive methylmalonic acidemia complicated by moderate renal insufficiency, chronic pancreatitis, anemia, and optic atrophy. Strict metabolic control was maintained throughout her pregnancy. The patient remained clinically asymptomatic during and after delivery, and her metabolic condition remained stable after discharge except for a slight decline in her renal function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<p><a href="#34" class="mim-tip-reference" title="Wilkemeyer, M. F., Crane, A. M., Ledley, F. D. &lt;strong&gt;Differential diagnosis of mut and cbl methylmalonic aciduria by DNA-mediated gene transfer in primary fibroblasts.&lt;/strong&gt; J. Clin. Invest. 87: 915-918, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1671869/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1671869&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115098&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1671869">Wilkemeyer et al. (1991)</a> showed that the mut and cbl forms of MMA can be differentiated not only by somatic cell complementation but also by DNA-mediated gene transfer of a methylmalonyl CoA mutase cDNA clone. Transfer of the MUT clone into mut fibroblasts reconstituted holoenzyme activity, whereas the same process had no effect on cbl fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
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<p><a href="#1" class="mim-tip-reference" title="Abramowicz, M. J., Andrien, M., Dupont, E., Dorchy, H., Parma, J., Duprez, L., Ledley, F. D., Courtens, W., Vamos, E. &lt;strong&gt;Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus.&lt;/strong&gt; J. Clin. Invest. 94: 418-421, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7913714/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7913714&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI117339&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7913714">Abramowicz et al. (1994)</a> studied a newborn female with a mut(0) form of MMA and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus (IDDM; <a href="/entry/222100">222100</a>). The patient died 2 weeks after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal uniparental isodisomy, involving at least a 25-cM portion of chromosome 6 that encompasses the major histocompatibility complex. Duplication of the mutated allele on chromosome 6 inherited from the father was thought to be responsible for methylmalonic acidemia. It was also considered likely that isodisomy was etiologically related to the agenesis of beta cells, and the authors postulated the existence of a gene on chromosome 6 involved in beta-cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p>In a patient with MMA mut(0), defined as having no residual enzyme activity, <a href="#11" class="mim-tip-reference" title="Jansen, R., Ledley, F. D. &lt;strong&gt;Heterozygous mutations at the mut locus in fibroblasts with mut-0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning.&lt;/strong&gt; Am. J. Hum. Genet. 47: 808-814, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1977311/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1977311&lt;/a&gt;]" pmid="1977311">Jansen and Ledley (1990)</a> identified compound heterozygosity for 2 mutations in the MUT gene (<a href="/entry/609058#0001">609058.0001</a> and <a href="/entry/609058#0002">609058.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1977311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with MMA mut(-), defined as having some residual enzyme activity, who had been reported by <a href="#15" class="mim-tip-reference" title="Ledley, F. D., Jansen, R., Nham, S.-U., Fenton, W. A., Rosenberg, L. E. &lt;strong&gt;Mutation eliminating mitochondrial leader sequence of methylmalonyl-CoA mutase causes mut-0 methylmalonic acidemia.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 3147-3150, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1970180/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1970180&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.8.3147&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1970180">Ledley et al. (1990)</a>, <a href="#5" class="mim-tip-reference" title="Crane, A. M., Jansen, R., Andrews, E. R., Ledley, F. D. &lt;strong&gt;Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut(-) methylmalonic aciduria.&lt;/strong&gt; J. Clin. Invest. 89: 385-391, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1346616/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1346616&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115597&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1346616">Crane et al. (1992)</a> identified a homozygous mutation in the MUT gene (<a href="/entry/609058#0005">609058.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1970180+1346616" 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="Acquaviva, C., Benoist, J.-F., Callebaut, I., Guffon, N., Ogier de Baulny, H., Touati, G., Aydin, A., Porquet, D., Elion, J. &lt;strong&gt;N219Y, a new frequent mutation among mut-0 forms of methylmalonic acidemia in Caucasian patients.&lt;/strong&gt; Europ. J. Hum. Genet. 