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<title>
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Entry
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- #246450 - 3-HYDROXY-3-METHYLGLUTARYL-CoA LYASE DEFICIENCY; HMGCLD
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- OMIM
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<span class="h4">#246450</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/246450"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3296&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/3440" 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/3-hydroxy-3-methylglutaryl-coa-lyase-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=246450[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/C5-OH.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/C5-OH-Elevated.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="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=20" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0070541" 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/246450" 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://omia.org/OMIA002454/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0070541" 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>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:246450" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 124611007<br />
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<strong>ORPHA:</strong> 20<br />
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<strong>DO:</strong> 0070541<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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246450
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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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|
|
3-HYDROXY-3-METHYLGLUTARYL-CoA LYASE DEFICIENCY; HMGCLD
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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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HMG-CoA LYASE DEFICIENCY<br />
|
|
HMGCL DEFICIENCY<br />
|
|
HL DEFICIENCY<br />
|
|
HYDROXYMETHYLGLUTARIC ACIDURIA
|
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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>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</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>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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<th>
|
|
Gene/Locus
|
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
|
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</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/280?start=-3&limit=10&highlight=280">
|
|
1p36.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HMG-CoA lyase deficiency
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/246450"> 246450 </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>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
HMGCL
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613898"> 613898 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
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|
|
</tbody>
|
|
</table>
|
|
</div>
|
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</div>
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<div>
|
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|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/246450" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
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|
<div class="btn-group">
|
|
<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/246450" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/246450" 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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<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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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Microcephaly (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Tachydyspnea <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538613&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538613</a>]</span><br /> -
|
|
Kussmal breathing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538614&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538614</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Recurrent vomiting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0750325&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750325</a>]</span><br /> -
|
|
Refusal of nutrition <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538611</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Paleness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398979000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398979000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R23.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R23.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/782.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">782.61</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241137</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000980" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000980</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000980" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000980</a>]</span><br />
|
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</span>
|
|
</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>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<span class="mim-font">
|
|
|
|
- Muscular 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> 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> <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 />
|
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- 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 /> -
|
|
Myoclonus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17450006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17450006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/333.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">333.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027066&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027066</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span><br /> -
|
|
Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
|
|
Coma (uncommon) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371632003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371632003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405809000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405809000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0543874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0543874</a>, <a href="https://bioportal.bioontology.org/search?q=C3146279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3146279</a>, <a href="https://bioportal.bioontology.org/search?q=C0009421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009421</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001259</a>]</span><br /> -
|
|
Abnormal MRI <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/169083003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">169083003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0436540&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0436540</a>]</span><br /> -
|
|
White matter abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0948163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0948163</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002500" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002500</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002500" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002500</a>]</span><br /> -
|
|
Abnormalities of the basal ganglia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4520981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4520981</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002134" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002134</a>]</span><br /> -
|
|
Abnormal EEG <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/274521009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">274521009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R94.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R94.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151611</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002353" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002353</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002353" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002353</a>]</span><br /> -
|
|
Psychomotor retardation, mild to severe (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538609&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538609</a>]</span> <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><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Apathy/lethargy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538610&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538610</a>]</span><br /> -
|
|
Somnolence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271782001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271782001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79519003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79519003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R40.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R40.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013144</a>, <a href="https://bioportal.bioontology.org/search?q=C2830004&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2830004</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002329" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002329</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002329" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002329</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Metabolic acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59455009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59455009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220981</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001942</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001942</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271737000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271737000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D64.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D64.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/285.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">285.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002871</a>, <a href="https://bioportal.bioontology.org/search?q=C1000483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1000483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span><br /> -
