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Entry
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- #266150 - PYRUVATE CARBOXYLASE DEFICIENCY
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- OMIM
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<p>
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<span class="h4">#266150</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/266150"><strong>Clinical Synopsis</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=PYRUVATE CARBOXYLASE 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>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8026&Typ=Pat" title="Pyruvate carboxylase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pyruvate carboxylase defic… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22134&Typ=Pat" title="Pyruvate carboxylase deficiency, infantile type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pyruvate carboxylase defic… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22135&Typ=Pat" title="Pyruvate carboxylase deficiency, severe neonatal type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pyruvate carboxylase defic… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22136&Typ=Pat" title="Pyruvate carboxylase deficiency, benign type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Pyruvate carboxylase defic… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK6852/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/6120" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/pyruvate-carboxylase-deficiency" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=266150[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimNewbornScreeningFold" id="mimNewbornScreeningToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Information and resources for newborn screening and genetics."><span id="mimNewbornScreeningToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Newborn Screening</div>
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<div id="mimNewbornScreeningFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Citrullinemia.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/Citrulline-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
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</div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3008" title="Pyruvate carboxylase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pyruvate carboxylase defic…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353308" title="Pyruvate carboxylase deficiency, infantile type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pyruvate carboxylase defic…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353314" title="Pyruvate carboxylase deficiency, severe neonatal type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pyruvate carboxylase defic…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353320" title="Pyruvate carboxylase deficiency, benign type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Pyruvate carboxylase defic…</a></div>
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</div>
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</div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:3651" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/266150" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:3651" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:266150" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 87694001<br />
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<strong>ICD10CM:</strong> E74.4<br />
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<strong>ORPHA:</strong> 3008, 353308, 353314, 353320<br />
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<strong>DO:</strong> 3651<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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266150
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
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<span class="mim-font">
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PYRUVATE CARBOXYLASE DEFICIENCY
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
PC DEFICIENCY<br />
|
|
ATAXIA WITH LACTIC ACIDOSIS II<br />
|
|
LEIGH NECROTIZING ENCEPHALOPATHY DUE TO PYRUVATE CARBOXYLASE DEFICIENCY<br />
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LEIGH SYNDROME DUE TO PYRUVATE CARBOXYLASE DEFICIENCY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
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<th>
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|
Phenotype
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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<th>
|
|
Gene/Locus
|
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/649?start=-3&limit=10&highlight=649">
|
|
11q13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Pyruvate carboxylase deficiency
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/266150"> 266150 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
PC
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608786"> 608786 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
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|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/266150" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
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|
|
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|
|
|
|
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|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/266150" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/266150" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
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|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
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|
|
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|
|
<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>
|
|
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|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> 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>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Kidneys </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Renal tubular acidosis, proximal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268435&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268435</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002049" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002049</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002049" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002049</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">
|
|
|
|
- Psychomotor retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398991009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398991009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1144814003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1144814003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424230</a>, <a href="https://bioportal.bioontology.org/search?q=C5441816&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441816</a>]</span><br /> -
|
|
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
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 /> -
|
|
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 /> -
|
|
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
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Clonus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36649002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36649002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009024</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002169" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002169</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002169" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002169</a>]</span><br /> -
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Cystic lesions consistent with Leigh syndrome (<a href="/entry/256000">256000</a>)<br /> -
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Neuronal loss in the cerebral cortex <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849485&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849485</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007190" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007190</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007190" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007190</a>]</span><br /> -
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Poor myelination <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849486&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849486</a>]</span><br /> -
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Periventricular leukomalacia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230769007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230769007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/P91.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">P91.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/779.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">779.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023529&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023529</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006970</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006970</a>]</span><br /> -
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Subcortical leukodystrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3151594&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3151594</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> METABOLIC FEATURES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Lactic acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91273001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91273001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001125&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001125</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003128" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003128</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003128" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003128</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Decreased pyruvate carboxylase (PC) activity (less than 5%) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4025641&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4025641</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003209</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003209</a>]</span><br /> -
