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<title>
Entry
- #231680 - MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD
- OMIM
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<span class="h4">#231680</span>
<br />
<strong>Table of Contents</strong>
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<li role="presentation">
<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
<a href="/clinicalSynopsis/231680"><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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<li role="presentation" style="margin-left: 1em">
<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8766&Typ=Pat" title="Multiple acyl-CoA dehydrogenase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Multiple acyl-CoA dehydrog…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22659&Typ=Pat" title="Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Multiple acyl-CoA dehydrog…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22660&Typ=Pat" title="Multiple acyl-CoA dehydrogenase deficiency, mild type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Multiple acyl-CoA dehydrog…&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK558236/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="#mimNewbornScreeningFold" id="mimNewbornScreeningToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Information and resources for newborn screening and genetics."><span id="mimNewbornScreeningToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Newborn Screening</div>
<div id="mimNewbornScreeningFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="https://www.acmg.net/PDFLibrary/Glutaric-Aciduria-Type-2-ACT-Sheet.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/C4-C5-Elevated-Algorithm.pdf" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Newborn Screening', 'domain': 'www.acmg.net'})">ACMG Algorithm</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Orphanet</div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=26791" title="Multiple acyl-CoA dehydrogenase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Multiple acyl-CoA dehydrog…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=394529" title="Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Multiple acyl-CoA dehydrog…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=394532" title="Multiple acyl-CoA dehydrogenase deficiency, mild type" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Multiple acyl-CoA dehydrog…</a></div>
</div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/a17271b9-f69a-46a8-b2ec-37780b9ddc26/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0060358" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/231680" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/OMIA001457/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0060358" 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>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:231680" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 22886006<br />
<strong>ICD10CM:</strong> E71.313<br />
<strong>ORPHA:</strong> 26791, 394529, 394532<br />
<strong>DO:</strong> 0060358<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
231680
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
GLUTARIC ACIDEMIA II; GA2<br />
GLUTARIC ACIDURIA II<br />
GA II<br />
ETHYLMALONIC-ADIPICACIDURIA; EMA
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
GLUTARIC ACIDEMIA IIA, INCLUDED; GA2A, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
ETFA DEFICIENCY, INCLUDED<br />
GLUTARIC ACIDEMIA IIB, INCLUDED; GA2B, INCLUDED<br />
ETFB DEFICIENCY, INCLUDED<br />
GLUTARIC ACIDEMIA IIC, INCLUDED; GA2C, INCLUDED<br />
ETFDH DEFICIENCY, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/638?start=-3&limit=10&highlight=638">
4q32.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Glutaric acidemia IIC
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/231680"> 231680 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ETFDH
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/231675"> 231675 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/408?start=-3&limit=10&highlight=408">
15q24.2-q24.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Glutaric acidemia IIA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/231680"> 231680 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ETFA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608053"> 608053 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/1025?start=-3&limit=10&highlight=1025">
19q13.41
</a>
</span>
</td>
<td>
<span class="mim-font">
Glutaric acidemia IIB
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/231680"> 231680 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ETFB
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/130410"> 130410 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/231680" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<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/231680" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/231680" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> Metabolic </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Neonatal acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/107421000119101" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">107421000119101</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4544436&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4544436</a>]</span><br /> - 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 />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> Misc </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sweaty feet odor<br /> - Stale breath odor<br /> - Neonatal death frequent<br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GI </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Nausea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422587007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422587007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027497&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027497</a>, <a href="https://bioportal.bioontology.org/search?q=C4255480&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4255480</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002018</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002018</a>]</span><br /> - Vomiting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422400008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422400008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/300359004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">300359004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249497008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249497008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R11.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R11.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002013</a>]</span><br /> - Fatty infiltration of liver <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/442191002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">442191002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197321007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197321007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2711227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2711227</a>, <a href="https://bioportal.bioontology.org/search?q=C0015695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015695</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001397" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001397</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001397" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001397</a>]</span><br /> - 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 /> - Hepatic periportal necrosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0546389&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0546389</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002614" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002614</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002614" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002614</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> Neuro </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypoglycemic coma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267384006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E15" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E15</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020617</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001325" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001325</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001325" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001325</a>]</span><br /> - Muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26544005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26544005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151786&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151786</a>, <a href="https://bioportal.bioontology.org/search?q=C0030552&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030552</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001324</a>]</span><br /> - 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 />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEENT </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Facial dysmorphism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248200007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248200007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398302004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398302004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32003007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32003007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398206004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398206004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424503&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424503</a>, <a href="https://bioportal.bioontology.org/search?q=C0266617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266617</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000271" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000271</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001999" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001999</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001999" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001999</a>]</span><br /> - Macrocephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12138000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12138000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1145403003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1145403003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221355&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221355</a>, <a href="https://bioportal.bioontology.org/search?q=C2243051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2243051</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001355</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Macrocephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> - Cerebral pachygyria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23024003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23024003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q04.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q04.8</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q04.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q04.