9: 577-582, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11528502/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11528502&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200675&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11528502">Acquaviva et al. (2001)</a> reported a novel MUT missense mutation (<a href="/entry/609058#0010">609058.0010</a>) in 5 unrelated families of French and Turkish descent from a population of 19 patients with MCM apoenzyme deficiency. All the patients exhibited a severe mut(0) methylmalonic acidemia phenotype, and 3 of them were homozygous for the mutation. The findings represented the first frequent MUT mutation reported in the Caucasian population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Champattanachai, V., Ketudat Cairns, J. R., Shotelersuk, V., Keeratichamroen, S., Sawangareetrakul, P., Srisomsap, C., Kaewpaluek, V., Svasti, J. &lt;strong&gt;Novel mutations in a Thai patient with methylmalonic acidemia.&lt;/strong&gt; Molec. Genet. Metab. 79: 300-302, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12948746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12948746&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s1096-7192(03)00106-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12948746">Champattanachai et al. (2003)</a> reported 2 novel mutations in a Thai patient with mut(0) methylmalonic acidemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12948746" 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="#9" class="mim-tip-reference" title="Hoffman, M. &lt;strong&gt;Scientific sleuths solve a murder mystery.&lt;/strong&gt; Science 254: 931 only, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1948075/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1948075&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1948075&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1948075">Hoffman (1991)</a> recounted the story of Patricia Stallings who was sentenced to life in prison for the presumed murder of her infant son with ethylene glycol, an ingredient of antifreeze. While in prison, the woman gave birth to a second son, who was found to have methylmalonic acidemia. William Sly and James Shoemaker at St. Louis University performed analyses of the first son's blood and did not detect ethylene glycol; Piero Rinaldo at Yale University demonstrated the biochemical features of methylmalonic acidemia and found no evidence of ethylene glycol in the body fluids. All charges against Patricia Stallings were dropped. <a href="#28" class="mim-tip-reference" title="Shoemaker, J. D., Lynch, R. E., Hoffmann, J. W., Sly, W. S. &lt;strong&gt;Misidentification of propionic acid as ethylene glycol in a patient with methylmalonic acidemia.&lt;/strong&gt; J. Pediat. 120: 417-421, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1538288/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1538288&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(05)80909-6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1538288">Shoemaker et al. (1992)</a> determined that the gas chromatographic peak that had been identified as ethylene glycol by a clinical laboratory was actually due to propionic acid. <a href="#36" class="mim-tip-reference" title="Woolf, A. D., Wynshaw-Boris, A., Rinaldo, P., Levy, H. L. &lt;strong&gt;Intentional infantile ethylene glycol poisoning presenting as an inherited metabolic disorder.&lt;/strong&gt; J. Pediat. 120: 421-424, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1538289/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1538289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(05)80910-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1538289">Woolf et al. (1992)</a> noted that the opposite situation could occur: intentional infantile ethylene glycol poisoning being misinterpreted as an inborn error of metabolism leading to recurrent infantile metabolic acidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1948075+1538288+1538289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
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<strong>See Also:</strong>
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<a href="#Fowlow1985" class="mim-tip-reference" title="Fowlow, S. B., Holmes, T. M., Morgan, K., Snyder, F. F. &lt;strong&gt;Screening for methylmalonic aciduria in Alberta: a voluntary program with particular significance for the Hutterite brethren.&lt;/strong&gt; Am. J. Med. Genet. 22: 513-519, 1985.">Fowlow et al. (1985)</a>; <a href="#Hsia1970" class="mim-tip-reference" title="Hsia, Y. E., Lilljeqvist, A. C., Rosenberg, L. E. &lt;strong&gt;Vitamin B12-dependent methylmalonic aciduria: amino acid toxicity, long chain ketonuria, and protective effect of vitamin B12.&lt;/strong&gt; Pediatrics 46: 497-507, 1970.">Hsia et al. (1970)</a>; <a href="#Rosenberg1969" class="mim-tip-reference" title="Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E., Rosenbloom, F. M. &lt;strong&gt;Vitamin B12 dependent methylmalonic-aciduria: defective B12 metabolism in cultured fibroblasts.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 37: 607-614, 1969.">Rosenberg et al. (1969)</a>; <a href="#Rosenberg1968" class="mim-tip-reference" title="Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E. &lt;strong&gt;Methylmalonic aciduria: metabolic block localization and vitamin B12 dependency.&lt;/strong&gt; Science 162: 805-807, 1968.">Rosenberg et al. (1968)</a>; <a href="#Rosenberg1968" class="mim-tip-reference" title="Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E. &lt;strong&gt;Methylmalonic aciduria: metabolic block localization and vitamin B12 dependency.&lt;/strong&gt; Science 162: 805-807, 1968.">Rosenberg et al. (1968)</a>; <a href="#Satoh1981" class="mim-tip-reference" title="Satoh, T., Narisawa, K., Igarashi, Y., Saitoh, T., Hayasaka, K., Ichinohazama, Y., Onodera, H., Tada, K., Oohara, K. &lt;strong&gt;Dietary therapy in two patients with vitamin B12-unresponsive methylmalonic acidemia.&lt;/strong&gt; Europ. J. Pediat. 135: 305-312, 1981.">Satoh et al.