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Increased serum lactate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5888306&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5888306</a>, <a href="https://bioportal.bioontology.org/search?q=C1836440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002151</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002151" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002151</a>]</span><br /> -
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Increased serum pyruvate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849488&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849488</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003542" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003542</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003542" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003542</a>]</span><br /> -
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Increased serum alanine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849489&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849489</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003348" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003348</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003348" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003348</a>]</span><br /> -
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Hypoglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237630007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237630007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271327008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271327008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302866003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302866003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1179458001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1179458001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020615</a>, <a href="https://bioportal.bioontology.org/search?q=C5767385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5767385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span><br /> -
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Increased serum ammonia (Group B) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849490&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849490</a>]</span><br /> -
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Increased serum citrulline (Group B) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849491&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849491</a>]</span><br /> -
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Increased serum lysine (Group B) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849492&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849492</a>]</span><br /> -
|
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Intracellular redox disturbance (reduced cytoplasm and oxidized mitochondria (Group B)) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849493&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849493</a>]</span><br /> -
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Increased lactate: pyruvate ratio (Group B) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849494</a>]</span><br /> -
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Increased acetoacetate: beta-hydroxybutyrate ratio (Group B) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849495&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849495</a>]</span><br /> -
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Immunoreactive PC protein <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849496&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849496</a>]</span><br /> -
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Presence of PC mRNA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849497&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849497</a>]</span><br /> -
|
|
A subset of Group B patients have absence of PC protein and mRNA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849498&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849498</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Onset at birth or in early infancy<br /> -
|
|
Some patients may respond to thiamine treatment<br /> -
|
|
Can be categorized into 3 groups<br /> -
|
|
Group A, found in North American Indians, has lactic acidosis and psychomotor retardation<br /> -
|
|
Group A patients die in the first years of life<br /> -
|
|
Group B, found in France and United Kingdom, severe phenotype<br /> -
|
|
Group B patients die by 3 months of age<br /> -
|
|
Group C is relatively benign<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the pyruvate carboxylase gene (PC, <a href="/entry/608786#0001">608786.0001</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because pyruvate carboxylase deficiency is caused by homozygous or compound heterozygous mutation in the pyruvate carboxylase gene (PC; <a href="/entry/608786">608786</a>) on chromosome 11q13.</p>
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<br />
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America ('group A') have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom ('group B') have a more complex biochemical phenotype with increased serum lactate, ammonia, citrulline, and lysine, as well as an intracellular redox disturbance in which the cytosolic compartment is more reduced and the mitochondrial compartment is more oxidized. Patients in group B have decreased survival compared to group A, and usually do not survive beyond 3 months of age (<a href="#21" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Saudubray, J. M., Marsac, C., Bartlett, K., Quan, R., Gravel, R. <strong>The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by (3)H-biotin incorporation, (35)S-streptavidin labeling, and Northern blotting with a cloned cDNA probe.</strong> Am. J. Hum. Genet. 40: 50-59, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3101494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3101494</a>]" pmid="3101494">Robinson et al., 1987</a>). Group C is relatively benign. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3101494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>North American Phenotype ('Group A')</em></strong></p><p>
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<a href="#27" class="mim-tip-reference" title="Tada, K., Yoshida, T., Konno, T., Wada, Y., Yokayama, Y., Arakawa, T. <strong>Hyperalaninemia with pyruvicemia.</strong> Tohoku J. Exp. Med. 97: 99-100, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5771860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5771860</a>] [<a href="https://doi.org/10.1620/tjem.97.99" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5771860">Tada et al. (1969)</a> reported a family in which 2 sisters were presumably affected with the same physical and mental retardation. The proband had elevated serum alanine and pyruvate, normal SGPT and liver pyruvate decarboxylase activities, but decreased activity of pyruvate carboxylase. Hyperalaninemia was likely secondary to the increased level of pyruvate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5771860" 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="Delvin, E., Neal, J. L., Scriver, C. R. <strong>Pyruvate carboxylase: two forms in human liver. (Abstract)</strong> Pediat. Res. 6: 392, 1972."None>Delvin et al. (1972)</a> noted that 2 forms of pyruvate carboxylase exist in liver, one with a high Km and the other with a low Km for pyruvate. They reported a patient with abnormality of gluconeogenesis and elevated plasma levels of pyruvate, lactate, and alanine in which the low Km enzyme was deficient.</p><p><a href="#1" class="mim-tip-reference" title="Atkin, B. M., Buist, N. R., Utter, M. F., Leiter, A. B., Banker, B. Q. <strong>Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease.</strong> Pediat. Res. 13: 109-116, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/219411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">219411</a>] [<a href="https://doi.org/10.1203/00006450-197902000-00005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="219411">Atkin et al. (1979)</a> reported a child with lactic acidosis, severe mental and developmental retardation, and proximal renal acidosis. Laboratory studies showed severe hepatic, renal cortical, and cerebral deficiencies of pyruvate carboxylase activity. Postmortem neuropathologic examination revealed no signs of Leigh syndrome (<a href="/entry/256000">256000</a>), but developmental and degenerative lesions were observed. <a href="#17" class="mim-tip-reference" title="Oizumi, J., Shaw, K. N. F., Giudici, T. A., Carter, M., Donnell, G. N., Ng, W. G. <strong>Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria.</strong> J. Inherit. Metab. Dis. 6: 89-94, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6422151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6422151</a>] [<a href="https://doi.org/10.1007/BF01800731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6422151">Oizumi et al. (1983)</a> reported a patient with PC deficiency associated with renal tubular acidosis and cystinuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6422151+219411" 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="#13" class="mim-tip-reference" title="Haworth, J. C., Robinson, B. H., Perry, T. L. <strong>Lactic acidosis due to pyruvate carboxylase deficiency.