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001302" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001302</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001302" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001302</a>]</span><br /> - Cerebral gliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/359580009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">359580009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81415000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81415000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017639</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002171</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002171</a>]</span><br /> - Large anterior fontanel <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866134</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000260</a>]</span><br /> - High forehead <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239676&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239676</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000348" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000348</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000348" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000348</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1ed202dc7ca7d5b2c5e34a787d713dec" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Hairline,High_Anterior-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=1ed202dc7ca7d5b2c5e34a787d713dec&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> - Flat nasal bridge <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836542</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005280</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005280</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=7043769fd21a78a413fd758918cdda17" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Bridge,Depressed-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=7043769fd21a78a413fd758918cdda17&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> - Telecanthus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246803005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246803005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423113&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423113</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000506" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000506</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000506" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000506</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=d87370f552af271a3bb27b2e061542cb" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Telecanthus-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=d87370f552af271a3bb27b2e061542cb&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> - Congenital cataract <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79410001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79410001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q12.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q12.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/743.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">743.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009691&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009691</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000519" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000519</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000519" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000519</a>]</span><br /> - Malformed ears <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0857379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0857379</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000377" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000377</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000377" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000377</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> Skin </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Jaundice <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18165001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18165001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R17" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R17</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2203646&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2203646</a>, <a href="https://bioportal.bioontology.org/search?q=C0022346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022346</a>, <a href="https://bioportal.bioontology.org/search?q=C2010848&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2010848</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000952" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000952</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000952" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000952</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> Respiratory </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Respiratory distress <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271825005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271825005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0476273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0476273</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002098</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002098</a>]</span><br /> - Pulmonary hypoplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80825009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80825009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265783&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265783</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002089" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002089</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002089" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002089</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GU </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Selective proximal tubular damage <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839603</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000114</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000114</a>]</span><br /> - Renal cortical cysts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969144</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000803" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000803</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000803" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000803</a>]</span><br /> - Polycystic kidneys <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82525005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82525005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q61.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q61.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/753.12" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">753.12</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1567435&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1567435</a>, <a href="https://bioportal.bioontology.org/search?q=C0022680&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022680</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000113" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000113</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000113" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000113</a>]</span><br /> - Genital defects <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0744356&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0744356</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000078</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000078</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> Lab </strong>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Glutaric aciduria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28987007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28987007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E72.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E72.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0268594&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0268594</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003150" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003150</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003150" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003150</a>]</span><br /> - Glutaric acidemia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4025603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4025603</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003530" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003530</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003530" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003530</a>]</span><br /> - Ethylmalonic aciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865353&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865353</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003219" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003219</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003219" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003219</a>]</span><br /> - Glycosuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45154002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45154002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/791.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">791.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017979&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017979</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003076" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003076</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003076" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003076</a>]</span><br /> - Generalized aminoaciduria <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847868&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847868</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002909" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002909</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002909" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002909</a>]</span><br /> - Defective dehydrogenation of isovaleryl CoA and butyryl CoA<br /> - Electron transfer flavoprotein-ubiquinone oxidoreductase defect <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4025586&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4025586</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003647" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003647</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003647" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003647</a>]</span><br />
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- 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 />
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<p>A number sign (#) is used with this entry because MADD, also known as glutaric acidemia II or glutaric aciduria II, can be caused by mutations in at least 3 different genes: ETFA (<a href="/entry/608053">608053</a>), ETFB (<a href="/entry/130410">130410</a>), and ETFDH (<a href="/entry/231675">231675</a>). These genes are all involved in electron transfer in the mitochondrial respiratory chain. The disorders resulting from defects in these 3 genes are referred to as glutaric acidemia IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotypes.</p>
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<p>Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1; <a href="/entry/231670">231670</a>) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (<a href="#15" class="mim-tip-reference" title="Goodman, S. I. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Denver, Colorado 5/20/1993."None>Goodman, 1993</a>; <a href="#33" class="mim-tip-reference" title="Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. &lt;strong&gt;Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency.&lt;/strong&gt; Hum. Mutat. 22: 12-23, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12815589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12815589&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10226&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12815589">Olsen et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by <a href="#12" class="mim-tip-reference" title="Frerman, F. E., Goodman, S. I. &lt;strong&gt;Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. (8th ed.)&lt;/strong&gt; New York: McGraw-Hill (pub.) 2001. Pp. 2357-2365."None>Frerman and Goodman, 2001</a>).</p><p>Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (<a href="#27" class="mim-tip-reference" title="Liang, W.-C., Ohkuma, A., Hayashi, Y. K., Lopez, L. C., Hirano, M., Nonaka, I., Noguchi, S., Chen, L.-H., Jong, Y.-J., Nishino, I. &lt;strong&gt;ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.&lt;/strong&gt; Neuromusc. Disord. 19: 212-216, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19249206/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19249206&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2009.01.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19249206">Liang et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19249206" 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><strong><em>Neonatal Onset</em></strong></p><p>