(1981)</a>; <a href="#Wilcken1977" class="mim-tip-reference" title="Wilcken, B., Kilham, H. A., Faull, K. &lt;strong&gt;Methylmalonic aciduria: a variant form of methylmalonyl coenzyme A apomutase deficiency.&lt;/strong&gt; J. Pediat. 91: 428-430, 1977.">Wilcken et al. (1977)</a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Abramowicz1994" class="mim-anchor"></a>
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Abramowicz, M. J., Andrien, M., Dupont, E., Dorchy, H., Parma, J., Duprez, L., Ledley, F. D., Courtens, W., Vamos, E.
<strong>Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus.</strong>
J. Clin. Invest. 94: 418-421, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913714</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7913714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI117339" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Acquaviva2001" class="mim-anchor"></a>
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<p class="mim-text-font">
Acquaviva, C., Benoist, J.-F., Callebaut, I., Guffon, N., Ogier de Baulny, H., Touati, G., Aydin, A., Porquet, D., Elion, J.
<strong>N219Y, a new frequent mutation among mut-0 forms of methylmalonic acidemia in Caucasian patients.</strong>
Europ. J. Hum. Genet. 9: 577-582, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528502</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/sj.ejhg.5200675" target="_blank">Full Text</a>]
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<a id="Barness1968" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Barness, L. A., Morrow, G., III.
<strong>Methylmalonic aciduria--a newly discovered inborn error.</strong>
Ann. Intern. Med. 69: 633-635, 1968.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5673182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5673182</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5673182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.7326/0003-4819-69-3-633_2" target="_blank">Full Text</a>]
</p>
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<a id="4" class="mim-anchor"></a>
<a id="Champattanachai2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Champattanachai, V., Ketudat Cairns, J. R., Shotelersuk, V., Keeratichamroen, S., Sawangareetrakul, P., Srisomsap, C., Kaewpaluek, V., Svasti, J.
<strong>Novel mutations in a Thai patient with methylmalonic acidemia.</strong>
Molec. Genet. Metab. 79: 300-302, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948746</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12948746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s1096-7192(03)00106-9" target="_blank">Full Text</a>]
</p>
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</li>
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<a id="5" class="mim-anchor"></a>
<a id="Crane1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Crane, A. M., Jansen, R., Andrews, E. R., Ledley, F. D.
<strong>Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut(-) methylmalonic aciduria.</strong>
J. Clin. Invest. 89: 385-391, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1346616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1346616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1346616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI115597" target="_blank">Full Text</a>]
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<a id="Fowlow1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Fowlow, S. B., Holmes, T. M., Morgan, K., Snyder, F. F.
<strong>Screening for methylmalonic aciduria in Alberta: a voluntary program with particular significance for the Hutterite brethren.</strong>
Am. J. Med. Genet. 22: 513-519, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2865895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2865895</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2865895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320220309" target="_blank">Full Text</a>]
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<a id="Giorgio1976" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Giorgio, A. J., Trowbridge, M., Boone, A. W., Patten, R. S.
<strong>Methylmalonic aciduria without vitamin B12 deficiency in an adult sibship.</strong>
New Eng. J. Med. 295: 310-313, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM197608052950604" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Gravel1975" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gravel, R. A., Mahoney, M. J., Ruddle, F. H., Rosenberg, L. E.
<strong>Genetic complementation in heterokaryons of human fibroblasts defective in cobalamin metabolism.</strong>
Proc. Nat. Acad. Sci. 72: 3181-3185, 1975.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1059104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1059104</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1059104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.72.8.3181" target="_blank">Full Text</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Hoffman1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hoffman, M.