</strong> J. Inherit. Metab. Dis. 4: 57-58, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6790846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6790846</a>] [<a href="https://doi.org/10.1007/BF02263589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6790846">Haworth et al. (1981)</a> reported 2 unrelated Canadian Indian infants with PC deficiency. Both presented in infancy with metabolic acidosis. Laboratory findings included increased plasma lactate, pyruvate, glutamic acid, proline, and alanine, and low PC activity in skin fibroblasts and liver. Both survived until at least 2 years of age with severe mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6790846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gilbert, E. F., Arya, S., Chun, R. <strong>Leigh's necrotizing encephalopathy with pyruvate carboxylase deficiency.</strong> Arch. Path. Lab. Med. 107: 162-166, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6402999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6402999</a>]" pmid="6402999">Gilbert et al. (1983)</a> reported an infant with pyruvate carboxylase deficiency. Pathologic studies showed extensive necrotic areas in the brain, which the authors considered to be consistent with Leigh disease (see <a href="/entry/265000">265000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6402999" 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="#6" class="mim-tip-reference" title="Carbone, M. A., MacKay, N., Ling, M., Cole, D. E. C., Douglas, C., Rigat, B., Feigenbaum, A., Clarke, J. T. R., Haworth, J. C., Greenberg, C. R., Seargeant, L., Robinson, B. H. <strong>Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations.</strong> Am. J. Hum. Genet. 62: 1312-1319, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585612</a>] [<a href="https://doi.org/10.1086/301884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585612">Carbone et al. (1998)</a> studied 11 males and 6 females from several Canadian Indian populations. Presentation was at birth in 7, and 1 to 8.5 months in 10. Presenting signs included metabolic acidosis in 10, seizures in 5, respiratory distress in 4, pneumonia in 3, and hypotonia in 3. The clinical course was characterized by frequent lactic acidosis, severe developmental delay, and muscular hypotonia in 17, seizures in 8, hypoglycemia in 4, and other CNS involvement (clonus or athetosis) in 4. Eleven patients died between ages 3 months and 4.75 years; 6 were surviving at ages ranging from 3 months to 19 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>'French form' ('Group B')</em></strong></p><p>
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The second form of PC deficiency, reported particularly from France, presents early with lactic acidosis, but also shows elevated blood levels of ammonia, citrulline, proline, and lysine. In addition, there is an intracellular redox disturbance, with increased lactate/pyruvate and acetoacetate/beta-hydroxybutyrate ratios.</p><p><a href="#25" class="mim-tip-reference" title="Saudubray, J. M., Marsac, C., Charpentier, C., Cathelineau, L., Leaud, M. B., Leroux, J. P. <strong>Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings.</strong> Acta Paediat. Scand. 65: 717-724, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/826106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">826106</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1976.tb18009.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="826106">Saudubray et al. (1976)</a> reported 2 familial cases of neonatal congenital lactic acidosis with liver PC deficiency. Disease onset was immediately after birth, characterized by major neurologic symptoms, hyperammonemia, and hyperketonemia. Hyperlactic acidemia was associated with an increased lactate/pyruvate ratio and an increased acetoacetate/beta-hydroxybutyrate ratio. The authors suggested that the unusual metabolic pattern resulted from decreased oxaloacetate synthesis resulting from PC deficiency and impaired oxaloacetate-dependent mitochondrial redox shuttles. The disease course was rapidly fatal. <a href="#7" class="mim-tip-reference" title="Coude, F. X., Ogier, H., Marsac, C., Munnich, A., Charpentier, C., Saudubray, J. M. <strong>Secondary citrullinemia with hyperammonemia in four neonatal cases of pyruvate carboxylase deficiency. (Letter)</strong> Pediatrics 68: 914 only, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6798542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6798542</a>]" pmid="6798542">Coude et al. (1981)</a> and <a href="#3" class="mim-tip-reference" title="Bartlett, K., Ghneim, H. K., Stirk, J.-H., Dale, G., Alberti, K. G. M. M. <strong>Pyruvate carboxylase deficiency.</strong> J. Inherit. Metab. Dis. 7: 74-78, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6434849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6434849</a>] [<a href="https://doi.org/10.1007/BF03047379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6434849">Bartlett et al. (1984)</a> also reported patients with the group B type of PC deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=826106+6798542+6434849" 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="#22" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Sherwood, W. G., Applegarth, D., Wong, L., Haworth, J., Goodyer, P., Casey, R., Zaleski, L. A. <strong>The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency.</strong> Am. J. Hum. Genet. 36: 283-294, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6424438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6424438</a>]" pmid="6424438">Robinson et al. (1984)</a> reported 8 patients from 7 families from Canada with pyruvate carboxylase deficiency. Five were of full Amerindian descent, 2 were unrelated Caucasians, and 1 was the offspring of related Egyptian parents. All presented from soon after birth to age 5 months with chronic metabolic acidosis, and 4 had at least 1 episode of hypoglycemia. Six patients died by age 2 years (range 10 days to 2 years), and the 2 living patients were mentally and physically retarded. Using (3)H-biotin labeling and (35)S-streptavidin to detect biotin-containing proteins, and immunodetection with PC antibodies, <a href="#22" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Sherwood, W. G., Applegarth, D., Wong, L., Haworth, J., Goodyer, P., Casey, R., Zaleski, L. A. <strong>The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency.</strong> Am. J. Hum. Genet. 36: 283-294, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6424438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6424438</a>]" pmid="6424438">Robinson et al. (1984)</a> distinguished 2 groups of patients: group 'A' synthesized PC subunits with a normal molecular mass and recognized by antibodies against PC, but showed very little enzymatic activity, (termed CRM(+ve) or type I), whereas group 'B' had no detectable PC subunits and no protein recognized by the antibody (termed CRM(-ve), or type II). The 2 patients with CRM(-ve) results, the Egyptian patient and 1 of the Caucasian patients, had additional biochemical features, including hyperammonemia, citrullinemia, lysinemia, and altered redox states (in 1 patient) similar to the features of patients reported in France. These 2 patients also died early (10 days and 7 weeks) and had hepatomegaly due to excessive fat storage. <a href="#22" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Sherwood, W. G., Applegarth, D., Wong, L., Haworth, J., Goodyer, P., Casey, R., Zaleski, L. A. <strong>The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency.</strong> Am. J. Hum. Genet. 36: 283-294, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6424438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6424438</a>]" pmid="6424438">Robinson et al. (1984)</a> concluded that the 2 subtle types of PC deficiency result from 2 different mutations in the PC gene, 1 that synthesizes an inactive protein and 1 that results in lack of protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6424438" 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 follow-up study of cultured skin fibroblasts from 16 patients with either French or American PC deficiency, <a href="#21" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Saudubray, J. M., Marsac, C., Bartlett, K., Quan, R., Gravel, R. <strong>The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by (3)H-biotin incorporation, (35)S-streptavidin labeling, and Northern blotting with a cloned cDNA probe.</strong> Am. J. Hum. Genet. 40: 50-59, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3101494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3101494</a>]" pmid="3101494">Robinson et al. (1987)</a> confirmed that the North American cases are associated with the presence of a mature biotin-containing protein of the correct molecular weight. Three families with the French presentation had absence of immunoreactive PC protein and PC mRNA; however, another 3 families with the French presentation had evidence of protein production as well as PC mRNA. <a href="#21" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Saudubray, J. M., Marsac, C., Bartlett, K., Quan, R., Gravel, R. <strong>The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by (3)H-biotin incorporation, (35)S-streptavidin labeling, and Northern blotting with a cloned cDNA probe.</strong> Am. J. Hum. Genet. 40: 50-59, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3101494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3101494</a>]" pmid="3101494">Robinson et al. (1987)</a> concluded that when a PC enzyme is produced in French cases, it has no activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3101494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Pineda, M., Campistol, J., Vilaseca, M. A., Briones, P., Ribes, A., Temudo, T., Pons, M., Cusi, V., Rolland, M.