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Decreased prothrombin time <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165569003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165569003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0580413&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0580413</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032198</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032198" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032198</a>]</span><br />
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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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- Acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/51387008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">51387008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.2</a>, <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">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/276.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">276.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001122&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001122</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001941" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001941</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001941" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001941</a>]</span><br /> -
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Hyperammonemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/9360008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">9360008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5574662&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5574662</a>, <a href="https://bioportal.bioontology.org/search?q=C0220994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220994</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001987" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001987</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001987" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001987</a>]</span><br /> -
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Increased anion gap <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237854004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237854004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342592&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342592</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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Hyperuricemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35885006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35885006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0740394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0740394</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002149" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002149</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002149" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002149</a>]</span><br /> -
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Elevated transaminase activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538612&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538612</a>]</span><br /> -
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Elevated lactate level <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4054756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4054756</a>]</span><br />
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</span>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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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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- Triggers for acute decompensation include infections, vaccinations, and dietary changes<br /> -
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Sensitivity to dietary leucine<br /> -
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Variable features present during metabolic decompensation<br /> -
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Long-term complications may include mental retardation, seizures, hypotonia, and spasticity<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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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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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 3-hydroxy-3-methylglutaryl-Coenzyme A lyase gene (HMGCL, <a href="/entry/613898#0001">613898.0001</a>)<br />
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</span>
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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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<br />
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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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<p>A number sign (#) is used with this entry because of evidence that 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is caused by homozygous or compound heterozygous mutation in the HMGCL gene (<a href="/entry/613898">613898</a>) on chromosome 1p36.</p>
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<a id="description" class="mim-anchor"></a>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<p>3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by <a href="#6" class="mim-tip-reference" title="Gibson, K. M., Breuer, J., Kaiser, K., Nyhan, W. L., McCoy, E. E., Ferreira, P., Greene, C. L., Blitzer, M. G., Shapira, E., Reverte, F., Conde, C., Bagnell, P., Cole, D. E. C. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients.</strong> J. Inherit. Metab. Dis. 11: 76-87, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3128690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3128690</a>] [<a href="https://doi.org/10.1007/BF01800058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3128690">Gibson et al., 1988</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3128690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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</h4>
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<p><a href="#4" class="mim-tip-reference" title="Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L. <strong>Patient with defect in leucine metabolism. (Letter)</strong> New Eng. J. Med. 294: 1013, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1256504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1256504</a>] [<a href="https://doi.org/10.1056/nejm197604292941823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1256504">Faull et al. (1976)</a> reported a 7-month-old male infant from Australia with metabolic acidosis and hypoglycemia, who excreted organic acids suggestive of a defect in 3-hydroxy-3-methylglutaryl CoA lyase, the enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. The profile of urinary organic acids was different from that of 3 previously identified defects of leucine degradation--maple syrup urine disease (<a href="/entry/248600">248600</a>), isovaleric acidemia (<a href="/entry/243500">243500</a>), and methylcrotonylglycinemia (<a href="/entry/210200">210200</a>). <a href="#27" class="mim-tip-reference" title="Wysocki, S. J., Hahnel, R. <strong>3-Hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaryl-coenzyme A lyase levels in leucocytes.</strong> Clin. Chim. Acta 73: 373-375, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1000856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1000856</a>] [<a href="https://doi.org/10.1016/0009-8981(76)90186-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1000856">Wysocki and Hahnel (1976)</a> demonstrated marked deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase activity in leukocytes from the infant reported by <a href="#4" class="mim-tip-reference" title="Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L. <strong>Patient with defect in leucine metabolism. (Letter)</strong> New Eng. J. Med. 294: 1013, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1256504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1256504</a>] [<a href="https://doi.org/10.1056/nejm197604292941823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1256504">Faull et al. (1976)</a>. Both parents had reduced levels of HMG-CoA lyase in leukocytes. The biochemical diagnosis is made by the finding of abnormal organic aciduria with greatly increased urinary excretion of 3-hydroxy-3-methylglutaric acid and related substances. The enzyme can be measured in leukocytes and fibroblasts. <a href="#21" class="mim-tip-reference" title="Shilkin, R., Wilson, G., Owles, E. <strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: follow-up of first described case.</strong> Acta Paediat. Scand. 70: 265-268, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6112838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6112838</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1981.tb05555.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6112838">Shilkin et al. (1981)</a> provided further follow-up on this patient. At the age of 4 years and 7 months, he appeared to be well and developing satisfactorily. His diet had been difficult to control and the biochemical defect was exceedingly sensitive to small amounts of leucine in the diet. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6112838+1000856+1256504" 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="#3" class="mim-tip-reference" title="Duran, M., Schutgens, R. B. H., Ketel, A., Heymans, H., Bertssen, M. W. J., Ketting, D., Wadman, S. K. <strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: postnatal management following prenatal diagnosis by analysis of maternal urine.