In the son of healthy parents from the same small town in Turkey, <a href="#36" class="mim-tip-reference" title="Przyrembel, H., Wendel, U., Becker, K., Bremer, H. J., Bruinvis, L., Ketting, D., Wadman, S. K. &lt;strong&gt;Glutaric aciduria type II: report on a previously undescribed metabolic disorder.&lt;/strong&gt; Clin. Chim. Acta 66: 227-239, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1245071/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1245071&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0009-8981(76)90060-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1245071">Przyrembel et al. (1976)</a> described fatal neonatal acidosis and hypoglycemia with a strong 'sweaty feet' odor. Large amounts of glutaric acid were found in the blood and urine. The defect was tentatively located to the metabolism of a range of acyl-CoA compounds. A possibly identically affected child died earlier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1245071" 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="Lehnert, W., Wendel, U., Lindenmaier, S., Bohm, N. &lt;strong&gt;Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis.&lt;/strong&gt; Europ. J. Pediat. 139: 56-59, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7173259/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7173259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00442081&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7173259">Lehnert et al. (1982)</a>, <a href="#4" class="mim-tip-reference" title="Bohm, N., Uy, J., Kiebling, M., Lehnert, W. &lt;strong&gt;Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis.&lt;/strong&gt; Europ. J. Pediat. 139: 60-65, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7173260/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7173260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00442082&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7173260">Bohm et al. (1982)</a>, and others described malformations with multiple acyl-CoA dehydrogenation deficiency: congenital polycystic kidneys, characteristic facies, etc. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7173260+7173259" 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>Typical clinical features of the disorder are respiratory distress, muscular hypotonia, sweaty feet odor, hepatomegaly, and death often in the neonatal period. Of the 12 previously reported cases reviewed by <a href="#32" class="mim-tip-reference" title="Niederwieser, A., Steinmann, B., Exner, U., Neuheiser, F., Redweik, U., Wang, M., Rampini, S., Wendel, U. &lt;strong&gt;Multiple acyl-CoA dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy: detection of N-isovalerylglutamic acid and its monoamide.&lt;/strong&gt; Helv. Paediat. Acta 38: 9-26, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6862997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6862997&lt;/a&gt;]" pmid="6862997">Niederwieser et al. (1983)</a>, 7 died in the first 5 days of life and only 2 patients survived to ages 5 and 19 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6862997" 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="Harkin, J. C., Gill, W. L., Shapira, E. &lt;strong&gt;Glutaric acidemia type II: phenotypic findings and ultrastructural studies of brain and kidney.&lt;/strong&gt; Arch. Path. Lab. Med. 110: 399-401, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3754423/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3754423&lt;/a&gt;]" pmid="3754423">Harkin et al. (1986)</a> described apparently characteristic and perhaps pathognomonic, cytoplasmic, homogeneous, and moderately electron-dense membrane-limited bodies in the central nervous system and renal tissues of a female patient who died at age 5 days. The kidneys were enlarged with numerous cortical cysts. Selective proximal tubular damage leads to glycosuria and generalized amino aciduria. The patient came from an inbred Louisiana Cajun community and had a sib who also died in the newborn period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3754423" 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>Patients with severe deficiency of the ETF dehydrogenase type have distinctive congenital malformations, whereas those with ETF deficiency do not; the severity of the metabolic block, rather than its location, and the resulting profound acidosis in utero may disturb normal morphogenesis. <a href="#5" class="mim-tip-reference" title="Colevas, A. D., Edwards, J. L., Hruban, R. H., Mitchell, G. A., Valle, D., Hutchins, G. M. &lt;strong&gt;Glutaric acidemia type II: comparison of pathologic features in two infants.&lt;/strong&gt; Arch. Path. Lab. Med. 112: 1133-1139, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3178428/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3178428&lt;/a&gt;]" pmid="3178428">Colevas et al. (1988)</a> described the pathologic findings in 2 cases. The pattern of lesions, in particular the striking localization of renal dysplasia to the medulla, suggested that the malformations may be the consequence of an accumulation of toxic metabolites that is not corrected by placental transfer. Other malformations included cerebral pachygyria, pulmonary hypoplasia, and facial dysmorphism. Lipid accumulation was demonstrated in the liver, heart, and renal tubular epithelium, all tissues that use fatty acids as a primary source of energy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3178428" 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="#40" class="mim-tip-reference" title="Wilson, G. N., de Chadarevian, J.-P., Kaplan, P., Loehr, J. P., Frerman, F. E., Goodman, S. I. &lt;strong&gt;Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy.&lt;/strong&gt; Am. J. Med. Genet. 32: 395-401, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2658591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2658591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320326&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2658591">Wilson et al. (1989)</a> found reports of malformations in 8 of 16 cases. The anomalies included macrocephaly, large anterior fontanel, high forehead, flat nasal bridge, telecanthus, and malformed ears. Abnormalities such as hypotonia, cerebral gliosis, heterotopias, hepatomegaly, hepatic periportal necrosis, polycystic kidneys, and genital defects were considered reminiscent of the anomalies in Zellweger syndrome, but elevations of glutaric, ethylmalonic, adipic, and isovaleric acids were considered distinctive for glutaric aciduria type II. <a href="#40" class="mim-tip-reference" title="Wilson, G. N., de Chadarevian, J.-P., Kaplan, P., Loehr, J. P., Frerman, F. E., Goodman, S. I. &lt;strong&gt;Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy.&lt;/strong&gt; Am. J. Med. Genet. 32: 395-401, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2658591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2658591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320326&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2658591">Wilson et al. (1989)</a> described a unique ultrastructural change in the glomerular basement membrane which they suggested may represent an early stage in renal cyst formation and provide a diagnostic criterion for glutaric aciduria II when enzyme studies are unavailable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2658591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Poplawski, N. K., Ranieri, E., Harrison, J. R., Fletcher, J. M. &lt;strong&gt;Multiple acyl-coenzyme A dehydrogenase deficiency: diagnosis by acyl-carnitine analysis of a 12-year-old newborn screening card.&lt;/strong&gt; J. Pediat. 134: 764-766, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10356148/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10356148&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(99)70295-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10356148">Poplawski et al. (1999)</a> reported a family in which an unexplained neonatal death had occurred. Twelve years after the death, they retrospectively diagnosed multiple acyl-CoA-dehydrogenase deficiency by demonstrating an abnormal acyl-carnitine profile in the child's archived neonatal screening card, using tandem mass spectrometry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10356148" 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="Angle, B., Burton, B. K. &lt;strong&gt;Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II.&lt;/strong&gt; Molec. Genet. Metab. 93: 36-39, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17977044/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17977044&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2007.09.015&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17977044">Angle and Burton (2008)</a> reported 3 unrelated infants with genetically confirmed MADD who experienced sudden acute life-threatening events in the first year of life, resulting in death in 2 infants. All had been correctly diagnosed via a newborn screening protocol. Each developed cardiopulmonary arrest concurrent with metabolic stress or limited caloric intake, including vomiting, upper respiratory infection, and rotaviral diarrhea. Although only 1 patient had a documented arrhythmia, <a href="#2" class="mim-tip-reference" title="Angle, B., Burton, B. K. &lt;strong&gt;Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II.&lt;/strong&gt; Molec. Genet. Metab. 93: 36-39, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17977044/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17977044&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ymgme.2007.09.015&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17977044">Angle and Burton (2008)</a> suggested that an intrinsic abnormality of myocardial function due to altered energy production may have played a role. The authors emphasized the importance of aggressive nutritional management in infants with MADD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17977044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Later Onset</em></strong></p><p>