<strong>Scientific sleuths solve a murder mystery.</strong>
Science 254: 931 only, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1948075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1948075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1948075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1948075" target="_blank">Full Text</a>]
</p>
</div>
</li>
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Hsia, Y. E., Lilljeqvist, A. C., Rosenberg, L. E.
<strong>Vitamin B12-dependent methylmalonic aciduria: amino acid toxicity, long chain ketonuria, and protective effect of vitamin B12.</strong>
Pediatrics 46: 497-507, 1970.
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Jansen, R., Ledley, F. D.
<strong>Heterozygous mutations at the mut locus in fibroblasts with mut-0 methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning.</strong>
Am. J. Hum. Genet. 47: 808-814, 1990.
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Kaplan, P., Ficicioglu, C., Mazur, A. T., Palmieri, M. J., Berry, G. T.
<strong>Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency.</strong>
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[<a href="https://doi.org/10.1016/j.ymgme.2006.04.003" target="_blank">Full Text</a>]
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Kolhouse, J. F., Utley, C., Fenton, W. A., Rosenberg, L. E.
<strong>Immunochemical studies on cultured fibroblasts from patients with inherited methylmalonic acidemia.</strong>
Proc. Nat. Acad. Sci. 78: 7737-7741, 1981.
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[<a href="https://doi.org/10.1073/pnas.78.12.7737" target="_blank">Full Text</a>]
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Kruszka, P. S., Manoli, I., Sloan, J. L., Kopp, J. B., Venditti, C. P.
<strong>Renal growth in isolated methylmalonic acidemia.</strong>
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[<a href="https://doi.org/10.1038/gim.2013.42" target="_blank">Full Text</a>]
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Ledley, F. D., Jansen, R., Nham, S.-U., Fenton, W. A., Rosenberg, L. E.
<strong>Mutation eliminating mitochondrial leader sequence of methylmalonyl-CoA mutase causes mut-0 methylmalonic acidemia.</strong>
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[<a href="https://doi.org/10.1073/pnas.87.8.3147" target="_blank">Full Text</a>]
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Ledley, F. D., Levy, H. L., Shih, V. E., Benjamin, R., Mahoney, M. J.
<strong>Benign methylmalonic aciduria.</strong>
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[<a href="https://doi.org/10.1056/NEJM198410183111604" target="_blank">Full Text</a>]
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Ledley, F. D.
<strong>Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl CoA mutase.</strong>
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[<a href="https://doi.org/10.1002/bies.950120706" target="_blank">Full Text</a>]
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Matsui, S. M., Mahoney, M. J., Rosenberg, L. E.
<strong>The natural history of the inherited methylmalonic acidemias.</strong>
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[<a href="https://doi.org/10.1056/NEJM198304143081501" target="_blank">Full Text</a>]
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Morrow, G., III, Barness, L. A., Cardinale, G. J., Abeles, R. H., Flaks, J. G.
<strong>Congenital methylmalonic acidemia: enzymatic evidence for two forms of the disease.</strong>
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[<a href="https://doi.org/10.1073/pnas.63.1.191" target="_blank">Full Text</a>]
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Niemi, A.-K., Kim, I. K., Krueger, C. E., Cowan, T. M., Baugh, N., Farrell, R., Bonham, C. A., Concepcion, W., Esquivel, C. O., Enns, G. M.
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[<a href="https://doi.org/10.1016/j.jpeds.2015.01.051" target="_blank">Full Text</a>]
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Oberholzer, V. G., Levin, B., Burgess, E. A., Young, W. F.
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[<a href="https://doi.org/10.1136/adc.42.225.492" target="_blank">Full Text</a>]
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Remacle, N., Forny, P., Cudre-Cung, H.-P., Gonzalez-Melo, M., do Vale-Pereira, S., Henry, H., Teav, T., Gallart-Ayala, H., Braissant, O., Baumgartner, M., Ballhausen, D.
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[<a href="https://doi.org/10.1016/j.ymgme.2018.06.008" target="_blank">Full Text</a>]
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Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E., Rosenbloom, F. M.
<strong>Vitamin B12 dependent methylmalonic-aciduria: defective B12 metabolism in cultured fibroblasts.</strong>
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[<a href="https://doi.org/10.1016/0006-291x(69)90853-5" target="_blank">Full Text</a>]
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Rosenberg, L. E., Lilljeqvist, A. C., Hsia, Y. E.