</strong> J. Pediat. 95: 1004-1007, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/91680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">91680</a>] [<a href="https://doi.org/10.1016/s0022-3476(79)80297-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="91680">Duran et al. (1979)</a> reported a Moroccan family in which 4 of 7 sibs had HMG-CoA lyase deficiency. Prenatal diagnosis was possible by demonstration of HMG acid in the mother's urine. Recessive inheritance was supported by intermediate levels of lyase activity in both parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=91680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Leonard, J. V., Seakins, J. W. T., Griffin, N. K. <strong>Beta-hydroxy-methylglutaricaciduria presenting as Reye's syndrome. (Letter)</strong> Lancet 313: 680 only, 1979. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/85928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">85928</a>] [<a href="https://doi.org/10.1016/s0140-6736(79)91137-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="85928">Leonard et al. (1979)</a> reported a patient with HMG-CoA lyase deficiency presenting as Reye syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=85928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Sherwood, W. G., Slyper, A. H., Heininger, J., Mamer, O. A. <strong>Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.</strong> Neurology 30: 714-718, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6156427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6156427</a>] [<a href="https://doi.org/10.1212/wnl.30.7.714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6156427">Robinson et al. (1980)</a> described the case of a 2-year-old boy with acute fever, malaise, and somnolence with hepatomegaly, hyperammonemia, high SGOT, hypoglycemia and mild acidosis. Liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes. Abnormal urinary metabolites included beta-hydroxy-beta-methyl-glutarate (HMG). In liver and cultured skin fibroblasts, HMG-CoA lyase activity was about 10% of normal. The urine had an odor resembling that of a cat. The child's parents were unrelated and came from San Miguel in the Azores. <a href="#18" class="mim-tip-reference" title="Robinson, B. H., Oei, J., Sherwood, W. G., Slyper, A. H., Heininger, J., Mamer, O. A. <strong>Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.</strong> Neurology 30: 714-718, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6156427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6156427</a>] [<a href="https://doi.org/10.1212/wnl.30.7.714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6156427">Robinson et al. (1980)</a> noted features resembling Reye syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6156427" 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="Wilson, W. G., Cass, M. B., Sovik, O., Gibson, K. M., Sweetman, L. <strong>A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong> Europ. J. Pediat. 142: 289-291, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6489380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6489380</a>] [<a href="https://doi.org/10.1007/BF00540255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6489380">Wilson et al. (1984)</a> stated that acute pancreatitis is found at autopsy in over 7% of cases of Reye syndrome. They reported a 5-year-old child with a history of recurrent hypoglycemia who presented with a Reye-like syndrome and acute pancreatitis. HMG-CoA lyase deficiency was established by enzymatic analysis of skin fibroblasts and lymphocytes. This disorder is one of an increasing list of inborn errors of metabolism that clinically present as Reye syndrome or nonketotic hypoglycemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6489380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Berry, H. K., Suchy, F. J., Norman, E. J. <strong>HMG CoA lyase deficiency in double first cousins: relation of leucine defect to fat metabolism. (Abstract)</strong> Am. J. Hum. Genet. 33: 37A, 1981."None>Berry et al. (1981)</a> found deficiency of 3-hydroxy-3-methylglutarate CoA lyase in liver and cultured fibroblasts of 2 related children ascertained because of abnormal metabolites in the urine: 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. A shortage of glucose-sparing ketone bodies normally produced during fasting was thought to be responsible for the hypoglycemia that characterizes this metabolic defect. The absence of ketonuria in this disorder is a direct consequence of the metabolic lesion. HMG-CoA lyase is involved in ketogenesis, and the patient with the deficiency is compromised in the ability to generate ketone bodies.</p><p>Despite the clinical heterogeneity observed with HMG-CoA lyase deficiency, <a href="#22" class="mim-tip-reference" title="Sovik, O., Sweetman, L., Gibson, K. M., Nyhan, W. L. <strong>Genetic complementation analysis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency in cultured fibroblasts.</strong> Am. J. Hum. Genet. 36: 791-801, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6475954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6475954</a>]" pmid="6475954">Sovik et al. (1984)</a> could find no evidence of biochemical heterogeneity (residual enzyme activity in cultured fibroblasts was equally low in all 7 cases studied) or genetic heterogeneity (no complementation was observed in heterokaryons). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6475954" 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="Roe, C. R., Millington, D. S., Maltby, D. A. <strong>Identification of 3-methylglutarylcarnitine: a new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.</strong> J. Clin. Invest. 77: 1391-1394, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3958190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3958190</a>] [<a href="https://doi.org/10.1172/JCI112446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3958190">Roe et al. (1986)</a> demonstrated 3-methylglutarylcarnitine in the urine of 4 patients with this disorder and suggested this as the cause of an apparently secondary carnitine deficiency. They suggested that dietary supplementation with carnitine may be warranted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3958190" 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="#28" class="mim-tip-reference" title="Wysocki, S. J., Hahnel, R. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: a review.</strong> J. Inherit. Metab. Dis. 9: 225-233, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3099065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3099065</a>] [<a href="https://doi.org/10.1007/BF01799652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3099065">Wysocki and Hahnel (1986)</a> reviewed 12 patients, and <a href="#6" class="mim-tip-reference" title="Gibson, K. M., Breuer, J., Kaiser, K., Nyhan, W. L., McCoy, E. E., Ferreira, P., Greene, C. L., Blitzer, M. G., Shapira, E., Reverte, F., Conde, C., Bagnell, P., Cole, D. E. C. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients.</strong> J. Inherit. Metab. Dis. 11: 76-87, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3128690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3128690</a>] [<a href="https://doi.org/10.1007/BF01800058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3128690">Gibson et al. (1988)</a> reported 5 others. <a href="#7" class="mim-tip-reference" title="Gibson, K. M., Breuer, J., Nyhan, W. L. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients.</strong> Europ. J. Pediat. 148: 180-186, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3063529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3063529</a>] [<a href="https://doi.org/10.1007/BF00441397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3063529">Gibson et al. (1988)</a> reviewed 18 reported cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3128690+3063529+3099065" 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="#17" class="mim-tip-reference" title="Ribes, A., Briones, P., Vilaseca, M. A., Baraibar, R., Gairi, J. M. <strong>Sudden death in an infant with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong> J. Inherit. Metab. Dis. 13: 752-753, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246860</a>] [<a href="https://doi.org/10.1007/BF01799579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246860">Ribes et al. (1990)</a> described sudden death in a 13-month-old boy with HMG-CoA lyase deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Barash, V., Mandel, H., Sella, S., Geiger, R. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations.</strong> J. Inherit. Metab. Dis. 13: 156-164, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116546</a>] [<a href="https://doi.org/10.1007/BF01799678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2116546">Barash et al. (1990)</a> determined HMG-CoA lyase activity by the spectrophotometric method of <a href="#23" class="mim-tip-reference" title="Wanders, R. J. A., Schutgens, R. B. H., Zoeters, P. H. M. <strong>3-Hydroxy-3-methylglutaryl-CoA lyase in human skin fibroblasts: study of its properties and deficient activity in 3-hydroxy-3-methylglutaric aciduria patients using a simple spectrophotometric method.</strong> Clin. Chim. Acta 171: 95-102, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2450702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2450702</a>] [<a href="https://doi.org/10.1016/0009-8981(88)90294-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2450702">Wanders et al. (1988)</a> in polymorphonuclear leukocytes and lymphocytes obtained from 33 persons in 4 generations of a highly consanguineous Arab-Bedouin family. Seven subjects were obligatory heterozygotes, being parents and grandparents of 3 propositi; in 7 additional subjects, enzyme activities in both cell types were in the heterozygous range. No asymptomatic homozygotes were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2450702+2116546" 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="Grunert, S. C., Schlatter, S. M., Schmitt, R. N., Gemperle-Britschgi, C., Mrazova, L., Balci, M. C., Bischof, F., Coker, M., Das, A. M., Dermirkol, M., de Vries, M., Gokcay, G., and 12 others. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients.</strong> Molec. Genet. Metab. 121: 206-215, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28583327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28583327</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28583327">Grunert et al. (2017)</a> reviewed the clinical presentation and outcome in a series of 37 patients with HMGCLD, including 30 patients from Turkey and the rest from Belgium, Germany, The Netherlands, and Switzerland. Most patients (94%) presented with an acute metabolic decompensation in the first year of life, approximately half in the neonatal period. The most common clinical symptoms were recurrent vomiting, seizures, and impaired vigilance. The most common laboratory findings were hypoglycemia, acidosis, an increased anion gap, hyperammonemia, and elevated transaminase activities. Of 32 patients, 10 had no further metabolic decompensations after diagnosis, and 22 had at least one more metabolic crisis, most often associated with infections, especially gastroenteritis or respiratory tract infections. Half of the patients had normal cognitive development, and the remainder had psychomotor deficits of variable severity. Six of the patients had died at a mean age of 11 years (range, 4 months to 40 years). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28583327" 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>HMG-CoA lyase deficiency is treatable by diet and avoidance of prolonged fasting. Leucine is restricted and supplementary glucose given to prevent hypoglycemia. Without treatment, death occurs early (<a href="#3" class="mim-tip-reference" title="Duran, M., Schutgens, R. B. H., Ketel, A., Heymans, H., Bertssen, M. W. J., Ketting, D., Wadman, S. K. <strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: postnatal management following prenatal diagnosis by analysis of maternal urine.</strong> J. Pediat. 95: 1004-1007, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/91680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">91680</a>] [<a href="https://doi.org/10.1016/s0022-3476(79)80297-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="91680">Duran et al., 1979</a>; <a href="#6" class="mim-tip-reference" title="Gibson, K. M., Breuer, J., Kaiser, K., Nyhan, W. L., McCoy, E. E., Ferreira, P., Greene, C. L., Blitzer, M. G., Shapira, E., Reverte, F., Conde, C., Bagnell, P., Cole, D. E. C. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients.</strong> J. Inherit. Metab. Dis. 11: 76-87, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3128690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3128690</a>] [<a href="https://doi.org/10.1007/BF01800058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3128690">Gibson et al., 1988</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3128690+91680" 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="#14" class="mim-tip-reference" title="Muroi, J., Yorifuji, T., Uematsu, A., Shigematsu, Y., Onigata, K., Maruyama, H., Nobutoki, T., Kitamura, A., Nakahata, T. <strong>Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency.</strong> Hum. Genet. 107: 320-326, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11129331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11129331</a>] [<a href="https://doi.org/10.1007/s004390000363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11129331">Muroi et al. (2000)</a> stated that the incidence of HMG-CoA lyase deficiency is low, except in Saudi Arabia where the deficiency comprises 16% of all organic acidemia (<a href="#16" class="mim-tip-reference" title="Ozand, P. T., Devol, E. B., Gascon, G. G. <strong>Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre.</strong> J. Child Neurol. 7 (suppl.): S4-S11, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1588014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1588014</a>] [<a href="https://doi.org/10.1177/08830738920070010211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1588014">Ozand et al., 1992</a>). Otherwise, only 41 cases had been reported in the English literature and only 5 cases had been reported from Japan. Ozand et al. (<a href="#15" class="mim-tip-reference" title="Ozand, P. T., Al Aqeel, A., Gascon, G., Brismar, J., Thomas, E., Gleispach, H. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia.</strong> J. Inherit. Metab. Dis. 14: 174-188, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1886403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1886403</a>] [<a href="https://doi.org/10.1007/BF01800590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1886403">1991</a>, <a href="#16" class="mim-tip-reference" title="Ozand, P. T., Devol, E. B., Gascon, G. G. <strong>Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre.</strong> J. Child Neurol. 7 (suppl.): S4-S11, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1588014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1588014</a>] [<a href="https://doi.org/10.1177/08830738920070010211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1588014">1992</a>) reported that the disorder in Saudi Arabian patients is particularly severe. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11129331+1588014+1886403" 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="#13" class="mim-tip-reference" title="Mitchell, G. A., Robert, M.-F., Hruz, P. W., Wang, S., Fontaine, G., Behnke, C. E., Mende-Mueller, L. M., Schappert, K., Lee, C., Gibson, K. M., Miziorko, H. M. <strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency.</strong> J. Biol. Chem. 268: 4376-4381, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8440722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8440722</a>]" pmid="8440722">Mitchell et al. (1993)</a> characterized mutation in the HMGCL gene causing human HL deficiency; see <a href="/entry/613898#0001">613898.0001</a>-<a href="/entry/613898#0002">613898.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8440722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genomic Southern blot analysis and exonic PCR, <a href="#25" class="mim-tip-reference" title="Wang, S. P., Robert, M.-F., Gibson, K. M., Wanders, R. J. A., Mitchell, G. A. <strong>3-Hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients.</strong> Genomics 33: 99-104, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8617516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8617516</a>] [<a href="https://doi.org/10.1006/geno.1996.0164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8617516">Wang et al. (1996)</a> found that 2 of 33 HMGCL-deficient patient probands were homozygous for different large deletions in the gene (see, e.g., <a href="/entry/613898#0003">613898.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8617516" 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="Muroi, J., Yorifuji, T., Uematsu, A., Shigematsu, Y., Onigata, K., Maruyama, H., Nobutoki, T., Kitamura, A., Nakahata, T. <strong>Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency.</strong> Hum. Genet. 107: 320-326, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11129331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11129331</a>] [<a href="https://doi.org/10.1007/s004390000363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11129331">Muroi et al. (2000)</a> presented the results of a molecular analysis of all known 5 Japanese cases of HMG-CoA lyase deficiency together with their clinical phenotypes. Five different mutations were identified: 1 large deletion, 1 nonsense mutation, 1 missense mutation, and 2 splice mutations. A glu279-to-lys (<a href="/entry/613898#0005">613898.0005</a>) mutation was found in homozygous state in 1 patient and in heterozygous state in a second; all of the other mutations were unique to each family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11129331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By gene targeting, <a href="#24" class="mim-tip-reference" title="Wang, S. P., Marth, J. D., Oligny, L. L., Vachon, M., Robert, M.-F., Ashmarina, L., Mitchell, G. A. <strong>3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice.</strong> Hum. Molec. Genet. 7: 2057-2062, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817922</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817922">Wang et al. (1998)</a> created a strain of HL-deficient mice. Heterozygous HL-deficient mice were clinically normal, and fibroblasts from homozygous HL-deficient embryos grew normally despite absence of HL activity. In contrast, homozygous HL-deficient embryos died at approximately 11.5 days postcoitum. Histologically, HL-deficient embryos showed marked vacuolization, particularly in the liver. Ultrastructural studies of hepatocytes obtained before death from HL-deficient embryos showed abnormal dilated mitochondria. HL-deficient mice are the first mammalian example of a disease primarily affecting CoA ester metabolism with abnormal prenatal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of redox homeostasis abnormalities in HL deficiency, <a href="#9" class="mim-tip-reference" title="Leipnitz, G., Vargas, C. R., Wajner, M. <strong>Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong> J. Inherit. Metab. Dis. 38: 1021-1028, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26041581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26041581</a>] [<a href="https://doi.org/10.1007/s10545-015-9863-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26041581">Leipnitz et al. (2015)</a> discussed that 3-hydroxy-3-methylglutaryl-CoA (HMG), 3-methylglutaric acid, 3-methyglutaconic acid, and 3-hydroxyisovaleric acid lead to lipid peroxidation in the rat cerebral cortex. HMG has the most significant effects. Only HMG caused lipid peroxidation in the rat liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26041581" 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="#29" class="mim-tip-reference" title="Yang, H., Wang, Y., Tang, M. C., Waters, P., Wang, S., Allard, P., Ryan, R. O., Nuyt, A. M., Paradis, P., Schiffrin, E. L., Furtos, A., Mitchell, G. A. <strong>Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers.</strong> Molec. Genet. Metab. 137: 257-264, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36228350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36228350</a>] [<a href="https://doi.org/10.1016/j.ymgme.2022.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36228350">Yang et al. (2022)</a> developed a cardiomyocyte-specific HL-deficient mouse. The mutant mice developed left ventricular cardiac hypertrophy by 9 months of age. After injection of 2-ketoisocaproic acid (a leucine metabolite), the mutant mice developed transient left ventricular dysfunction and elevated leucine-associated acyl-CoA metabolites in the heart compared to wildtype mice. Acyl-CoA profiles in the liver of the mutant mice were the same as those in wildtype mice. <a href="#29" class="mim-tip-reference" title="Yang, H., Wang, Y., Tang, M. C., Waters, P., Wang, S., Allard, P., Ryan, R. O., Nuyt, A. M., Paradis, P., Schiffrin, E. L., Furtos, A., Mitchell, G. A. <strong>Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers.</strong> Molec. Genet. Metab. 137: 257-264, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36228350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36228350</a>] [<a href="https://doi.org/10.1016/j.ymgme.2022.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36228350">Yang et al. (2022)</a> demonstrated further that in liver-specific HL-deficient mice, the cardiac acyl-CoA levels were the same as those in wildtype mice. <a href="#29" class="mim-tip-reference" title="Yang, H., Wang, Y., Tang, M. C., Waters, P., Wang, S., Allard, P., Ryan, R. O., Nuyt, A. M., Paradis, P., Schiffrin, E. L., Furtos, A., Mitchell, G. A. <strong>Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers.</strong> Molec. Genet. Metab. 137: 257-264, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36228350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36228350</a>] [<a href="https://doi.org/10.1016/j.ymgme.2022.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36228350">Yang et al. (2022)</a> concluded that abnormal acyl-CoA metabolites occur in an organ-autonomous manner in the heart and liver in HL deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36228350" 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="#Faull1976" class="mim-tip-reference" title="Faull, K. F., Bolton, P. D., Halpern, B., Hammond, J., Danks, D. M. <strong>The urinary organic acid profile associated with 3-hydroxy-3-methylglutaric aciduria.</strong> Clin. Chim. Acta 73: 553-559, 1976.">Faull et al. (1976)</a>; <a href="#Mitchell1998" class="mim-tip-reference" title="Mitchell, G. A., Ozand, P. T., Robert, M.-F., Ashmarina, L., Roberts, J., Gibson, K. M., Wanders, R. J., Wang, S., Chevalier, I., Plochl, R., Miziorko, H. <strong>HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.</strong> Am. J. Hum. Genet. 62: 295-300, 1998.">Mitchell et al. (1998)</a>; <a href="#Schutgens1979" class="mim-tip-reference" title="Schutgens, R. B. H., Heymans, H., Ketel, A., Veder, H. A., Duran, M., Ketting, D., Wadman, S. K. <strong>Lethal hypoglycemia in a child with a deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase.</strong> J. Pediat. 94: 89-91, 1979.">Schutgens et al. (1979)</a>
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Barash, V., Mandel, H., Sella, S., Geiger, R.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations.</strong>
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J. Inherit. Metab. Dis. 13: 156-164, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2116546" 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/BF01799678" target="_blank">Full Text</a>]
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Berry, H. K., Suchy, F. J., Norman, E. J.
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<strong>HMG CoA lyase deficiency in double first cousins: relation of leucine defect to fat metabolism. (Abstract)</strong>
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Am. J. Hum. Genet. 33: 37A, 1981.
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<strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: postnatal management following prenatal diagnosis by analysis of maternal urine.</strong>
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J. Pediat. 95: 1004-1007, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/91680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">91680</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=91680" 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/s0022-3476(79)80297-8" target="_blank">Full Text</a>]
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Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L.
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<strong>Patient with defect in leucine metabolism. (Letter)</strong>
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New Eng. J. Med. 294: 1013, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1256504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1256504</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1256504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Faull, K. F., Bolton, P. D., Halpern, B., Hammond, J., Danks, D. M.
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[<a href="https://doi.org/10.1016/0009-8981(76)90160-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00441397" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2017.05.014" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390000363" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01800590" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/08830738920070010211" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6475954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6475954</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6475954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<a id="23" class="mim-anchor"></a>
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<a id="Wanders1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wanders, R. J. A., Schutgens, R. B. H., Zoeters, P. H. M.
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|
<strong>3-Hydroxy-3-methylglutaryl-CoA lyase in human skin fibroblasts: study of its properties and deficient activity in 3-hydroxy-3-methylglutaric aciduria patients using a simple spectrophotometric method.</strong>
|
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Clin. Chim. Acta 171: 95-102, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2450702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2450702</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2450702" 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/10.1016/0009-8981(88)90294-x" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
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<a id="Wang1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, S. P., Marth, J. D., Oligny, L. L., Vachon, M., Robert, M.-F., Ashmarina, L., Mitchell, G. A.
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|
<strong>3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice.</strong>
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Hum. Molec. Genet. 7: 2057-2062, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817922</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/7.13.2057" target="_blank">Full Text</a>]
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<a id="25" class="mim-anchor"></a>
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<a id="Wang1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, S. P., Robert, M.-F., Gibson, K. M., Wanders, R. J. A., Mitchell, G. A.
|
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<strong>3-Hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients.</strong>
|
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Genomics 33: 99-104, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8617516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8617516</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8617516" 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/10.1006/geno.1996.0164" target="_blank">Full Text</a>]
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Wilson1984" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, W. G., Cass, M. B., Sovik, O., Gibson, K. M., Sweetman, L.
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<strong>A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong>
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Europ. J. Pediat. 142: 289-291, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6489380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6489380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6489380" 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/BF00540255" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
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<a id="Wysocki1976" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wysocki, S. J., Hahnel, R.
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<strong>3-Hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaryl-coenzyme A lyase levels in leucocytes.</strong>
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Clin. Chim. Acta 73: 373-375, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1000856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1000856</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1000856" 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/10.1016/0009-8981(76)90186-8" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Wysocki1986" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wysocki, S. J., Hahnel, R.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: a review.</strong>
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J. Inherit. Metab. Dis. 9: 225-233, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3099065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3099065</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3099065" 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/BF01799652" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Yang2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, H., Wang, Y., Tang, M. C., Waters, P., Wang, S., Allard, P., Ryan, R. O., Nuyt, A. M., Paradis, P., Schiffrin, E. L., Furtos, A., Mitchell, G. A.