Hypoglycemia caused by inborn errors of metabolism, including disturbances of organic-acid metabolism, usually appear during infancy or childhood. Thus, the case reported by <a href="#10" class="mim-tip-reference" title="Dusheiko, G., Kew, M. C., Joffe, B. I., Lewin, J. R., Mantagos, S., Tanaka, K. &lt;strong&gt;Recurrent hypoglycemia associated with glutaric aciduria type II in an adult.&lt;/strong&gt; New Eng. J. Med. 301: 1405-1409, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/514320/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;514320&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197912273012601&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="514320">Dusheiko et al. (1979)</a> was unusual. A 19-year-old woman had episodic vomiting, severe hypoglycemia, and fatty infiltration of the liver. The parents were not related. One of her sisters, at age 7, developed nausea, vomiting, and a 'stale' odor to the breath, and died after 3 days in hypoglycemic coma. At age 10, a second sister was found to have jaundice, hepatomegaly, and hypoglycemia after an acute febrile illness. She recovered from that illness but died 'in her sleep' 2 years later. Excess amounts of glutaric and ethylmalonic acids were found in the urine, consistent with defective dehydrogenation of isovaleryl CoA and butyryl CoA, respectively. These organic acids plus others are excreted in the urine in excess in Jamaican vomiting sickness, caused by the ingestion of unripe akee. Unripe akee contains the toxin hypoglycin, which inhibits several acyl CoA dehydrogenases. Cultured fibroblasts in the patient of <a href="#10" class="mim-tip-reference" title="Dusheiko, G., Kew, M. C., Joffe, B. I., Lewin, J. R., Mantagos, S., Tanaka, K. &lt;strong&gt;Recurrent hypoglycemia associated with glutaric aciduria type II in an adult.&lt;/strong&gt; New Eng. J. Med. 301: 1405-1409, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/514320/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;514320&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM197912273012601&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="514320">Dusheiko et al. (1979)</a> showed reduced ability to oxidize radiolabeled butyrate and lysine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=514320" 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="#30" class="mim-tip-reference" title="Mongini, T., Doriguzzi, C., Palmucci, L., De Francesco, A., Bet, L., Manfredi, L., Ponzetto, C., Bresolin, N. &lt;strong&gt;Lipid storage myopathy in multiple acyl-CoA dehydrogenase deficiency: an adult case.&lt;/strong&gt; Europ. Neurol. 32: 170-176, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1592075/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1592075&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000116817&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1592075">Mongini et al. (1992)</a> reported a 25-year-old woman who complained of episodes of muscle weakness, nausea and vomiting since the age of 10 years. She had been born with bilateral cataracts and strabismus. Muscle biopsy showed free fatty acid accumulation. Low-fat diet reduced the episodes of muscle weakness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1592075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Horvath, R., Schneiderat, P., Schoser, B. G. H., Gempel, K., Neuen-Jacob, E., Ploger, H., Muller-Hocker, J., Pongratz, D. E., Naini, A., DiMauro, S., Lochmuller, H. &lt;strong&gt;Coenzyme Q10 deficiency and isolated myopathy.&lt;/strong&gt; Neurology 66: 253-255, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16434667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16434667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000194241.35115.7c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16434667">Horvath et al. (2006)</a> reported 3 unrelated patients with myopathy associated with coenzyme Q10 deficiency: a 32-year-old German woman who developed proximal muscle weakness during pregnancy; a 29-year-old Turkish man who developed difficulty walking and premature fatigue; and a 6-year-old Hungarian boy who had exercise intolerance and generalized hypotonia. All patients had significantly increased serum creatine kinase, increased serum lactate, myopathic changes on EMG, and hypo- or areflexia. None had myoglobinuria, ataxia, or seizures. Muscle biopsies showed lipid storage myopathy, respiratory chain complex deficiencies, and CoQ10 levels below 50% of normal. All 3 patients showed marked improvement after 3 to 6 months of oral CoQ10 supplementation. <a href="#13" class="mim-tip-reference" title="Gempel, K., Topaloglu, H., Talim, B., Schneiderat, P., Schoser, B. G. H., Hans, V. H., Palmafy, B., Kale, G., Tokatli, A., Quinzii, C., Hirano, M., Naini, A., DiMauro, S., Prokisch, H., Lochmuller, H., Horvath, R. &lt;strong&gt;The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.&lt;/strong&gt; Brain 130: 2037-2044, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17412732/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17412732&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17412732[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awm054&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17412732">Gempel et al. (2007)</a> reported follow-up on the patients reported by <a href="#20" class="mim-tip-reference" title="Horvath, R., Schneiderat, P., Schoser, B. G. H., Gempel, K., Neuen-Jacob, E., Ploger, H., Muller-Hocker, J., Pongratz, D. E., Naini, A., DiMauro, S., Lochmuller, H. &lt;strong&gt;Coenzyme Q10 deficiency and isolated myopathy.&lt;/strong&gt; Neurology 66: 253-255, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16434667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16434667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000194241.35115.7c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16434667">Horvath et al. (2006)</a>. The German woman had developed abnormal liver enzymes and recurrence of muscle weakness, and laboratory studies showed increased multiple acyl-CoA derivatives in serum. The Turkish man had proximal muscle weakness with scapular winging and waddling gait, and laboratory studies were consistent with MADD. <a href="#13" class="mim-tip-reference" title="Gempel, K., Topaloglu, H., Talim, B., Schneiderat, P., Schoser, B. G. H., Hans, V. H., Palmafy, B., Kale, G., Tokatli, A., Quinzii, C., Hirano, M., Naini, A., DiMauro, S., Prokisch, H., Lochmuller, H., Horvath, R. &lt;strong&gt;The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.&lt;/strong&gt; Brain 130: 2037-2044, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17412732/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17412732&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17412732[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awm054&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17412732">Gempel et al. (2007)</a> also reported 5 patients from 3 additional consanguineous families with late-onset MADD manifest as childhood-onset muscle weakness, muscle pain, and increased serum creatine kinase. All 7 patients responded favorably to riboflavin and/or coenzyme Q supplementation. Muscle biopsies showed a myopathy with lipid accumulation and small vacuoles; only 2 patients had ragged-red fibers. All had a decrease of respiratory complex I+III and II+III activity, and all had decreased muscle CoQ10 levels. Molecular analysis identified biallelic pathogenic mutations in the ETFDH gene in all patients (see, e.g., <a href="/entry/231675#0007">231675.0007</a> and <a href="/entry/231675#0008">231675.0008</a>), thus confirming the diagnosis of MADD. <a href="#13" class="mim-tip-reference" title="Gempel, K., Topaloglu, H., Talim, B., Schneiderat, P., Schoser, B. G. H., Hans, V. H., Palmafy, B., Kale, G., Tokatli, A., Quinzii, C., Hirano, M., Naini, A., DiMauro, S., Prokisch, H., Lochmuller, H., Horvath, R. &lt;strong&gt;The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.&lt;/strong&gt; Brain 130: 2037-2044, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17412732/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17412732&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17412732[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awm054&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17412732">Gempel et al. (2007)</a> concluded that MADD due to ETFDH mutations can result in isolated myopathy with secondary coenzyme Q10 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16434667+17412732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Liang, W.-C., Ohkuma, A., Hayashi, Y. K., Lopez, L. C., Hirano, M., Nonaka, I., Noguchi, S., Chen, L.-H., Jong, Y.-J., Nishino, I. &lt;strong&gt;ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.&lt;/strong&gt; Neuromusc. Disord. 19: 212-216, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19249206/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19249206&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2009.01.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19249206">Liang et al. (2009)</a> reported 4 Taiwanese patients from 3 unrelated families with MADD due to mutations in the ETFDH gene (<a href="/entry/231675#0003">231675.0003</a>-<a href="/entry/231675#0005">231675.0005</a>). There was marked phenotypic variability, even between 2 affected sibs with the same genotype. The first patient was a 27-year-old woman who had exercise intolerance since early childhood. In her teens, she developed several episodes of acute pancreatitis. At age 19, she developed dysphagia with progressive weakness of neck and proximal limb muscles, and later had a more severe episode of muscle weakness with acute respiratory failure, but no metabolic acidosis and hypoketotic hypoglycemia. Serum creatine kinase was elevated, and muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. Urinary profile was consistent with MADD. Her older sister had a milder phenotype, with 2 bouts of muscle weakness and difficulty climbing stairs and combing her hair. She never had metabolic crisis, hypoketotic hypoglycemia, or respiratory failure. Laboratory studies showed low serum carnitine, increased serum acylcarnitine levels, and elevated glutaric, ethylmalonic, 2-hydroxylglutaric, 3-methylglutaconic, and lactic acids in urine. Both patients responded well to riboflavin and carnitine treatment. The third patient developed exercise intolerance, dysphagia, poor head control, and limb weakness at age 14 years, and was wheelchair-bound by age 16. He had neck and proximal muscle weakness with wasting, lordosis, winged scapula, and absent tendon reflexes. He did not have metabolic acidosis or hypoketotic hypoglycemia. Pulmonary function tests demonstrated a severe restrictive ventilatory defect. Muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. He also responded well to riboflavin and carnitine treatment. The last patient was a 10-year-old girl who was a slow runner since childhood. She had an upper respiratory tract infection followed by progressive proximal muscle weakness. A few days after discharge from the hospital, her condition rapidly deteriorated and she developed fatal cardiopulmonary failure associated with marked metabolic acidosis, hyperammonemia, and hypoglycemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19249206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Lan, M.-Y., Fu, M.-H., Liu, Y.-F., Huang, C.-C., Chang, Y.-Y., Liu, J.-S., Peng, C.-H., Chen, S.-S. &lt;strong&gt;High frequency of ETFDH c.250G-A mutation in Taiwanese patients with late-onset lipid storage myopathy.&lt;/strong&gt; Clin. Genet. 78: 565-569, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20370797/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20370797&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2010.01421.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20370797">Lan et al. (2010)</a> reported 7 Han Taiwanese patients with genetically confirmed MADD. The patients were identified retrospectively by review of muscle biopsies ascertained for lipid storage myopathy, and all were asymptomatic when recruited. The age at diagnosis ranged from 7 to 43 years, and the patients' ages at the time of the report were between 22 and 44 years. All had a history of episodic myalgia and limb weakness predominantly affecting the proximal muscles during an acute stage of myopathy. Four had dysphagia and 2 had respiratory failure. Serum creatine kinase was increased during the acute attacks. Three had 1 episode, whereas 4 had recurrent episodes. Four patients had extramuscular features, including encephalopathy, seizures, hypoglycemia, and heart failure in 1; vomiting and cardiac arrhythmia in 1; encephalopathy, liver function impairment and lactic acidosis in 1; and vomiting and liver function impairment in 1. All except 1 regained normal muscle strength after the acute stage. Trigger factors in some patients included prolonged fasting and exercise. Blood analysis showed increased acylcarnitines ranging from C8 to C16. Genetic analysis showed that 6 of the patients were homozygous for an A84T mutation in the ETFDH gene (<a href="/entry/231675#0003">231675.0003</a>), and 1 was compound heterozygous for A84T and R175H (<a href="/entry/231675#0006">231675.0006</a>). This patient also had a heterozygous substitution in the PNPLA2 gene (<a href="/entry/609059">609059</a>), which was not thought to contribute to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20370797" 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="#24" class="mim-tip-reference" title="Lalani, S. R., Vladutiu, G. D., Plunkett, K., Lotze, T. E., Adesina, A. M., Scaglia, F. &lt;strong&gt;Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency.&lt;/strong&gt; Arch. Neurol. 62: 317-320, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15710863/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15710863&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.62.2.317&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15710863">Lalani et al. (2005)</a> reported a boy who presented at 11.5 years of age with exercise intolerance and ragged-red fibers identified on muscle histology. Muscle CoQ10 was reduced (46% of normal) and complex I, I+III, and II+III activity was decreased. He was originally diagnosed with primary muscle coenzyme Q10 deficiency (<a href="/entry/607426">607426</a>), and treatment with CoQ10 supplementation resulted in significant clinical improvement. However, he presented again at age 23 with relapse of muscle weakness, myalgia, and extreme fatigue. Laboratory studies showed elevated creatine kinase, aspartate transaminase, and alanine transaminase, and ultrasound showed signs of fatty liver disease. Acylcarnitine profile in blood demonstrated elevation of C14-C18 species, and urine organic acids showed elevation in ethylmalonic acid, isovaleric acid, glutaric acid, and hexanoyl glycine. A diagnosis of MADD was confirmed by direct gene sequencing, and he was started on riboflavin and ubiquinol in place of ubiquinone. After 4 months of treatment, the patient experienced improvement of symptoms and had normalization of laboratory values. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15710863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="biochemicalFeatures" class="mim-anchor"></a>