-O. <strong>An atypical French form of pyruvate carboxylase deficiency.</strong> Brain Dev. 17: 276-279, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7503391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7503391</a>] [<a href="https://doi.org/10.1016/0387-7604(95)00057-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7503391">Pineda et al. (1995)</a> reported an infant with what they termed the 'French' type of pyruvate carboxylase deficiency, with somewhat less severity. The initial neonatal symptoms were respiratory distress, severe metabolic acidosis, and a tendency to hypoglycemia. At age 6 months, he presented with acute neurologic symptoms, lactic acidosis, and hyperammonemia, and died of pneumonia, cardiac failure, and renal insufficiency. Pyruvate carboxylase deficiency was confirmed by enzymatic studies. Postmortem analysis showed periventricular cysts and diffuse hypomyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7503391" 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="Brun, N., Robitaille, Y., Grignon, A., Robinson, B. H., Mitchell, G. A., Lambert, M. <strong>Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form.</strong> Am. J. Med. Genet. 84: 94-101, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323732</a>]" pmid="10323732">Brun et al. (1999)</a> reported brother and sister with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was less than 2% of control. The lesions were detected at a time of maximal periventricular metabolic demand. <a href="#4" class="mim-tip-reference" title="Brun, N., Robitaille, Y., Grignon, A., Robinson, B. H., Mitchell, G. A., Lambert, M. <strong>Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form.</strong> Am. J. Med. Genet. 84: 94-101, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323732</a>]" pmid="10323732">Brun et al. (1999)</a> postulated that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. The authors noted that discovery of cystic periventricular leukomalacia on cerebral ultrasound at birth in a newborn presenting with primary lactic acidemia is highly suggestive of PC deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>'Benign' type ('Group C')</em></strong></p><p>
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<a href="#29" class="mim-tip-reference" title="Van Coster, R. N., Fernhoff, P. M., de Vivo, D. C. <strong>Pyruvate carboxylase deficiency: a benign variant with normal development.</strong> Pediat. Res. 30: 1-4, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1909777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1909777</a>] [<a href="https://doi.org/10.1203/00006450-199107000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1909777">Van Coster et al. (1991)</a> reported a 7-year-old girl with metabolic and biochemical features of the North American type of PC deficiency who had a benign disease course with preservation of motor and mental abilities. She had several episodes of metabolic acidosis with elevated lactate, pyruvate, alanine, beta-hydroxybutyrate, acetoacetate, lysine, and proline values, which were well-managed by rehydration and bicarbonate therapy. PC activity was 1.8% of normal, and she was CRM(+ve). The authors commented on the unique phenotypic expression in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1909777" 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="#26" class="mim-tip-reference" title="Schiff, M., Levrat, V., Acquaviva, C., Vianey-Saban, C., Rolland, M.-O., Guffon, N. <strong>A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation.</strong> Molec. Genet. Metab. 87: 175-177, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16325442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16325442</a>] [<a href="https://doi.org/10.1016/j.ymgme.2005.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16325442">Schiff et al. (2006)</a> reported a patient with atypical PC deficiency and long survival. He presented at 3 days of age with acute ketoacidosis, tachypnea, and hypotonia. Laboratory studies showed lactacidemia with normal plasma amino acids and ammonia. After successful treatment, he was discharged with an increased lactate-to-pyruvate ratio and avoidance of fasting was advised. During the first 2 years of life, he had mild psychomotor delay and failure to thrive with intermittent acute decompensation. PC activity in cultured skin fibroblasts was severely decreased, leading to the correct diagnosis. Brain MRI at age 18 months showed bilateral high signal intensities in frontoparietal subcortical white matter. At the time of the report, he was 9 years old and showed mild and global psychomotor delay with dysarthria and dysgraphia. Treatment included biotin, L-carnitine, sodium bicarbonate, sodium citrate, and avoidance of fasting. <a href="#26" class="mim-tip-reference" title="Schiff, M., Levrat, V., Acquaviva, C., Vianey-Saban, C., Rolland, M.-O., Guffon, N. <strong>A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation.</strong> Molec. Genet. Metab. 87: 175-177, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16325442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16325442</a>] [<a href="https://doi.org/10.1016/j.ymgme.2005.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16325442">Schiff et al. (2006)</a> noted that relatively long survival into childhood is not a frequent finding for this usually very severe disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16325442" 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 href="#28" class="mim-tip-reference" title="Tsuchiyama, A., Oyanagi, K., Hirano, S., Tachi, N., Sogawa, H., Wagatsuma, K., Nakao, T., Tsugawa, S., Kawamura, Y. <strong>A case of pyruvate carboxylase deficiency with later prenatal diagnosis of an unaffected sibling.</strong> J. Inherit. Metab. Dis. 6: 85-88, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6422150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6422150</a>] [<a href="https://doi.org/10.1007/BF01800730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6422150">Tsuchiyama et al. (1983)</a> reported a patient with PC deficiency and PC activity of about 5% of normal. A prenatal diagnosis was performed in the second pregnancy and the PC activities of the cultured amniotic fluid cells obtained by amniocentesis were within normal limits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6422150" 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 family at risk for PC deficiency, <a href="#23" class="mim-tip-reference" title="Robinson, B. H., Toone, J. R., Benedict, R. P., Dimmick, J. E., Oei, J., Applegarth, D. A. <strong>Prenatal diagnosis of pyruvate carboxylase deficiency.</strong> Prenatal Diag. 5: 67-71, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3919380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3919380</a>] [<a href="https://doi.org/10.1002/pd.1970050112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3919380">Robinson et al. (1985)</a> confirmed the diagnosis in a fetus by enzyme assay and (3)H-biotin labeling of proteins in cultured fetal skin fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3919380" 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="Delvin, E., Scriver, C. R., Gagnan-Brunette, M., Hazel, B. <strong>Mechanism for thiamine responsiveness in pyruvic acidemia due to pyruvate carboxylase deficiency: a proposal. (Abstract)</strong> Proc. Canad. Fed. Biol. Sci. 14: 168, 1971."None>Delvin et al. (1971)</a> found responsiveness to thiamine administration in a patient with PC deficiency. As thiamine pyrophosphate is the coenzyme for pyruvate dehydrogenase, a key enzyme for an alternate route of pyruvate metabolism, the authors suggested that thiamine restored pyruvate metabolism by facilitating an alternative mechanism for its oxidation.</p><p><a href="#15" class="mim-tip-reference" title="Maesaka, H., Komiya, K., Misugi, K., Tada, K. <strong>Hyperalaninemia, hyperpyruvicemia and lactic acidosis due to pyruvate carboxylase deficiency of the liver; treatment with thiamine and lipoic acid.</strong> Europ. J. Pediat. 122: 159-168, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/817914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">817914</a>] [<a href="https://doi.org/10.1007/BF00466274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="817914">Maesaka et al. (1976)</a> described 2 sisters with pyruvate carboxylase deficiency, severe mental and motor retardation, and Leigh syndrome. The proband had lactic acidosis, low CSF glucose, hyperalaninemia, and increased urinary lactate, pyruvate, and alanine. Both sibs improved clinically and biochemically after treatment with thiamine and lipoic acid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=817914" 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 PC deficiency associated with renal tubular acidosis and cystinuria, <a href="#17" class="mim-tip-reference" title="Oizumi, J., Shaw, K. N. F., Giudici, T. A., Carter, M., Donnell, G. N., Ng, W. G. <strong>Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria.</strong> J. Inherit. Metab. Dis. 6: 89-94, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6422151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6422151</a>] [<a href="https://doi.org/10.1007/BF01800731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6422151">Oizumi et al. (1983)</a> reported successful treatment with dietary supplement of aspartic acid, asparagine, glutamic acid, and glutamine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6422151" 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="Lasio, M. L. D., Leshinski, A. C., Ducich, N. H., Flore, L. A., Lehman, A., Shur, N., Jayakar, P. B., Hainline, B. E., Basinger, A. A., Wilson, W. G., Diaz, G. A., Erbe, R. W., Koeberl, D. D., Vockley, J., Bedoyan, J. K. <strong>Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.</strong> Molec. Genet. Metab. 