|
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<strong>Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers.</strong>
|
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Molec. Genet. Metab. 137: 257-264, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36228350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36228350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36228350" 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.2022.09.008" target="_blank">Full Text</a>]
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<br />
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 02/21/2023
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini - updated : 07/14/2017<br>Carol A. Bocchini - reorganized : 4/13/2011<br>Victor A. McKusick - updated : 11/28/2000<br>Victor A. McKusick - updated : 1/7/1999<br>Victor A. McKusick - updated : 5/2/1998
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/3/1986
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/21/2023
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/17/2017<br>carol : 07/14/2017<br>carol : 04/22/2011<br>carol : 4/18/2011<br>terry : 4/14/2011<br>carol : 4/13/2011<br>carol : 4/13/2011<br>terry : 3/5/2009<br>terry : 4/20/2005<br>terry : 4/6/2005<br>carol : 3/17/2004<br>mcapotos : 12/5/2000<br>mcapotos : 12/1/2000<br>terry : 11/28/2000<br>terry : 4/25/2000<br>carol : 1/18/1999<br>terry : 1/7/1999<br>alopez : 12/10/1998<br>dholmes : 5/11/1998<br>carol : 5/2/1998<br>terry : 3/27/1998<br>alopez : 8/7/1997<br>mark : 4/17/1996<br>terry : 4/10/1996<br>terry : 5/7/1994<br>warfield : 3/9/1994<br>mimadm : 2/19/1994<br>carol : 10/28/1993<br>carol : 9/21/1993<br>carol : 9/13/1993
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</span>
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<span class="mim-font">
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<strong>#</strong> 246450
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</h3>
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<h3>
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<span class="mim-font">
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3-HYDROXY-3-METHYLGLUTARYL-CoA LYASE DEFICIENCY; HMGCLD
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</span>
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</h3>
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<div>
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<br />
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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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HMG-CoA LYASE DEFICIENCY<br />
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HMGCL DEFICIENCY<br />
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HL DEFICIENCY<br />
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HYDROXYMETHYLGLUTARIC ACIDURIA
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</span>
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</h4>
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</div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 124611007;
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<strong>ORPHA:</strong> 20;
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<strong>DO:</strong> 0070541;
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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1p36.11
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</span>
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</td>
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<td>
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<span class="mim-font">
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HMG-CoA lyase deficiency
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</span>
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</td>
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<td>
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<span class="mim-font">
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246450
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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HMGCL
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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613898
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</span>
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</td>
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</tbody>
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</table>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is caused by homozygous or compound heterozygous mutation in the HMGCL gene (613898) on chromosome 1p36.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Description</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>3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</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>Faull et al. (1976) reported a 7-month-old male infant from Australia with metabolic acidosis and hypoglycemia, who excreted organic acids suggestive of a defect in 3-hydroxy-3-methylglutaryl CoA lyase, the enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. The profile of urinary organic acids was different from that of 3 previously identified defects of leucine degradation--maple syrup urine disease (248600), isovaleric acidemia (243500), and methylcrotonylglycinemia (210200). Wysocki and Hahnel (1976) demonstrated marked deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase activity in leukocytes from the infant reported by Faull et al. (1976). Both parents had reduced levels of HMG-CoA lyase in leukocytes. The biochemical diagnosis is made by the finding of abnormal organic aciduria with greatly increased urinary excretion of 3-hydroxy-3-methylglutaric acid and related substances. The enzyme can be measured in leukocytes and fibroblasts. Shilkin et al. (1981) provided further follow-up on this patient. At the age of 4 years and 7 months, he appeared to be well and developing satisfactorily. His diet had been difficult to control and the biochemical defect was exceedingly sensitive to small amounts of leucine in the diet. </p><p>Duran et al. (1979) reported a Moroccan family in which 4 of 7 sibs had HMG-CoA lyase deficiency. Prenatal diagnosis was possible by demonstration of HMG acid in the mother's urine. Recessive inheritance was supported by intermediate levels of lyase activity in both parents. </p><p>Leonard et al. (1979) reported a patient with HMG-CoA lyase deficiency presenting as Reye syndrome. </p><p>Robinson et al. (1980) described the case of a 2-year-old boy with acute fever, malaise, and somnolence with hepatomegaly, hyperammonemia, high SGOT, hypoglycemia and mild acidosis. Liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes. Abnormal urinary metabolites included beta-hydroxy-beta-methyl-glutarate (HMG). In liver and cultured skin fibroblasts, HMG-CoA lyase activity was about 10% of normal. The urine had an odor resembling that of a cat. The child's parents were unrelated and came from San Miguel in the Azores. Robinson et al. (1980) noted features resembling Reye syndrome. </p><p>Wilson et al. (1984) stated that acute pancreatitis is found at autopsy in over 7% of cases of Reye syndrome. They reported a 5-year-old child with a history of recurrent hypoglycemia who presented with a Reye-like syndrome and acute pancreatitis. HMG-CoA lyase deficiency was established by enzymatic analysis of skin fibroblasts and lymphocytes. This disorder is one of an increasing list of inborn errors of metabolism that clinically present as Reye syndrome or nonketotic hypoglycemia. </p><p>Berry et al. (1981) found deficiency of 3-hydroxy-3-methylglutarate CoA lyase in liver and cultured fibroblasts of 2 related children ascertained because of abnormal metabolites in the urine: 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. A shortage of glucose-sparing ketone bodies normally produced during fasting was thought to be responsible for the hypoglycemia that characterizes this metabolic defect. The absence of ketonuria in this disorder is a direct consequence of the metabolic lesion. HMG-CoA lyase is involved in ketogenesis, and the patient with the deficiency is compromised in the ability to generate ketone bodies.