<strong>Methylmalonic aciduria: an inborn error leading to metabolic acidosis, long-chain ketonuria and hyperglycinemia.</strong>
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[<a href="https://doi.org/10.1056/NEJM196806132782404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.162.3855.805" target="_blank">Full Text</a>]
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Satoh, T., Narisawa, K., Igarashi, Y., Saitoh, T., Hayasaka, K., Ichinohazama, Y., Onodera, H., Tada, K., Oohara, K.
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[<a href="https://doi.org/10.1007/BF00442109" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320450521" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(05)80909-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2009.333" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1005493015489" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01800229" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1005597722237" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Wilcken, B., Kilham, H. A., Faull, K.
<strong>Methylmalonic aciduria: a variant form of methylmalonyl coenzyme A apomutase deficiency.</strong>
J. Pediat. 91: 428-430, 1977.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19569</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(77)81313-9" target="_blank">Full Text</a>]
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<a id="Wilkemeyer1991" class="mim-anchor"></a>
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Wilkemeyer, M. F., Crane, A. M., Ledley, F. D.
<strong>Differential diagnosis of mut and cbl methylmalonic aciduria by DNA-mediated gene transfer in primary fibroblasts.</strong>
J. Clin. Invest. 87: 915-918, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671869</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI115098" target="_blank">Full Text</a>]
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<a id="Willard1977" class="mim-anchor"></a>
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Willard, H. F., Rosenberg, L. E.
<strong>Inherited deficiencies of human methylmalonyl CaA (sic) mutase activity: reduced affinity of mutant apoenzyme for adenosylcobalamin.</strong>
Biochem. Biophys. Res. Commun. 78: 927-934, 1977.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20894</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0006-291x(77)90511-3" target="_blank">Full Text</a>]
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<a id="Woolf1992" class="mim-anchor"></a>
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Woolf, A. D., Wynshaw-Boris, A., Rinaldo, P., Levy, H. L.
<strong>Intentional infantile ethylene glycol poisoning presenting as an inherited metabolic disorder.</strong>
J. Pediat. 120: 421-424, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1538289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1538289</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1538289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(05)80910-2" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 09/15/2021
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Ada Hamosh - updated : 12/07/2018<br>Ada Hamosh - updated : 1/9/2014<br>Cassandra L. Kniffin - updated : 10/11/2010<br>Ada Hamosh - updated : 6/28/2007<br>Cassandra L. Kniffin - reorganized : 12/10/2004<br>Cassandra L. Kniffin - updated : 12/6/2004<br>Ada Hamosh - updated : 10/9/2003<br>Michael B. Petersen - updated : 2/8/2002<br>Wilson H. Y. Lo - updated : 11/17/1999<br>Victor A. McKusick - updated : 12/2/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 9/22/1997
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Creation Date:
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Victor A. McKusick : 6/4/1986
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carol : 10/02/2024
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carol : 09/25/2024<br>carol : 03/11/2024<br>carol : 06/14/2022<br>alopez : 09/15/2021<br>carol : 11/20/2020<br>alopez : 12/07/2018<br>carol : 12/30/2015<br>alopez : 1/9/2014<br>wwang : 10/29/2010<br>ckniffin : 10/11/2010<br>alopez : 7/6/2007<br>terry : 6/28/2007<br>terry : 4/20/2005<br>terry : 4/6/2005<br>tkritzer : 3/16/2005<br>carol : 12/10/2004<br>carol : 12/10/2004<br>ckniffin : 12/6/2004<br>carol : 3/17/2004<br>alopez : 10/9/2003<br>terry : 10/9/2003<br>alopez : 2/11/2002<br>alopez : 2/8/2002<br>alopez : 2/8/2002<br>carol : 11/17/1999<br>carol : 11/17/1999<br>mgross : 6/18/1999<br>carol : 12/8/1998<br>terry : 12/2/1998<br>carol : 5/8/1998<br>terry : 4/29/1998<br>terry : 11/10/1997<br>mark : 9/23/1997<br>terry : 9/22/1997<br>terry : 1/23/1997<br>terry : 1/21/1997<br>mark : 6/24/1996<br>terry : 6/12/1996<br>terry : 10/27/1994<br>jason : 7/26/1994<br>warfield : 4/15/1994<br>mimadm : 4/8/1994<br>carol : 3/24/1993<br>carol : 2/10/1993
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<h3>
<span class="mim-font">
<strong>#</strong> 251000
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<h3>
<span class="mim-font">
METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY; MAMM