139: 107605, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37207470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37207470</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37207470">Lasio et al. (2023)</a> reported safety and efficacy in 11 patients with PC deficiency treated with triheptanoin on an open-label compassionate use protocol. Patients received triheptanoin for a range of 6 days to 7 years. Scores on the Pediatric Quality of Life Inventory were analyzed for 7 of the patients; with treatment, 2 patients had worse scores, 3 patients had stable scores, and 2 patients had improved scores. Blood lactate levels were not significantly improved in the cohort, although a trend towards lactate improvement was observed in selected patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37207470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 11 Ojibwa and 2 Cree patients with type A pyruvate carboxylase deficiency, <a href="#6" class="mim-tip-reference" title="Carbone, M. A., MacKay, N., Ling, M., Cole, D. E. C., Douglas, C., Rigat, B., Feigenbaum, A., Clarke, J. T. R., Haworth, J. C., Greenberg, C. R., Seargeant, L., Robinson, B. H. <strong>Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations.</strong> Am. J. Hum. Genet. 62: 1312-1319, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585612</a>] [<a href="https://doi.org/10.1086/301884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585612">Carbone et al. (1998)</a> identified a missense mutation in the PC gene (<a href="/entry/608786#0001">608786.0001</a>). Two brothers of Micmac origin had a transversion mutation in the PC gene (<a href="/entry/608786#0002">608786.0002</a>). Carrier frequency was estimated to be as high as 1 in 10 in some groupings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585612" 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 2 brothers with type B PC deficiency, <a href="#5" class="mim-tip-reference" title="Carbone, M. A., Applegarth, D. A., Robinson, B. H. <strong>Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings.</strong> Hum. Mutat. 20: 48-56, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112657</a>] [<a href="https://doi.org/10.1002/humu.10093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112657">Carbone et al. (2002)</a> identified compound heterozygosity for 2 mutations in the PC gene (<a href="/entry/608786#0005">608786.0005</a>; <a href="/entry/608786#0006">608786.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Monnot, S., Serre, V., Chadefaux-Vekemans, B., Aupetit, J., Romano, S., De Lonlay, P., Rival, J.-M., Munnich, A., Steffann, J., Bonnefont, J.-P. <strong>Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency.</strong> Hum. Mutat. 30: 734-740, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19306334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19306334</a>] [<a href="https://doi.org/10.1002/humu.20908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19306334">Monnot et al. (2009)</a> identified 9 novel mutations in the PC gene (see, e.g., <a href="/entry/608786#0007">608786.0007</a>-<a href="/entry/608786#0009">608786.0009</a>) in 5 unrelated patients with PC deficiency: 3 had the more severe type B PC, and 2 had type A. PC activity in cultured fibroblasts was undetectable in all patients. Three mutations were frameshift, predicted to introduce a premature termination codon, 1 was an in-frame deletion, and 5 were missense substitutions. Although most PC mutations were suggested to interfere with biotin metabolism, none of the patients was biotin-responsive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19306334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 5 patients with PC, <a href="#16" class="mim-tip-reference" title="Monnot, S., Serre, V., Chadefaux-Vekemans, B., Aupetit, J., Romano, S., De Lonlay, P., Rival, J.-M., Munnich, A., Steffann, J., Bonnefont, J.-P. <strong>Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency.</strong> Hum. Mutat. 30: 734-740, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19306334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19306334</a>] [<a href="https://doi.org/10.1002/humu.20908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19306334">Monnot et al. (2009)</a> noted that type B was consistently associated with at least 1 truncating mutation, whereas type A always resulted from 2 missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19306334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Carbone, M. A., MacKay, N., Ling, M., Cole, D. E. C., Douglas, C., Rigat, B., Feigenbaum, A., Clarke, J. T. R., Haworth, J. C., Greenberg, C. R., Seargeant, L., Robinson, B. H. <strong>Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations.</strong> Am. J. Hum. Genet. 62: 1312-1319, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585612</a>] [<a href="https://doi.org/10.1086/301884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585612">Carbone et al. (1998)</a> noted that the Canadian Indian population had been strongly represented in their study of CRM(+ve) PC deficiency, there being cases in the Micmac, Cree, and Ojibwa. This common linguistic group was derived from a founder group in southern Ontario approximately 300 B.C. It had been suggested that there could be one or more disease-causing mutations in the PC gene that are unique to the 'Algonkian-speaking peoples' of North America. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585612" 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>REFERENCES</strong>
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Atkin, B. M.
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[<a href="https://doi.org/10.1203/00006450-197910000-00003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF03047379" target="_blank">Full Text</a>]
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Carbone, M. A., Applegarth, D. A., Robinson, B. H.
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[<a href="https://doi.org/10.1002/humu.10093" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301884" target="_blank">Full Text</a>]
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<a id="Coude1981" class="mim-anchor"></a>
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<div class="">
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<a id="Delvin1971" class="mim-anchor"></a>
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Delvin, E., Scriver, C. R., Gagnan-Brunette, M., Hazel, B.
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<a id="Freytag1984" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Freytag, S. O., Ledbetter, D. H., Collier, K., Gage, P.
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<strong>Cloning of the human pyruvate carboxylase gene. (Abstract)</strong>
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Fed. Proc. 43: 1726, 1984.
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[<a href="https://doi.org/10.1007/BF02263589" target="_blank">Full Text</a>]
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Lasio, M. L. D., Leshinski, A. C., Ducich, N. H., Flore, L. A., Lehman, A., Shur, N., Jayakar, P. B., Hainline, B. E., Basinger, A. A., Wilson, W. G., Diaz, G. A., Erbe, R. W., Koeberl, D. D., Vockley, J., Bedoyan, J. K.
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<strong>Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.</strong>
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[<a href="https://doi.org/10.1016/j.ymgme.2023.107605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00466274" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20908" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6422151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6422151</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6422151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01800731" target="_blank">Full Text</a>]
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<a id="Perucca-Lostanlen1997" class="mim-anchor"></a>
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Perucca-Lostanlen, D., Hecht, B. K., Courseaux, A., Grosgeorge, J., Hecht, F., Gaudray, P.
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<strong>Mapping FRA11A, a folate-sensitive fragile site in human chromosome band 11q13.3.</strong>
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[<a href="https://doi.org/10.1159/000134689" target="_blank">Full Text</a>]
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<a id="Pineda1995" class="mim-anchor"></a>
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Pineda, M., Campistol, J., Vilaseca, M. A., Briones, P., Ribes, A., Temudo, T., Pons, M., Cusi, V., Rolland, M.-O.
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<strong>An atypical French form of pyruvate carboxylase deficiency.</strong>
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Brain Dev. 17: 276-279, 1995.
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[<a href="https://doi.org/10.1016/0387-7604(95)00057-i" target="_blank">Full Text</a>]
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<a id="Pollock1986" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pollock, M. A., Cumberbatch, M., Bennett, M. J., Gray, R. G. F., Brand, M., Hyland, K., Congdon, P. J., Pitts-Tucker, T., Gray, S.
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<strong>Pyruvate carboxylase deficiency in twins.</strong>
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J. Inherit. Metab. Dis. 9: 29-30, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3088322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3088322</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3088322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01813898" target="_blank">Full Text</a>]
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<a id="Robinson1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Robinson, B. H., Oei, J., Saudubray, J. M., Marsac, C., Bartlett, K., Quan, R., Gravel, R.