</p><p>Despite the clinical heterogeneity observed with HMG-CoA lyase deficiency, Sovik et al. (1984) could find no evidence of biochemical heterogeneity (residual enzyme activity in cultured fibroblasts was equally low in all 7 cases studied) or genetic heterogeneity (no complementation was observed in heterokaryons). </p><p>Roe et al. (1986) demonstrated 3-methylglutarylcarnitine in the urine of 4 patients with this disorder and suggested this as the cause of an apparently secondary carnitine deficiency. They suggested that dietary supplementation with carnitine may be warranted. </p><p>Wysocki and Hahnel (1986) reviewed 12 patients, and Gibson et al. (1988) reported 5 others. Gibson et al. (1988) reviewed 18 reported cases. </p><p>Ribes et al. (1990) described sudden death in a 13-month-old boy with HMG-CoA lyase deficiency. </p><p>Barash et al. (1990) determined HMG-CoA lyase activity by the spectrophotometric method of Wanders et al. (1988) in polymorphonuclear leukocytes and lymphocytes obtained from 33 persons in 4 generations of a highly consanguineous Arab-Bedouin family. Seven subjects were obligatory heterozygotes, being parents and grandparents of 3 propositi; in 7 additional subjects, enzyme activities in both cell types were in the heterozygous range. No asymptomatic homozygotes were found. </p><p>Grunert et al. (2017) reviewed the clinical presentation and outcome in a series of 37 patients with HMGCLD, including 30 patients from Turkey and the rest from Belgium, Germany, The Netherlands, and Switzerland. Most patients (94%) presented with an acute metabolic decompensation in the first year of life, approximately half in the neonatal period. The most common clinical symptoms were recurrent vomiting, seizures, and impaired vigilance. The most common laboratory findings were hypoglycemia, acidosis, an increased anion gap, hyperammonemia, and elevated transaminase activities. Of 32 patients, 10 had no further metabolic decompensations after diagnosis, and 22 had at least one more metabolic crisis, most often associated with infections, especially gastroenteritis or respiratory tract infections. Half of the patients had normal cognitive development, and the remainder had psychomotor deficits of variable severity. Six of the patients had died at a mean age of 11 years (range, 4 months to 40 years). </p>
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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 class="mim-text-font">
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<p>HMG-CoA lyase deficiency is treatable by diet and avoidance of prolonged fasting. Leucine is restricted and supplementary glucose given to prevent hypoglycemia. Without treatment, death occurs early (Duran et al., 1979; Gibson et al., 1988). </p>
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<h4>
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<strong>Inheritance</strong>
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<span class="mim-text-font">
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<p>HMG-CoA lyase deficiency is an autosomal recessive disorder (Mitchell et al., 1992).</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>Muroi et al. (2000) stated that the incidence of HMG-CoA lyase deficiency is low, except in Saudi Arabia where the deficiency comprises 16% of all organic acidemia (Ozand et al., 1992). Otherwise, only 41 cases had been reported in the English literature and only 5 cases had been reported from Japan. Ozand et al. (1991, 1992) reported that the disorder in Saudi Arabian patients is particularly severe. </p>
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</span>
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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 class="mim-text-font">
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<p>Mitchell et al. (1993) characterized mutation in the HMGCL gene causing human HL deficiency; see 613898.0001-613898.0002. </p><p>By genomic Southern blot analysis and exonic PCR, Wang et al. (1996) found that 2 of 33 HMGCL-deficient patient probands were homozygous for different large deletions in the gene (see, e.g., 613898.0003). </p><p>Muroi et al. (2000) presented the results of a molecular analysis of all known 5 Japanese cases of HMG-CoA lyase deficiency together with their clinical phenotypes. Five different mutations were identified: 1 large deletion, 1 nonsense mutation, 1 missense mutation, and 2 splice mutations. A glu279-to-lys (613898.0005) mutation was found in homozygous state in 1 patient and in heterozygous state in a second; all of the other mutations were unique to each family. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>By gene targeting, Wang et al. (1998) created a strain of HL-deficient mice. Heterozygous HL-deficient mice were clinically normal, and fibroblasts from homozygous HL-deficient embryos grew normally despite absence of HL activity. In contrast, homozygous HL-deficient embryos died at approximately 11.5 days postcoitum. Histologically, HL-deficient embryos showed marked vacuolization, particularly in the liver. Ultrastructural studies of hepatocytes obtained before death from HL-deficient embryos showed abnormal dilated mitochondria. HL-deficient mice are the first mammalian example of a disease primarily affecting CoA ester metabolism with abnormal prenatal development. </p><p>In a review of redox homeostasis abnormalities in HL deficiency, Leipnitz et al. (2015) discussed that 3-hydroxy-3-methylglutaryl-CoA (HMG), 3-methylglutaric acid, 3-methyglutaconic acid, and 3-hydroxyisovaleric acid lead to lipid peroxidation in the rat cerebral cortex. HMG has the most significant effects. Only HMG caused lipid peroxidation in the rat liver. </p><p>Yang et al. (2022) developed a cardiomyocyte-specific HL-deficient mouse. The mutant mice developed left ventricular cardiac hypertrophy by 9 months of age. After injection of 2-ketoisocaproic acid (a leucine metabolite), the mutant mice developed transient left ventricular dysfunction and elevated leucine-associated acyl-CoA metabolites in the heart compared to wildtype mice. Acyl-CoA profiles in the liver of the mutant mice were the same as those in wildtype mice. Yang et al. (2022) demonstrated further that in liver-specific HL-deficient mice, the cardiac acyl-CoA levels were the same as those in wildtype mice. Yang et al. (2022) concluded that abnormal acyl-CoA metabolites occur in an organ-autonomous manner in the heart and liver in HL deficiency. </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>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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Faull et al. (1976); Mitchell et al. (1998); Schutgens et al. (1979)
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</span>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Barash, V., Mandel, H., Sella, S., Geiger, R.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: biochemical studies and family investigation of four generations.</strong>
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J. Inherit. Metab. Dis. 13: 156-164, 1990.
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[PubMed: 2116546]
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[Full Text: https://doi.org/10.1007/BF01799678]
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<p class="mim-text-font">
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Berry, H. K., Suchy, F. J., Norman, E. J.
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<strong>HMG CoA lyase deficiency in double first cousins: relation of leucine defect to fat metabolism. (Abstract)</strong>
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Am. J. Hum. Genet. 33: 37A, 1981.
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</p>
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Duran, M., Schutgens, R. B. H., Ketel, A., Heymans, H., Bertssen, M. W. J., Ketting, D., Wadman, S. K.
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<strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: postnatal management following prenatal diagnosis by analysis of maternal urine.</strong>
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J. Pediat. 95: 1004-1007, 1979.
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[PubMed: 91680]
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[Full Text: https://doi.org/10.1016/s0022-3476(79)80297-8]
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<p class="mim-text-font">
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Faull, K., Bolton, P., Halpern, B., Hammond, J., Danks, D. M., Hahnel, R., Wilkinson, S. P., Wysocki, S. J., Masters, P. L.