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<em>Alternative titles; symbols</em>
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METHYLMALONIC ACIDEMIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY<br />
MMA DUE TO MCM DEFICIENCY<br />
METHYLMALONIC ACIDURIA, mut TYPE
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Other entities represented in this entry:
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METHYLMALONIC ACIDURIA, mut(0) TYPE, INCLUDED
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METHYLMALONIC ACIDURIA, mut(-) TYPE, INCLUDED
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<strong>ORPHA:</strong> 27, 289916, 79312; &nbsp;
<strong>DO:</strong> 0060740; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
6p12.3
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Methylmalonic aciduria, mut(0) type
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251000
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Autosomal recessive
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3
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MMUT
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609058
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because methylmalonic aciduria (MMA) of the complementation group 'mut' (MAMM) is caused by homozygous or compound heterozygous mutation in the gene encoding methylmalonyl-CoA mutase (MUT; 609058) on chromosome 6p12.</p>
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<strong>Description</strong>
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<p>Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group: cblA (251100), caused by mutation in the MMAA gene (607481) on chromosome 4q31, cblB (251110), caused by mutation in the MMAB gene (607568) on 12q24, and cblD (620953), caused by mutation in the MMADHC gene (611935).</p><p>Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (277400), cblD (277410), and cblF (277380).</p><p>See the comprehensive review of Ledley (1990). </p>
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<strong>Clinical Features</strong>
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<p>The clinical spectrum of methylmalonic aciduria is wide, ranging from a benign condition (Ledley et al., 1984) to fatal neonatal disease (Matsui et al., 1983). </p><p>Oberholzer et al. (1967) reported an inborn error of metabolism characterized by methylmalonic aciduria associated with developmental retardation and chronic metabolic acidosis. Treatment with cobalamin was ineffective. Barness and Morrow (1968) noted that some cases of methylmalonic aciduria responded to vitamin B12. Of those not responsive to B12, only a subset had hyperglycinemia. Morrow et al. (1969) provided enzymatic proof of 2 forms of the disease with regard to response to cobalamin treatment: methylmalonyl-CoA mutase activity was essentially absent from the liver in a vitamin B12-unresponsive case, whereas residual enzyme activity increased to normal with added coenzyme in a vitamin B12-responsive case. The latter case was interpreted as having a defect in AdoCbl synthesis. </p><p>Gravel et al. (1975) confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls. </p><p>Willard and Rosenberg (1977) found that the mutase enzyme in cells from some MMA patients showed decreased affinity for AdoCbl with abnormally high Km for the coenzyme. These cases were considered to represent a structurally abnormal enzyme and were characteristic of the mut(-) phenotype. By immunohistochemical analysis of the mutase enzyme, Kolhouse et al. (1981) found that cell lines from mut(-) patients had detectable crossreacting material (CRM) ranging from 20 to 100% of control, whereas cells from mut(0) patients had CRM ranging from no detectable protein to 40% of controls. </p><p>Matsui et al. (1983) collected detailed information on 45 patients with MMA: 15 with mut(0) type, 5 with mut(-), 14 with cblA, and 11 with cblB. The most common presenting symptoms at onset were lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and hypotonia. Other common features included hepatomegaly, developmental delay, and coma. Mut(0) patients presented earlier in infancy than the 3 other groups. All patients had methylmalonic acidemia and normal serum cobalamin, and most had metabolic acidosis, ketonuria, hyperammonemia, and hyperglycinemia. Approximately half of all the patients had pancytopenia. Most cblA and nearly half of cblB patients showed a decrease in urine and blood concentrations of methylmalonic acid in response to vitamin B12 supplementation, whereas none of the mut(0) or mut(-) responded. Most cblA, cblB, and mut(-) patients were still living at the time of the report; most mut(0) patients died during the first few months of life. </p><p>Shevell et al. (1993) compared the clinical features in 11 mut(0) patients with those in 9 mut(-) patients. All 11 mut(0) patients had an early neonatal presentation; 6 of these patients died in infancy and 3 of 5 survivors had a poor neurologic outcome as evidenced by severe developmental delay or spastic quadriparesis with dystonia. The 2 other survivors included a 27-month-old child