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<strong>The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by (3)H-biotin incorporation, (35)S-streptavidin labeling, and Northern blotting with a cloned cDNA probe.</strong>
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Am. J. Hum. Genet. 40: 50-59, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3101494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3101494</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3101494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Robinson1984" class="mim-anchor"></a>
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Robinson, B. H., Oei, J., Sherwood, W. G., Applegarth, D., Wong, L., Haworth, J., Goodyer, P., Casey, R., Zaleski, L. A.
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<strong>The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency.</strong>
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Am. J. Hum. Genet. 36: 283-294, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6424438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6424438</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6424438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Robinson, B. H., Toone, J. R., Benedict, R. P., Dimmick, J. E., Oei, J., Applegarth, D. A.
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<strong>Prenatal diagnosis of pyruvate carboxylase deficiency.</strong>
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Prenatal Diag. 5: 67-71, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3919380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3919380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3919380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/pd.1970050112" target="_blank">Full Text</a>]
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<a id="Rochelle1992" class="mim-anchor"></a>
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Rochelle, J. M., Watson, M. L., Oakey, R. J., Seldin, M. F.
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<strong>A linkage map of mouse chromosome 19: definition of comparative mapping relationships with human chromosomes 10 and 11 including the MEN1 locus.</strong>
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Genomics 14: 26-31, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1358795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1358795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1358795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0888-7543(05)80278-2" target="_blank">Full Text</a>]
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<a id="Saudubray1976" class="mim-anchor"></a>
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Saudubray, J. M., Marsac, C., Charpentier, C., Cathelineau, L., Leaud, M. B., Leroux, J. P.
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<strong>Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings.</strong>
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Acta Paediat. Scand. 65: 717-724, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/826106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">826106</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=826106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1651-2227.1976.tb18009.x" target="_blank">Full Text</a>]
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<a id="Schiff2006" class="mim-anchor"></a>
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Schiff, M., Levrat, V., Acquaviva, C., Vianey-Saban, C., Rolland, M.-O., Guffon, N.
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<strong>A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation.</strong>
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Molec. Genet. Metab. 87: 175-177, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16325442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16325442</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16325442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2005.10.007" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
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<a id="Tada1969" class="mim-anchor"></a>
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<div class="">
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Tada, K., Yoshida, T., Konno, T., Wada, Y., Yokayama, Y., Arakawa, T.
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<strong>Hyperalaninemia with pyruvicemia.</strong>
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Tohoku J. Exp. Med. 97: 99-100, 1969.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5771860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5771860</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5771860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1620/tjem.97.99" target="_blank">Full Text</a>]
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Tsuchiyama, A., Oyanagi, K., Hirano, S., Tachi, N., Sogawa, H., Wagatsuma, K., Nakao, T., Tsugawa, S., Kawamura, Y.
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<strong>A case of pyruvate carboxylase deficiency with later prenatal diagnosis of an unaffected sibling.</strong>
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J. Inherit. Metab. Dis. 6: 85-88, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6422150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6422150</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6422150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01800730" target="_blank">Full Text</a>]
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Van Coster, R. N., Fernhoff, P. M., de Vivo, D. C.
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<strong>Pyruvate carboxylase deficiency: a benign variant with normal development.</strong>
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Pediat. Res. 30: 1-4, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1909777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1909777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1909777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1203/00006450-199107000-00001" target="_blank">Full Text</a>]
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Walker, M. E., Baker, E., Wallace, J. C., Sutherland, G. R.
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<strong>Assignment of the human pyruvate carboxylase gene (PC) to 11q13.4 by fluorescence in situ hybridisation.</strong>
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Cytogenet. Cell Genet. 69: 187-189, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698008</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7698008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000133958" target="_blank">Full Text</a>]
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Wexler, I. D., Kerr, D. S., Du, Y., Kaung, M. M., Stephenson, W., Lusk, M. M., Wappner, R. S., Higgins, J. J.
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<strong>Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families.</strong>
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Pediat. Res. 43: 579-584, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1203/00006450-199805000-00004" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/17/2023
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Cassandra L. Kniffin - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - reorganized : 7/13/2004<br>Cassandra L. Kniffin - updated : 7/12/2004<br>Victor A. McKusick - updated : 8/27/2002<br>Victor A. McKusick - updated : 5/10/1999<br>Victor A. McKusick - updated : 2/2/1999<br>Victor A. McKusick - updated : 6/23/1998<br>Victor A. McKusick - updated : 4/24/1998<br>Orest Hurko - updated : 4/1/1996
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Victor A. McKusick : 6/4/1986
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carol : 02/09/2021<br>carol : 10/29/2018<br>joanna : 07/19/2014<br>wwang : 3/3/2010<br>wwang : 2/15/2010<br>ckniffin : 1/4/2010<br>wwang : 9/4/2009<br>ckniffin : 8/18/2009<br>terry : 3/22/2006<br>terry : 4/6/2005<br>terry : 4/6/2005<br>ckniffin : 8/19/2004<br>carol : 7/13/2004<br>ckniffin : 7/12/2004<br>alopez : 3/17/2004<br>tkritzer : 9/10/2002<br>tkritzer : 8/29/2002<br>terry : 8/27/2002<br>alopez : 2/23/2000<br>carol : 9/8/1999<br>mgross : 5/13/1999<br>mgross : 5/12/1999<br>terry : 5/10/1999<br>carol : 2/15/1999<br>terry : 2/2/1999<br>carol : 6/25/1998<br>terry : 6/23/1998<br>terry : 4/24/1998<br>terry : 4/15/1996<br>terry : 4/1/1996<br>terry : 3/22/1996<br>mark : 6/27/1995<br>warfield : 4/20/1994<br>mimadm : 3/12/1994<br>carol : 9/22/1992<br>supermim : 3/17/1992<br>carol : 2/11/1992
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<span class="mim-font">
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<strong>#</strong> 266150
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</h3>