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<strong>Patient with defect in leucine metabolism. (Letter)</strong>
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New Eng. J. Med. 294: 1013, 1976.
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[PubMed: 1256504]
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[Full Text: https://doi.org/10.1056/nejm197604292941823]
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Faull, K. F., Bolton, P. D., Halpern, B., Hammond, J., Danks, D. M.
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<strong>The urinary organic acid profile associated with 3-hydroxy-3-methylglutaric aciduria.</strong>
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Clin. Chim. Acta 73: 553-559, 1976.
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[PubMed: 1000872]
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[Full Text: https://doi.org/10.1016/0009-8981(76)90160-1]
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Gibson, K. M., Breuer, J., Kaiser, K., Nyhan, W. L., McCoy, E. E., Ferreira, P., Greene, C. L., Blitzer, M. G., Shapira, E., Reverte, F., Conde, C., Bagnell, P., Cole, D. E. C.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients.</strong>
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J. Inherit. Metab. Dis. 11: 76-87, 1988.
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[PubMed: 3128690]
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[Full Text: https://doi.org/10.1007/BF01800058]
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Gibson, K. M., Breuer, J., Nyhan, W. L.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients.</strong>
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Europ. J. Pediat. 148: 180-186, 1988.
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[PubMed: 3063529]
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[Full Text: https://doi.org/10.1007/BF00441397]
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Grunert, S. C., Schlatter, S. M., Schmitt, R. N., Gemperle-Britschgi, C., Mrazova, L., Balci, M. C., Bischof, F., Coker, M., Das, A. M., Dermirkol, M., de Vries, M., Gokcay, G., and 12 others.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients.</strong>
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Molec. Genet. Metab. 121: 206-215, 2017.
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[PubMed: 28583327]
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[Full Text: https://doi.org/10.1016/j.ymgme.2017.05.014]
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Leipnitz, G., Vargas, C. R., Wajner, M.
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<strong>Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong>
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J. Inherit. Metab. Dis. 38: 1021-1028, 2015.
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[PubMed: 26041581]
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[Full Text: https://doi.org/10.1007/s10545-015-9863-3]
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Leonard, J. V., Seakins, J. W. T., Griffin, N. K.
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<strong>Beta-hydroxy-methylglutaricaciduria presenting as Reye's syndrome. (Letter)</strong>
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Lancet 313: 680 only, 1979. Note: Originally Volume I.
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[PubMed: 85928]
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[Full Text: https://doi.org/10.1016/s0140-6736(79)91137-1]
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Mitchell, G. A., Ozand, P. T., Robert, M.-F., Ashmarina, L., Roberts, J., Gibson, K. M., Wanders, R. J., Wang, S., Chevalier, I., Plochl, R., Miziorko, H.
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<strong>HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.</strong>
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Am. J. Hum. Genet. 62: 295-300, 1998.
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[PubMed: 9463337]
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[Full Text: https://doi.org/10.1086/301730]
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Mitchell, G. A., Robert, M.-F., Fontaine, G., Wang, S., Lambert, M., Cole, D., Lee, C., Gibson, M., Miziorko, H.
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<strong>HMG CoA lyase (HL) deficiency: detection of a causal mutation in an affected French-Canadian sibship. (Abstract)</strong>
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Am. J. Hum. Genet. 51 (suppl.): A173, 1992.
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Mitchell, G. A., Robert, M.-F., Hruz, P. W., Wang, S., Fontaine, G., Behnke, C. E., Mende-Mueller, L. M., Schappert, K., Lee, C., Gibson, K. M., Miziorko, H. M.
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<strong>3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency.</strong>
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J. Biol. Chem. 268: 4376-4381, 1993.
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Muroi, J., Yorifuji, T., Uematsu, A., Shigematsu, Y., Onigata, K., Maruyama, H., Nobutoki, T., Kitamura, A., Nakahata, T.
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<strong>Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency.</strong>
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Hum. Genet. 107: 320-326, 2000.
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Ozand, P. T., Al Aqeel, A., Gascon, G., Brismar, J., Thomas, E., Gleispach, H.
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<strong>3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia.</strong>
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J. Inherit. Metab. Dis. 14: 174-188, 1991.
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[PubMed: 1886403]
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[Full Text: https://doi.org/10.1007/BF01800590]
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Ozand, P. T., Devol, E. B., Gascon, G. G.
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<strong>Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre.</strong>
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J. Child Neurol. 7 (suppl.): S4-S11, 1992.
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[Full Text: https://doi.org/10.1177/08830738920070010211]
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</p>
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<li>
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<p class="mim-text-font">
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Ribes, A., Briones, P., Vilaseca, M. A., Baraibar, R., Gairi, J. M.
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<strong>Sudden death in an infant with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong>
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J. Inherit. Metab. Dis. 13: 752-753, 1990.
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[PubMed: 2246860]
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[Full Text: https://doi.org/10.1007/BF01799579]
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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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Robinson, B. H., Oei, J., Sherwood, W. G., Slyper, A. H., Heininger, J., Mamer, O. A.
|
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<strong>Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.</strong>
|
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Neurology 30: 714-718, 1980.
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[PubMed: 6156427]
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[Full Text: https://doi.org/10.1212/wnl.30.7.714]
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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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Roe, C. R., Millington, D. S., Maltby, D. A.
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<strong>Identification of 3-methylglutarylcarnitine: a new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.</strong>
|
|
J. Clin. Invest. 77: 1391-1394, 1986.
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[PubMed: 3958190]
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[Full Text: https://doi.org/10.1172/JCI112446]
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<strong>3-Hydroxy-3-methylglutaryl-CoA lyase in human skin fibroblasts: study of its properties and deficient activity in 3-hydroxy-3-methylglutaric aciduria patients using a simple spectrophotometric method.</strong>
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Wang, S. P., Robert, M.-F., Gibson, K. M., Wanders, R. J. A., Mitchell, G. A.
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Wilson, W. G., Cass, M. B., Sovik, O., Gibson, K. M., Sweetman, L.
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<strong>A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.</strong>
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Yang, H., Wang, Y., Tang, M. C., Waters, P., Wang, S., Allard, P., Ryan, R. O., Nuyt, A. M., Paradis, P., Schiffrin, E. L., Furtos, A., Mitchell, G. A.
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