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<strong>Biochemical Features</strong>
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<p>By fusion of isovaleric acidemia (<a href="/entry/243500">243500</a>) cells with those of GA II, <a href="#9" class="mim-tip-reference" title="Dubiel, B., Dabrowski, C., Wetts, R., Tanaka, K. &lt;strong&gt;Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.&lt;/strong&gt; J. Clin. Invest. 72: 1543-1552, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6630517/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6630517&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI111113&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6630517">Dubiel et al. (1983)</a> showed that these disorders are genetically distinct, since complementation was observed. In both disorders, isovaleryl-CoA dehydrogenation is blocked. The defect in GA II is in one of the proteins involved in the transfer of electrons from acyl-CoA dehydrogenases to coenzyme Q of the mitochondrial electron transport chain. Sarcosinemia and sarcosinuria are also observed in this disorder (<a href="#14" class="mim-tip-reference" title="Goodman, S. I., McCabe, E. R. B., Fennessey, P. V., Mace, J. W. &lt;strong&gt;Multiple acyl Co-A dehydrogenase deficiency (glutaric aciduria type II) with transient hypersarcosinemia and sarcosinuria; possible inherited deficiency of an electron transfer flavoprotein.&lt;/strong&gt; Pediat. Res. 14: 12-17, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7360517/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7360517&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-198001000-00004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7360517">Goodman et al., 1980</a>; <a href="#16" class="mim-tip-reference" title="Gregersen, N., Kolvraa, S., Rasmussen, K., Christensen, E., Brandt, N. J., Ebbesen, F., Hansen, F. H. &lt;strong&gt;Biochemical studies in a patient with defects in the metabolism of acyl-CoA and sarcosine: another possible case of glutaric aciduria type II.&lt;/strong&gt; J. Inherit. Metab. Dis. 3: 67-72, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6158623/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6158623&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF02312527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6158623">Gregersen et al., 1980</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6630517+7360517+6158623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Ikeda, Y., Keese, S., Tanaka, K. &lt;strong&gt;Molecular heterogeneity of electron transfer flavoprotein (ETF) in glutaric acidemia type II due to an ETF deficiency. (Abstract)&lt;/strong&gt; Pediat. Res. 19: 249A, 1985."None>Ikeda et al. (1985)</a> concluded that defective synthesis of ETFA was the fundamental defect in 3 cell lines from patients with severe MADD.</p><p><a href="#31" class="mim-tip-reference" title="Moon, A., Rhead, W. J. &lt;strong&gt;Complementation analysis of fatty acid oxidation disorders.&lt;/strong&gt; J. Clin. Invest. 79: 59-64, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3793932/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3793932&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI112808&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3793932">Moon and Rhead (1987)</a> detected 2 complementation groups in cell lines from patients with severe multiple acyl-CoA dehydrogenation disorder. This was consistent with the different defects in glutaric aciduria IIA and glutaric aciduria IIB. The metabolic block in the cell lines from the latter disorder was 3 times more severe than the former, as assayed by oxidation of radiolabelled palmitate. No intragenic complementation was observed within either group. Complementation was started after polyethylene glycol fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3793932" 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="#34" class="mim-tip-reference" title="Onkenhout, W., Venizelos, V., Scholte, H. R., De Klerk, J. B. C., Poorthuis, B. J. H. M. &lt;strong&gt;Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects.&lt;/strong&gt; J. Inherit. Metab. Dis. 24: 337-344, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11486898/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11486898&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1010592232317&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11486898">Onkenhout et al. (2001)</a> determined the fatty acid composition of liver, skeletal muscle, and heart obtained postmortem from patients with deficiency of 1 of 3 types of acyl-CoA dehydrogenase: medium-chain (MCAD; <a href="/entry/607008">607008</a>), multiple (MADD), and very long-chain (VLCADD; <a href="/entry/201475">201475</a>). Increased amounts of multiple unsaturated fatty acids were found exclusively in the triglyceride fraction. They could not be detected in the free fatty acid or phospholipid fractions. <a href="#34" class="mim-tip-reference" title="Onkenhout, W., Venizelos, V., Scholte, H. R., De Klerk, J. B. C., Poorthuis, B. J. H. M. &lt;strong&gt;Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects.&lt;/strong&gt; J. Inherit. Metab. Dis. 24: 337-344, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11486898/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11486898&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1023/a:1010592232317&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11486898">Onkenhout et al. (2001)</a> concluded that intermediates of unsaturated fatty acid oxidation that accumulate as a consequence of MCADD, MADD, and VLCADD are transported to the endoplasmic reticulum for esterification into neutral glycerolipids. The pattern of accumulation is characteristic for each disease, which makes fatty acid analysis of total lipid of postmortem tissues a useful tool in the detection of mitochondrial fatty acid oxidation defects in patients who have died unexpectedly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486898" 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>Riboflavin-responsive multiple acylcoenzyme A dehydrogenase deficiency is characterized by, among other features, a decrease in fatty acid beta-oxidation capacity. Muscle uncoupling protein-3 (UCP3; <a href="/entry/602044">602044</a>) is upregulated under conditions that either increase the levels of circulating free fatty acid and/or decrease fatty acid beta-oxidation. Using a relatively large cohort of 7 MADD patients, <a href="#38" class="mim-tip-reference" title="Russell, A. P., Schrauwen, P., Somm, E., Gastaldi, G., Hesselink, M. K. C., Schaart, G., Kornips, E., Lo, S. K., Bufano, D., Giacobino, J.-P., Muzzin, P., Ceccon, M., Angelini, C., Vergani, L. &lt;strong&gt;Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 5921-5926, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14671191/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14671191&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-030885&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14671191">Russell et al. (2003)</a> studied the metabolic disturbances of this disease and determined if they might increase UCP3 expression. Biochemical and molecular tests demonstrated decreases in fatty acid beta-oxidation and in the activities of respiratory chain complexes I (see <a href="/entry/157655">157655</a>) and II (see <a href="/entry/600857">600857</a>). These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acid/acylCoA. The authors considered MADD an optimal model to study the hypothesis that UCP3 is involved in the outward translocation of an excess of fatty acid from the mitochondria and to show that, in humans, the effects of fatty acid on UCP3 expression are direct and independent of fatty acid beta-oxidation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p><a href="#28" class="mim-tip-reference" title="Mantagos, S., Genel, M., Tanaka, K. &lt;strong&gt;Ethylmalonic-adipic aciduria: in vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases.&lt;/strong&gt; J. Clin. Invest. 64: 1580-1589, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/500826/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;500826&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI109619&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="500826">Mantagos et al. (1979)</a> proved autosomal recessive inheritance of MADD by demonstration of partial enzyme deficiency in each parent of a female patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=500826" 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="#32" class="mim-tip-reference" title="Niederwieser, A., Steinmann, B., Exner, U., Neuheiser, F., Redweik, U., Wang, M., Rampini, S., Wendel, U. &lt;strong&gt;Multiple acyl-CoA dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy: detection of N-isovalerylglutamic acid and its monoamide.&lt;/strong&gt; Helv. Paediat. Acta 38: 9-26, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6862997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6862997&lt;/a&gt;]" pmid="6862997">Niederwieser et al. (1983)</a> reported the case of the son of consanguineous Jewish parents who died at age 7 months. In a note added in proof, they described the prenatal diagnosis of an affected female of the same parentage, indicating autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6862997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#7" class="mim-tip-reference" title="Costa, C. G., Verhoeven, N. M., Kneepkens, C. M. F., Douwes, A. C., Wanders, R. J. A., Tavares De Almeida, I., Duran, M., Jakobs, C. &lt;strong&gt;Organic acid profiles resembling a beta-oxidation defect in two patients with coeliac disease.&lt;/strong&gt; J. Inherit. Metab. Dis. 19: 177-180, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8739959/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8739959&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01799423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8739959">Costa et al. (1996)</a> noted that a number of subclinical deficiencies caused by malabsorption could be misdiagnosed as inherited mitochondrial fatty acid oxidation defects. They suggested that in the presence of organic acid profiles reminiscent of a defect in the beta-oxidation pathway or a profile reminiscent of glutaric aciduria type II, a possible digestive disorder should be ruled out. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8739959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