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<h3>
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PYRUVATE CARBOXYLASE DEFICIENCY
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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PC DEFICIENCY<br />
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ATAXIA WITH LACTIC ACIDOSIS II<br />
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LEIGH NECROTIZING ENCEPHALOPATHY DUE TO PYRUVATE CARBOXYLASE DEFICIENCY<br />
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LEIGH SYNDROME DUE TO PYRUVATE CARBOXYLASE DEFICIENCY
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<strong>SNOMEDCT:</strong> 87694001;
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<strong>ICD10CM:</strong> E74.4;
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<strong>ORPHA:</strong> 3008, 353308, 353314, 353320;
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<strong>DO:</strong> 3651;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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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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<tbody>
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<span class="mim-font">
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11q13.2
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<span class="mim-font">
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Pyruvate carboxylase deficiency
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<span class="mim-font">
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266150
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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PC
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<span class="mim-font">
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608786
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because pyruvate carboxylase deficiency is caused by homozygous or compound heterozygous mutation in the pyruvate carboxylase gene (PC; 608786) on chromosome 11q13.</p>
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<strong>Clinical Features</strong>
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<p>PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America ('group A') have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom ('group B') have a more complex biochemical phenotype with increased serum lactate, ammonia, citrulline, and lysine, as well as an intracellular redox disturbance in which the cytosolic compartment is more reduced and the mitochondrial compartment is more oxidized. Patients in group B have decreased survival compared to group A, and usually do not survive beyond 3 months of age (Robinson et al., 1987). Group C is relatively benign. </p><p><strong><em>North American Phenotype ('Group A')</em></strong></p><p>
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Tada et al. (1969) reported a family in which 2 sisters were presumably affected with the same physical and mental retardation. The proband had elevated serum alanine and pyruvate, normal SGPT and liver pyruvate decarboxylase activities, but decreased activity of pyruvate carboxylase. Hyperalaninemia was likely secondary to the increased level of pyruvate. </p><p>Delvin et al. (1972) noted that 2 forms of pyruvate carboxylase exist in liver, one with a high Km and the other with a low Km for pyruvate. They reported a patient with abnormality of gluconeogenesis and elevated plasma levels of pyruvate, lactate, and alanine in which the low Km enzyme was deficient.</p><p>Atkin et al. (1979) reported a child with lactic acidosis, severe mental and developmental retardation, and proximal renal acidosis. Laboratory studies showed severe hepatic, renal cortical, and cerebral deficiencies of pyruvate carboxylase activity. Postmortem neuropathologic examination revealed no signs of Leigh syndrome (256000), but developmental and degenerative lesions were observed. Oizumi et al. (1983) reported a patient with PC deficiency associated with renal tubular acidosis and cystinuria. </p><p>Haworth et al. (1981) reported 2 unrelated Canadian Indian infants with PC deficiency. Both presented in infancy with metabolic acidosis. Laboratory findings included increased plasma lactate, pyruvate, glutamic acid, proline, and alanine, and low PC activity in skin fibroblasts and liver. Both survived until at least 2 years of age with severe mental retardation. </p><p>Gilbert et al. (1983) reported an infant with pyruvate carboxylase deficiency. Pathologic studies showed extensive necrotic areas in the brain, which the authors considered to be consistent with Leigh disease (see 265000). </p><p>Carbone et al. (1998) studied 11 males and 6 females from several Canadian Indian populations. Presentation was at birth in 7, and 1 to 8.5 months in 10. Presenting signs included metabolic acidosis in 10, seizures in 5, respiratory distress in 4, pneumonia in 3, and hypotonia in 3. The clinical course was characterized by frequent lactic acidosis, severe developmental delay, and muscular hypotonia in 17, seizures in 8, hypoglycemia in 4, and other CNS involvement (clonus or athetosis) in 4. Eleven patients died between ages 3 months and 4.75 years; 6 were surviving at ages ranging from 3 months to 19 years. </p><p><strong><em>'French form' ('Group B')</em></strong></p><p>
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The second form of PC deficiency, reported particularly from France, presents early with lactic acidosis, but also shows elevated blood levels of ammonia, citrulline, proline, and lysine. In addition, there is an intracellular redox disturbance, with increased lactate/pyruvate and acetoacetate/beta-hydroxybutyrate ratios.</p><p>Saudubray et al. (1976) reported 2 familial cases of neonatal congenital lactic acidosis with liver PC deficiency. Disease onset was immediately after birth, characterized by major neurologic symptoms, hyperammonemia, and hyperketonemia. Hyperlactic acidemia was associated with an increased lactate/pyruvate ratio and an increased acetoacetate/beta-hydroxybutyrate ratio. The authors suggested that the unusual metabolic pattern resulted from decreased oxaloacetate synthesis resulting from PC deficiency and impaired oxaloacetate-dependent mitochondrial redox shuttles. The disease course was rapidly fatal. Coude et al. (1981) and Bartlett et al. (1984) also reported patients with the group B type of PC deficiency. </p><p>Robinson et al. (1984) reported 8 patients from 7 families from Canada with pyruvate carboxylase deficiency. Five were of full Amerindian descent, 2 were unrelated Caucasians, and 1 was the offspring of related Egyptian parents. All presented from soon after birth to age 5 months with chronic metabolic acidosis, and 4 had at least 1 episode of hypoglycemia. Six patients died by age 2 years (range 10 days to 2 years), and the 2 living patients were mentally and physically retarded. Using (3)H-biotin labeling and (35)S-streptavidin to detect biotin-containing proteins, and immunodetection with PC antibodies, Robinson et al. (1984) distinguished 2 groups of patients: group 'A' synthesized PC subunits with a normal molecular mass and recognized by antibodies against PC, but showed very little enzymatic activity, (termed CRM(+ve) or type I), whereas group 'B' had no detectable PC subunits and no protein recognized by the antibody (termed CRM(-ve), or type II). The 2 patients with CRM(-ve) results, the Egyptian patient and 1 of the Caucasian patients, had additional biochemical features, including hyperammonemia, citrullinemia, lysinemia, and altered redox states (in 1 patient) similar to the features of patients reported in France. These 2 patients also died early (10 days and 7 weeks) and had hepatomegaly due to excessive fat storage. Robinson et al. (1984) concluded that the 2 subtle types of PC deficiency result from 2 different mutations in the PC gene, 1 that synthesizes an inactive protein and 1 that results in lack of protein expression. </p><p>In a follow-up study of cultured skin fibroblasts from 16 patients with either French or American PC deficiency, Robinson et al. (1987) confirmed that the North American cases are associated with the presence of a mature biotin-containing protein of the correct molecular weight. Three families with the French presentation had absence of immunoreactive PC protein and PC mRNA; however, another 3 families with the French presentation had evidence of protein production as well as PC mRNA. Robinson et al. (1987) concluded that when a PC enzyme is produced in French cases, it has no activity. </p><p>Pineda et al. (1995) reported an infant with what they termed the 'French' type of pyruvate carboxylase deficiency, with somewhat less severity. The initial neonatal symptoms were respiratory distress, severe metabolic acidosis, and a tendency to hypoglycemia. At age 6 months, he presented with acute neurologic symptoms, lactic acidosis, and hyperammonemia, and died of pneumonia, cardiac failure, and renal insufficiency. Pyruvate carboxylase deficiency was confirmed by enzymatic studies. Postmortem analysis showed periventricular cysts and diffuse hypomyelination. </p><p>Brun et al. (1999) reported brother and sister with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was less than 2% of control. The lesions were detected at a time of maximal periventricular metabolic demand. Brun et al. (1999) postulated that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. The authors noted that discovery of cystic periventricular leukomalacia on cerebral ultrasound at birth in a newborn presenting with primary lactic acidemia is highly suggestive of PC deficiency. </p><p><strong><em>'Benign' type ('Group C')</em></strong></p><p>