with mild delay in verbal and fine motor skills and an adolescent with low normal intelligence. Of the 9 mut(-) patients, 7 became symptomatic in late infancy or childhood and 2 were found on screening. No episode of metabolic decompensation had occurred in 2 of the 9, yet both were neurologically compromised, one being severely retarded and autistic and the other mildly delayed. Four mut(-) patients had had episodic acidosis and were neurologically moderately affected, while 3 had had episodic acidosis but were neurologically intact. Although a broad correlation was found between mutase class and phenotype, survival with good outcome was possible among mut(0) patients and, conversely, significant morbidity occurred among mut(-) patients. Acidosis and metabolic imbalance were not necessary preconditions for significant morbidity. van den Bergh et al. (1992) reported sudden death in a child with MMA. </p><p>Giorgio et al. (1976) reported 2 French-Canadian brothers, aged 62 and 70 years, who had a benign form of MMA due to methylmalonyl-CoA mutase deficiency. Neither had anemia or hepatic dysfunction. Serum vitamin B12 was normal and the methylmalonic aciduria was unaffected by administration of vitamin B12 in large dosage. The brothers had presented with adult-onset diabetes mellitus. Ledley et al. (1984) reported a benign form of MMA due to deficiency of methylmalonyl-CoA mutase in 8 children identified through routine neonatal screening or screening of infants with affected sibs. Despite lack of dietary or vitamin therapy, the children had normal growth and development (age range, 18 months to 13 years) and performed as well as their unaffected sibs on psychometric tests. None responded to vitamin B12 treatment and there was no other evidence of a cofactor defect. In 2 sibs, complementation studies showed a defect in the mutase apoenzyme. </p><p>Renal insufficiency is frequently reported in mutase-deficient methylmalonic acidemia. Van Calcar et al. (1998) reported a patient with mut(-) MMA who developed chronic tubulointerstitial nephropathy during adolescence. After 24 years of age, she developed end-stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant. </p><p>In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with branched-chain organic aciduria, including isovaleric aciduria (243500), propionic aciduria (606054), and methylmalonic aciduria can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation. </p><p>Kruszka et al. (2013) studied renal growth in isolated MMA. Fifty patients with MMA (35 mut subtype, 9 cblA subtype, and 6 cblB subtype), followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple regression analyses. Comparisons with age-matched controls showed that renal length in subjects with MMA was significantly decreased (p less than 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C (604312), and serum methylmalonic acid concentrations best predicted kidney size. Kruszka et al. (2013) concluded that renal length, reflective of kidney growth, significantly decreased in patients with MMA over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. </p>
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<strong>Clinical Management</strong>
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<p>Kaplan et al. (2006) reported the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the United States and provided new biochemical data that indicated why transplanted patients remain susceptible to 'metabolic strokes.' In their 10-year-old male patient, there was clear evidence that the de novo synthesis of propionyl-CoA within the central nervous system led to brain methylmalonate accumulation that was largely unaffected by transplantation. Kaplan et al. (2006) concluded that liver transplantation is not a cure for methylmalonic acidopathy. </p><p>Niemi et al. (2015) reported the outcome of 14 MMA patients who underwent liver transplantation (6 patients) or liver-kidney transplantation (8 patients) at a mean age of 8.2 years (range 0.8 to 20.7 years). At mean follow-up of 3.25 years, survival was 100%, liver allograft survival was 93% (1 patient required retransplantation due to hepatic artery thrombosis) and renal allograft survival was 100%. Following transplantation, there were no metabolic decompensations, and neurodevelopmental abilities were maintained or improved. </p>
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<strong>Pathogenesis</strong>
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<p>Using 3D organotypic brain cell cultures derived from embryos of a brain-specific Mut -/- mouse, Remacle et al. (2018) investigated mechanisms leading to brain damage in methylmalonic aciduria. The in vitro model was challenged with the catabolic stress of temperature shift. Remacle et al. (2018) found typical metabolites for methylmalonic aciduria as well as a massive ammonia increase in the media of mutant mouse brain cultures. Investigation of pathways involved in intracerebral ammonia production revealed increased expression of glutaminase-2 (GLS2; 606365) and diminished expression of glutamate dehydrogenase-1 (GLUD1; 138130) in Mut -/- aggregates. Astrocytes showed swollen fibers and cell bodies, and oligodendrocytes showed inhibited axonal elongation and delayed myelination. Most effects were even more pronounced after 48 hours at 39 degrees C. Microglia activation and an increased apoptosis rate suggested degeneration of Mut -/- brain cells. </p>