Yamaguchi et al. (<a href="#42" class="mim-tip-reference" title="Yamaguchi, S., Orii, T., Maeda, K., Oshima, M., Hashimoto, T. &lt;strong&gt;A new variant of glutaric aciduria type II: deficiency of beta-subunit of electron transfer flavoprotein.&lt;/strong&gt; J. Inherit. Metab. Dis. 13: 783-786, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2246866/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2246866&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01799588&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2246866">1990</a>, <a href="#43" class="mim-tip-reference" title="Yamaguchi, S., Orii, T., Suzuki, Y., Maeda, K., Oshima, M., Hashimoto, T. &lt;strong&gt;Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II.&lt;/strong&gt; Pediat. Res. 29: 60-63, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2000260/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2000260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-199101000-00012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2000260">1991</a>) described type II glutaric aciduria due to deficiency of ETFB. The patient had a neonatal onset of intermittent illness without congenital anomalies. The diagnosis was made at the age of 10 months. Subsequently, the parents of the patient of <a href="#43" class="mim-tip-reference" title="Yamaguchi, S., Orii, T., Suzuki, Y., Maeda, K., Oshima, M., Hashimoto, T. &lt;strong&gt;Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II.&lt;/strong&gt; Pediat. Res. 29: 60-63, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2000260/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2000260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-199101000-00012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2000260">Yamaguchi et al. (1991)</a> had another pregnancy and <a href="#44" class="mim-tip-reference" title="Yamaguchi, S., Shimizu, N., Orii, T., Fukao, T., Suzuki, Y., Maeda, K., Hashimoto, T., Previs, S. F., Rinaldo, P. &lt;strong&gt;Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency.&lt;/strong&gt; Pediat. Res. 30: 439-443, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1754299/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1754299&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-199111000-00009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1754299">Yamaguchi et al. (1991)</a> performed prenatal diagnosis by immunochemical procedures on cultured amniocytes and by organic acid analysis of amniotic fluid, using a stable isotope dilution method. They also described the monitoring of the clinical course and metabolite excretion in early infancy when the patient had no symptoms. Glutarate concentration was increased in the cell-free supernatant of the amniotic fluid. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2000260+1754299+2246866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalManagement" class="mim-anchor"></a>
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<strong>Clinical Management</strong>
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<p><a href="#17" class="mim-tip-reference" title="Gregersen, N., Wintzensen, H., Christensen, S. K. E., Christensen, M. F., Brandt, N. J., Rasmussen, K. &lt;strong&gt;C(6)-C(10)-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects.&lt;/strong&gt; Pediat. Res. 16: 861-868, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7145508/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7145508&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-198210000-00012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7145508">Gregersen et al. (1982)</a> reported successful treatment of a 5 year old with riboflavin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7145508" 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>Riboflavin-responsive glutaric aciduria type II was reported by <a href="#39" class="mim-tip-reference" title="Uziel, G., Garavaglia, B., Ciceri, E., Moroni, I., Rimoldi, M. &lt;strong&gt;Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy.&lt;/strong&gt; Pediat. Neurol. 13: 333-335, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8771170/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8771170&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0887-8994(95)00187-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8771170">Uziel et al. (1995)</a> in a boy who developed gradually progressive spastic ataxia and a leukodystrophy without ever having experienced episodic metabolic crises. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8771170" 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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<div>
<a id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Glutaric aciduria IIA</em></strong></p><p>
<a href="#22" class="mim-tip-reference" title="Indo, Y., Glassberg, R., Yokota, I., Tanaka, K. &lt;strong&gt;Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient.&lt;/strong&gt; Am. J. Hum. Genet. 49: 575-580, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1882842/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1882842&lt;/a&gt;]" pmid="1882842">Indo et al. (1991)</a>, <a href="#37" class="mim-tip-reference" title="Rhead, W. J., Freneaux, E., Sheffield, V. C., Molin, L., Shires, A. &lt;strong&gt;Glutaric acidemia type II (GAII): heterogeneity in beta-oxidation flux, polypeptide synthesis and cDNA mutations in the alpha-subunit of electron transfer flavoprotein in 8 patients. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A175, 1992."None>Rhead et al. (1992)</a>, and <a href="#11" class="mim-tip-reference" title="Freneaux, E., Sheffield, V. C., Molin, L., Shires, A., Rhead, W. J. &lt;strong&gt;Glutaric acidemia type II: heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha-subunit of electron transfer flavoprotein in eight patients.&lt;/strong&gt; J. Clin. Invest. 90: 1679-1686, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1430199/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1430199&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116040&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1430199">Freneaux et al. (1992)</a> identified mutations in the ETFA gene in patients with GA IIA (e.g., <a href="/entry/608053#0001">608053.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1882842+1430199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Glutaric aciduria IIB</em></strong></p><p>
<a href="#6" class="mim-tip-reference" title="Colombo, I., Finocchiaro, G., Garavaglia, B., Garbuglio, N., Yamaguchi, S., Frerman, F. E., Berra, B., DiDonato, S. &lt;strong&gt;Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaricacidemia type II.&lt;/strong&gt; Hum. Molec. Genet. 3: 429-435, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7912128/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7912128&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/3.3.429&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7912128">Colombo et al. (1994)</a> identified mutations in the ETFB gene in patients with GA IIB (e.g., <a href="/entry/130410#0001">130410.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7912128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Glutaric aciduria IIC</em></strong></p><p>
<a href="#3" class="mim-tip-reference" title="Beard, S. E., Spector, E. B., Seltzer, W. K., Frerman, F. E., Goodman, S. I. &lt;strong&gt;Mutations in electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II (GA2). (Abstract)&lt;/strong&gt; Clin. Res. 41: 271A, 1993."None>Beard et al. (1993)</a> identified 5 mutations in the ETFDH gene (e.g., <a href="/entry/231675#0001">231675.0001</a>) in 4 patients with GA IIC. All 5 mutations were rare and caused total lack of enzyme activity and antigen.</p><p>In 4 Taiwanese patients from 3 unrelated families with relatively late-onset MADD, <a href="#27" class="mim-tip-reference" title="Liang, W.-C., Ohkuma, A., Hayashi, Y. K., Lopez, L. C., Hirano, M., Nonaka, I., Noguchi, S., Chen, L.-H., Jong, Y.-J., Nishino, I. &lt;strong&gt;ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.&lt;/strong&gt; Neuromusc. Disord. 19: 212-216, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19249206/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19249206&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.nmd.2009.01.008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19249206">Liang et al. (2009)</a> identified homozygous or compound heterozygous mutations in the ETFDH gene (<a href="/entry/231675#0003">231675.0003</a>-<a href="/entry/231675#0005">231675.0005</a>). The A84T mutation (<a href="/entry/231675#0003">231675.0003</a>) was present in all 4 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19249206" 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 7 patients from 5 families with late-onset of an isolated myopathy associated with coenzyme Q10 deficiency, <a href="#13" class="mim-tip-reference" title="Gempel, K., Topaloglu, H., Talim, B., Schneiderat, P., Schoser, B. G. H., Hans, V. H., Palmafy, B., Kale, G., Tokatli, A., Quinzii, C., Hirano, M., Naini, A., DiMauro, S., Prokisch, H., Lochmuller, H., Horvath, R. &lt;strong&gt;The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.&lt;/strong&gt; Brain 130: 2037-2044, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17412732/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17412732&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17412732[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awm054&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17412732">Gempel et al. (2007)</a> identified homozygous or compound heterozygous mutations in the ETFDH gene (see, e.g., <a href="/entry/231675#0007">231675.0007</a> and <a href="/entry/231675#0008">231675.0008</a>). Two of the patients had previously been reported by <a href="#20" class="mim-tip-reference" title="Horvath, R., Schneiderat, P., Schoser, B. G. H., Gempel, K., Neuen-Jacob, E., Ploger, H., Muller-Hocker, J., Pongratz, D. E., Naini, A., DiMauro, S., Lochmuller, H. &lt;strong&gt;Coenzyme Q10 deficiency and isolated myopathy.&lt;/strong&gt; Neurology 66: 253-255, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16434667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16434667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000194241.35115.7c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16434667">Horvath et al. (2006)</a> as having primary coenzyme Q10 deficiency (see, e.g., COQ10D1, <a href="/entry/607426">607426</a>). All patients had increased levels of multiple acyl-CoA derivatives, and all showed marked improvement upon treatment with oral CoQ10 and/or riboflavin. <a href="#13" class="mim-tip-reference" title="Gempel, K., Topaloglu, H., Talim, B., Schneiderat, P., Schoser, B. G. H., Hans, V. H., Palmafy, B., Kale, G., Tokatli, A., Quinzii, C., Hirano, M., Naini, A., DiMauro, S., Prokisch, H., Lochmuller, H., Horvath, R. &lt;strong&gt;The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.&lt;/strong&gt; Brain 130: 2037-2044, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17412732/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17412732&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17412732[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/awm054&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17412732">Gempel et al. (2007)</a> concluded that MADD due to ETFDH mutations can result in isolated myopathy with secondary coenzyme Q10 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16434667+17412732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with late-onset glutaric acidemia IIC, who was originally reported by <a href="#24" class="mim-tip-reference" title="Lalani, S. R., Vladutiu, G. D., Plunkett, K., Lotze, T. E., Adesina, A. M., Scaglia, F. &lt;strong&gt;Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency.&lt;/strong&gt; Arch. Neurol. 62: 317-320, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15710863/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15710863&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.62.2.317&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15710863">Lalani et al. (2005)</a> with primary coenzyme Q10 deficiency, <a href="#41" class="mim-tip-reference" title="Xiao, C., Astiazaran-Symonds, E., Basu, S., Kisling, M., Scaglia, F., Chapman, K. A., Wang, Y., Vockley, J., Ferreira, C. R. &lt;strong&gt;Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia type 2.