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Van Coster et al. (1991) reported a 7-year-old girl with metabolic and biochemical features of the North American type of PC deficiency who had a benign disease course with preservation of motor and mental abilities. She had several episodes of metabolic acidosis with elevated lactate, pyruvate, alanine, beta-hydroxybutyrate, acetoacetate, lysine, and proline values, which were well-managed by rehydration and bicarbonate therapy. PC activity was 1.8% of normal, and she was CRM(+ve). The authors commented on the unique phenotypic expression in this patient. </p><p>Schiff et al. (2006) reported a patient with atypical PC deficiency and long survival. He presented at 3 days of age with acute ketoacidosis, tachypnea, and hypotonia. Laboratory studies showed lactacidemia with normal plasma amino acids and ammonia. After successful treatment, he was discharged with an increased lactate-to-pyruvate ratio and avoidance of fasting was advised. During the first 2 years of life, he had mild psychomotor delay and failure to thrive with intermittent acute decompensation. PC activity in cultured skin fibroblasts was severely decreased, leading to the correct diagnosis. Brain MRI at age 18 months showed bilateral high signal intensities in frontoparietal subcortical white matter. At the time of the report, he was 9 years old and showed mild and global psychomotor delay with dysarthria and dysgraphia. Treatment included biotin, L-carnitine, sodium bicarbonate, sodium citrate, and avoidance of fasting. Schiff et al. (2006) noted that relatively long survival into childhood is not a frequent finding for this usually very severe disease. </p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Tsuchiyama et al. (1983) reported a patient with PC deficiency and PC activity of about 5% of normal. A prenatal diagnosis was performed in the second pregnancy and the PC activities of the cultured amniotic fluid cells obtained by amniocentesis were within normal limits. </p><p>In a family at risk for PC deficiency, Robinson et al. (1985) confirmed the diagnosis in a fetus by enzyme assay and (3)H-biotin labeling of proteins in cultured fetal skin fibroblasts. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Delvin et al. (1971) found responsiveness to thiamine administration in a patient with PC deficiency. As thiamine pyrophosphate is the coenzyme for pyruvate dehydrogenase, a key enzyme for an alternate route of pyruvate metabolism, the authors suggested that thiamine restored pyruvate metabolism by facilitating an alternative mechanism for its oxidation.</p><p>Maesaka et al. (1976) described 2 sisters with pyruvate carboxylase deficiency, severe mental and motor retardation, and Leigh syndrome. The proband had lactic acidosis, low CSF glucose, hyperalaninemia, and increased urinary lactate, pyruvate, and alanine. Both sibs improved clinically and biochemically after treatment with thiamine and lipoic acid. </p><p>In a patient with PC deficiency associated with renal tubular acidosis and cystinuria, Oizumi et al. (1983) reported successful treatment with dietary supplement of aspartic acid, asparagine, glutamic acid, and glutamine. </p><p>Lasio et al. (2023) reported safety and efficacy in 11 patients with PC deficiency treated with triheptanoin on an open-label compassionate use protocol. Patients received triheptanoin for a range of 6 days to 7 years. Scores on the Pediatric Quality of Life Inventory were analyzed for 7 of the patients; with treatment, 2 patients had worse scores, 3 patients had stable scores, and 2 patients had improved scores. Blood lactate levels were not significantly improved in the cohort, although a trend towards lactate improvement was observed in selected patients. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 11 Ojibwa and 2 Cree patients with type A pyruvate carboxylase deficiency, Carbone et al. (1998) identified a missense mutation in the PC gene (608786.0001). Two brothers of Micmac origin had a transversion mutation in the PC gene (608786.0002). Carrier frequency was estimated to be as high as 1 in 10 in some groupings. </p><p>In 2 brothers with type B PC deficiency, Carbone et al. (2002) identified compound heterozygosity for 2 mutations in the PC gene (608786.0005; 608786.0006). </p><p>Monnot et al. (2009) identified 9 novel mutations in the PC gene (see, e.g., 608786.0007-608786.0009) in 5 unrelated patients with PC deficiency: 3 had the more severe type B PC, and 2 had type A. PC activity in cultured fibroblasts was undetectable in all patients. Three mutations were frameshift, predicted to introduce a premature termination codon, 1 was an in-frame deletion, and 5 were missense substitutions. Although most PC mutations were suggested to interfere with biotin metabolism, none of the patients was biotin-responsive. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 5 patients with PC, Monnot et al. (2009) noted that type B was consistently associated with at least 1 truncating mutation, whereas type A always resulted from 2 missense mutations. </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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<span class="mim-text-font">
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<p>Carbone et al. (1998) noted that the Canadian Indian population had been strongly represented in their study of CRM(+ve) PC deficiency, there being cases in the Micmac, Cree, and Ojibwa. This common linguistic group was derived from a founder group in southern Ontario approximately 300 B.C. It had been suggested that there could be one or more disease-causing mutations in the PC gene that are unique to the 'Algonkian-speaking peoples' of North America. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Atkin (1979); Freytag and Collier (1984); Freytag et al. (1984);
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Perucca-Lostanlen et al. (1997); Pollock et al. (1986); Rochelle et
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al. (1992); Walker et al. (1995); Wexler et al. (1998)
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Atkin, B. M., Buist, N. R., Utter, M. F., Leiter, A. B., Banker, B. Q.
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<strong>Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease.</strong>
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Pediat. Res. 13: 109-116, 1979.
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[PubMed: 219411]
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[Full Text: https://doi.org/10.1203/00006450-197902000-00005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Atkin, B. M.
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<strong>Carrier detection of pyruvate carboxylase deficiency in fibroblasts and lymphocytes.</strong>
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Pediat. Res. 13: 1101-1104, 1979.
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[PubMed: 116187]
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[Full Text: https://doi.org/10.1203/00006450-197910000-00003]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bartlett, K., Ghneim, H. K., Stirk, J.-H., Dale, G., Alberti, K. G. M. M.
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<strong>Pyruvate carboxylase deficiency.</strong>
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Hilary J. Vernon - updated : 08/17/2023<br>Cassandra L. Kniffin - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - reorganized : 7/13/2004<br>Cassandra L. Kniffin - updated : 7/12/2004<br>Victor A. McKusick - updated : 8/27/2002<br>Victor A. McKusick - updated : 5/10/1999<br>Victor A. McKusick - updated : 2/2/1999<br>Victor A. McKusick - updated : 6/23/1998<br>Victor A. McKusick - updated : 4/24/1998<br>Orest Hurko - updated : 4/1/1996
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Victor A. McKusick : 6/4/1986
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