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<strong>Other Features</strong>
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<p>Because of improvements in therapy, many patients with MMA reach childbearing age. Wasserstein et al. (1999) reported a successful pregnancy and delivery of a healthy baby to a 20-year-old woman with vitamin B12-unresponsive methylmalonic acidemia complicated by moderate renal insufficiency, chronic pancreatitis, anemia, and optic atrophy. Strict metabolic control was maintained throughout her pregnancy. The patient remained clinically asymptomatic during and after delivery, and her metabolic condition remained stable after discharge except for a slight decline in her renal function. </p>
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<strong>Diagnosis</strong>
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<p>Wilkemeyer et al. (1991) showed that the mut and cbl forms of MMA can be differentiated not only by somatic cell complementation but also by DNA-mediated gene transfer of a methylmalonyl CoA mutase cDNA clone. Transfer of the MUT clone into mut fibroblasts reconstituted holoenzyme activity, whereas the same process had no effect on cbl fibroblasts. </p>
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<strong>Cytogenetics</strong>
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<p>Abramowicz et al. (1994) studied a newborn female with a mut(0) form of MMA and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus (IDDM; 222100). The patient died 2 weeks after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal uniparental isodisomy, involving at least a 25-cM portion of chromosome 6 that encompasses the major histocompatibility complex. Duplication of the mutated allele on chromosome 6 inherited from the father was thought to be responsible for methylmalonic acidemia. It was also considered likely that isodisomy was etiologically related to the agenesis of beta cells, and the authors postulated the existence of a gene on chromosome 6 involved in beta-cell differentiation. </p>
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<strong>Molecular Genetics</strong>
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<p>In a patient with MMA mut(0), defined as having no residual enzyme activity, Jansen and Ledley (1990) identified compound heterozygosity for 2 mutations in the MUT gene (609058.0001 and 609058.0002). </p><p>In a patient with MMA mut(-), defined as having some residual enzyme activity, who had been reported by Ledley et al. (1990), Crane et al. (1992) identified a homozygous mutation in the MUT gene (609058.0005). </p><p>Acquaviva et al. (2001) reported a novel MUT missense mutation (609058.0010) in 5 unrelated families of French and Turkish descent from a population of 19 patients with MCM apoenzyme deficiency. All the patients exhibited a severe mut(0) methylmalonic acidemia phenotype, and 3 of them were homozygous for the mutation. The findings represented the first frequent MUT mutation reported in the Caucasian population. </p><p>Champattanachai et al. (2003) reported 2 novel mutations in a Thai patient with mut(0) methylmalonic acidemia. </p>
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<strong>History</strong>
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<p>Hoffman (1991) recounted the story of Patricia Stallings who was sentenced to life in prison for the presumed murder of her infant son with ethylene glycol, an ingredient of antifreeze. While in prison, the woman gave birth to a second son, who was found to have methylmalonic acidemia. William Sly and James Shoemaker at St. Louis University performed analyses of the first son's blood and did not detect ethylene glycol; Piero Rinaldo at Yale University demonstrated the biochemical features of methylmalonic acidemia and found no evidence of ethylene glycol in the body fluids. All charges against Patricia Stallings were dropped. Shoemaker et al. (1992) determined that the gas chromatographic peak that had been identified as ethylene glycol by a clinical laboratory was actually due to propionic acid. Woolf et al. (1992) noted that the opposite situation could occur: intentional infantile ethylene glycol poisoning being misinterpreted as an inborn error of metabolism leading to recurrent infantile metabolic acidosis. </p>
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<strong>See Also:</strong>
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Fowlow et al. (1985); Hsia et al. (1970); Rosenberg et al. (1969);
Rosenberg et al. (1968); Rosenberg et al. (1968); Satoh et al.
(1981); Wilcken et al. (1977)
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<strong>REFERENCES</strong>
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