&lt;/strong&gt; Am. J. Med. Genet. 182A: 2426-2431, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32804429/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32804429&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61786&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32804429">Xiao et al. (2020)</a> identified compound heterozygous mutations in the ETFDH gene (<a href="/entry/231675#0009">231675.0009</a>-<a href="/entry/231675#0010">231675.0010</a>). Western blot analysis in patient fibroblasts revealed decreased expression of the ETFHD, TFP-alpha (HADHA; <a href="/entry/600890">600890</a>), and VLCAD (<a href="/entry/609575">609575</a>) proteins, and minimally reduced TFP-beta (HADHB <a href="/entry/143450">143450</a>) protein. Mitochondrial superoxide was increased in patient fibroblasts, and steady-state ATP levels and maximal respiration-basal respiration were decreased. <a href="#41" class="mim-tip-reference" title="Xiao, C., Astiazaran-Symonds, E., Basu, S., Kisling, M., Scaglia, F., Chapman, K. A., Wang, Y., Vockley, J., Ferreira, C. R. &lt;strong&gt;Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia type 2.&lt;/strong&gt; Am. J. Med. Genet. 182A: 2426-2431, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32804429/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32804429&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61786&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="32804429">Xiao et al. (2020)</a> concluded that these studies provided evidence for widespread mitochondrial dysfunction in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32804429+15710863" 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>To examine whether the different clinical forms of MADD can be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, <a href="#33" class="mim-tip-reference" title="Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. &lt;strong&gt;Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency.&lt;/strong&gt; Hum. Mutat. 22: 12-23, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12815589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12815589&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10226&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12815589">Olsen et al. (2003)</a> investigated the molecular genetic basis for disease development in 9 patients representing the phenotypic spectrum of MADD. They identified and characterized 7 novel and 3 previously reported disease-causing mutations. Studies of these 9 patients yielded results consistent with 3 clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of the disease. Homozygosity for 2 null mutations caused fetal development of congenital anomalies, resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seemed to be sufficient to prevent embryonic development of congenital anomalies, giving rise to type II disease. Studies of an asp128-to-asn mutation of the ETFB gene (D128N; <a href="/entry/130410#0003">130410.0003</a>), identified in a patient with type III disease, showed that the residual activity of the enzyme could be rescued up to 59% of that of wildtype activity when ETFB(D128N)-transformed E. coli cells were grown at low temperature. This suggested that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors such as cellular temperature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815589" 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 neonatal lethal form, called 'GA IIA' by <a href="#8" class="mim-tip-reference" title="Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., Saudubray, J. M., Frezal, J. &lt;strong&gt;Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder.&lt;/strong&gt; Hum. Genet. 59: 263-265, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7199025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7199025&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00283677&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7199025">Coude et al. (1981)</a>, was thought possibly to be X-linked. <a href="#8" class="mim-tip-reference" title="Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., Saudubray, J. M., Frezal, J. &lt;strong&gt;Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder.&lt;/strong&gt; Hum. Genet. 59: 263-265, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7199025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7199025&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00283677&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7199025">Coude et al. (1981)</a> reported a pedigree supportive of X-linked inheritance because of the occurrence of a total of 5 proved or presumed cases in 3 sibships related through 5 presumptive carrier females. ('GA IIB' was the designation used by <a href="#8" class="mim-tip-reference" title="Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., Saudubray, J. M., Frezal, J. &lt;strong&gt;Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder.&lt;/strong&gt; Hum. Genet. 59: 263-265, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7199025/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7199025&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00283677&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7199025">Coude et al. (1981)</a> for a mild form that presented as recurrent hypoglycemia without ketosis and showed a less severe evolution with survival to adulthood.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7199025" 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="#Amendt1986" class="mim-tip-reference" title="Amendt, B. A., Rhead, W. J. &lt;strong&gt;The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria: mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts.&lt;/strong&gt; J. Clin. Invest. 78: 205-213, 1986.">Amendt and Rhead (1986)</a>; <a href="#Gregersen1985" class="mim-tip-reference" title="Gregersen, N. &lt;strong&gt;The acyl-CoA dehydrogenation deficiencies.&lt;/strong&gt; Scand. J. Clin. Lab. Invest. 45 (suppl. 174): 1-60, 1985.">Gregersen (1985)</a>; <a href="#Jakobs1984" class="mim-tip-reference" title="Jakobs, C., Sweetman, L., Wadman, S. K., Duran, M., Saudubray, J.-M., Nyhan, W. L. &lt;strong&gt;Prenatal diagnosis of glutaric aciduria type II by direct chemical analysis of dicarboxylic acids in amniotic fluid.&lt;/strong&gt; Europ. J. Pediat. 141: 153-157, 1984.">Jakobs et al. (1984)</a>; <a href="#Mitchell1983" class="mim-tip-reference" title="Mitchell, G., Saudubray, J. M., Benoit, Y., Rocchiccioli, F., Charpentier, C., Ogier, H., Boue, J. &lt;strong&gt;Antenatal diagnosis of glutaricaciduria type II. (Letter)&lt;/strong&gt; Lancet 321: 1099 only, 1983. Note: Originally Volume I.">Mitchell et al. (1983)</a>
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<a id="1" class="mim-anchor"></a>
<a id="Amendt1986" class="mim-anchor"></a>
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Amendt, B. A., Rhead, W. J.
<strong>The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria: mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts.</strong>
J. Clin. Invest. 78: 205-213, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3722376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3722376</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3722376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI112553" target="_blank">Full Text</a>]
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<a id="Angle2008" class="mim-anchor"></a>
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Angle, B., Burton, B. K.
<strong>Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II.</strong>
Molec. Genet. Metab. 93: 36-39, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17977044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17977044</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17977044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ymgme.2007.09.015" target="_blank">Full Text</a>]
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Beard, S. E., Spector, E. B., Seltzer, W. K., Frerman, F. E., Goodman, S. I.
<strong>Mutations in electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II (GA2). (Abstract)</strong>
Clin. Res. 41: 271A, 1993.
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Bohm, N., Uy, J., Kiebling, M., Lehnert, W.
<strong>Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis.</strong>
Europ. J. Pediat. 139: 60-65, 1982.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7173260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7173260</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7173260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00442082" target="_blank">Full Text</a>]
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Colevas, A. D., Edwards, J. L., Hruban, R. H., Mitchell, G. A., Valle, D., Hutchins, G. M.
<strong>Glutaric acidemia type II: comparison of pathologic features in two infants.</strong>
Arch. Path. Lab. Med. 112: 1133-1139, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3178428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3178428</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3178428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Colombo1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
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[<a href="https://doi.org/10.1093/hmg/3.3.429" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01799423" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00283677" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197912273012601" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116040" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awm054" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198001000-00004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02312527" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198210000-00012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000194241.35115.7c" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00443213" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.62.2.317" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2010.01421.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00442081" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2009.01.008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI109619" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(83)91929-3" target="_blank">Full Text</a>]
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<div class="">
<p class="mim-text-font">
Mongini, T., Doriguzzi, C., Palmucci, L., De Francesco, A., Bet, L., Manfredi, L., Ponzetto, C., Bresolin, N.
<strong>Lipid storage myopathy in multiple acyl-CoA dehydrogenase deficiency: an adult case.</strong>
Europ. Neurol. 32: 170-176, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1592075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1592075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1592075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000116817" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="31" class="mim-anchor"></a>
<a id="Moon1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Moon, A., Rhead, W. J.
<strong>Complementation analysis of fatty acid oxidation disorders.</strong>
J. Clin. Invest. 79: 59-64, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3793932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3793932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3793932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI112808" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="32" class="mim-anchor"></a>
<a id="Niederwieser1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Niederwieser, A., Steinmann, B., Exner, U., Neuheiser, F., Redweik, U., Wang, M., Rampini, S., Wendel, U.
<strong>Multiple acyl-CoA dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy: detection of N-isovalerylglutamic acid and its monoamide.</strong>
Helv. Paediat. Acta 38: 9-26, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6862997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6862997</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6862997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="33" class="mim-anchor"></a>
<a id="Olsen2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N.
<strong>Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency.</strong>
Hum. Mutat. 22: 12-23, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12815589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12815589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12815589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.10226" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="34" class="mim-anchor"></a>
<a id="Onkenhout2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Onkenhout, W., Venizelos, V., Scholte, H. R., De Klerk, J. B. C., Poorthuis, B. J. H. M.
<strong>Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects.</strong>
J. Inherit. Metab. Dis. 24: 337-344, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1023/a:1010592232317" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="35" class="mim-anchor"></a>
<a id="Poplawski1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Poplawski, N. K., Ranieri, E., Harrison, J. R., Fletcher, J. M.
<strong>Multiple acyl-coenzyme A dehydrogenase deficiency: diagnosis by acyl-carnitine analysis of a 12-year-old newborn screening card.</strong>
J. Pediat. 134: 764-766, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10356148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10356148</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10356148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(99)70295-7" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="36" class="mim-anchor"></a>
<a id="Przyrembel1976" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Przyrembel, H., Wendel, U., Becker, K., Bremer, H. J., Bruinvis, L., Ketting, D., Wadman, S. K.
<strong>Glutaric aciduria type II: report on a previously undescribed metabolic disorder.</strong>
Clin. Chim. Acta 66: 227-239, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1245071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1245071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1245071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0009-8981(76)90060-7" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="37" class="mim-anchor"></a>
<a id="Rhead1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rhead, W. J., Freneaux, E., Sheffield, V. C., Molin, L., Shires, A.
<strong>Glutaric acidemia type II (GAII): heterogeneity in beta-oxidation flux, polypeptide synthesis and cDNA mutations in the alpha-subunit of electron transfer flavoprotein in 8 patients. (Abstract)</strong>
Am. J. Hum. Genet. 51 (suppl.): A175, 1992.
</p>
</div>
</li>
<li>
<a id="38" class="mim-anchor"></a>
<a id="Russell2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Russell, A. P., Schrauwen, P., Somm, E., Gastaldi, G., Hesselink, M. K. C., Schaart, G., Kornips, E., Lo, S. K., Bufano, D., Giacobino, J.-P., Muzzin, P., Ceccon, M., Angelini, C., Vergani, L.
<strong>Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3.</strong>
J. Clin. Endocr. Metab. 88: 5921-5926, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14671191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14671191</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2003-030885" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="39" class="mim-anchor"></a>
<a id="Uziel1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Uziel, G., Garavaglia, B., Ciceri, E., Moroni, I., Rimoldi, M.
<strong>Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy.</strong>
Pediat. Neurol. 13: 333-335, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8771170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8771170</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8771170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0887-8994(95)00187-5" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="40" class="mim-anchor"></a>
<a id="Wilson1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wilson, G. N., de Chadarevian, J.-P., Kaplan, P., Loehr, J. P., Frerman, F. E., Goodman, S. I.
<strong>Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy.</strong>
Am. J. Med. Genet. 32: 395-401, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2658591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2658591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2658591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320320326" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="41" class="mim-anchor"></a>
<a id="Xiao2020" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Xiao, C., Astiazaran-Symonds, E., Basu, S., Kisling, M., Scaglia, F., Chapman, K. A., Wang, Y., Vockley, J., Ferreira, C. R.
<strong>Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia type 2.</strong>
Am. J. Med. Genet. 182A: 2426-2431, 2020.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32804429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32804429</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32804429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.61786" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="42" class="mim-anchor"></a>
<a id="Yamaguchi1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yamaguchi, S., Orii, T., Maeda, K., Oshima, M., Hashimoto, T.
<strong>A new variant of glutaric aciduria type II: deficiency of beta-subunit of electron transfer flavoprotein.</strong>
J. Inherit. Metab. Dis. 13: 783-786, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246866</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF01799588" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="43" class="mim-anchor"></a>
<a id="Yamaguchi1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yamaguchi, S., Orii, T., Suzuki, Y., Maeda, K., Oshima, M., Hashimoto, T.
<strong>Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II.</strong>
Pediat. Res. 29: 60-63, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2000260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2000260</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2000260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1203/00006450-199101000-00012" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="44" class="mim-anchor"></a>
<a id="Yamaguchi1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yamaguchi, S., Shimizu, N., Orii, T., Fukao, T., Suzuki, Y., Maeda, K., Hashimoto, T., Previs, S. F., Rinaldo, P.
<strong>Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency.</strong>
Pediat. Res. 30: 439-443, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1754299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1754299</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1754299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1203/00006450-199111000-00009" target="_blank">Full Text</a>]
</p>
</div>
</li>
</ol>
<div>
<br />
</div>
</div>
</div>
<div>
<a id="contributors" class="mim-anchor"></a>
<div class="row">
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="mim-text-font">
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Hilary J. Vernon - updated : 07/12/2021
</span>
</div>
</div>
<div class="row collapse" id="mimCollapseContributors">
<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">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 5/23/2012<br>Cassandra L. Kniffin - updated : 5/17/2012<br>Cassandra L. Kniffin - updated : 3/19/2010<br>Cassandra L. Kniffin - updated : 11/3/2009<br>John A. Phillips, III - updated : 4/1/2005<br>Victor A. McKusick - updated : 8/18/2003<br>Ada Hamosh - updated : 8/30/2001<br>Victor A. McKusick - updated : 8/5/1999<br>Jon B. Obray - updated : 7/13/1996<br>Orest Hurko - updated : 3/26/1996
</span>
</div>
</div>
</div>
<div>
<a id="creationDate" class="mim-anchor"></a>
<div class="row">
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="text-nowrap mim-text-font">
Creation Date:
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Victor A. McKusick : 6/3/1986
</span>
</div>
</div>
</div>
<div>
<a id="editHistory" class="mim-anchor"></a>
<div class="row">
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="text-nowrap mim-text-font">
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
carol : 07/13/2021
</span>
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<div class="row collapse" id="mimCollapseEditHistory">
<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">
<span class="mim-text-font">
carol : 07/12/2021<br>carol : 03/06/2018<br>carol : 07/09/2016<br>carol : 5/25/2012<br>terry : 5/25/2012<br>ckniffin : 5/23/2012<br>carol : 5/17/2012<br>ckniffin : 5/17/2012<br>carol : 7/27/2011<br>wwang : 3/29/2010<br>ckniffin : 3/19/2010<br>ckniffin : 3/19/2010<br>wwang : 11/19/2009<br>ckniffin : 11/3/2009<br>ckniffin : 11/3/2009<br>terry : 3/4/2009<br>carol : 5/10/2007<br>terry : 12/20/2005<br>terry : 4/20/2005<br>terry : 4/6/2005<br>alopez : 4/1/2005<br>alopez : 4/1/2005<br>carol : 7/22/2004<br>mgross : 8/25/2003<br>mgross : 8/20/2003<br>mgross : 8/19/2003<br>mgross : 8/19/2003<br>terry : 8/18/2003<br>ckniffin : 6/13/2002<br>cwells : 9/14/2001<br>cwells : 9/4/2001<br>terry : 8/30/2001<br>carol : 8/26/1999<br>jlewis : 8/26/1999<br>terry : 8/5/1999<br>carol : 12/13/1998<br>carol : 12/13/1998<br>alopez : 6/16/1997<br>carol : 7/13/1996<br>mark : 4/17/1996<br>terry : 4/10/1996<br>mark : 3/26/1996<br>terry : 3/21/1996<br>warfield : 4/15/1994<br>mimadm : 4/14/1994<br>carol : 10/11/1993<br>carol : 5/21/1993<br>carol : 5/7/1993<br>carol : 12/17/1992
</span>
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</div>
</div>
</div>
<div class="container visible-print-block">
<div class="row">
<div class="col-md-8 col-md-offset-1">
<div>
<div>
<h3>
<span class="mim-font">
<strong>#</strong> 231680
</span>
</h3>
</div>
<div>
<h3>
<span class="mim-font">
MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
GLUTARIC ACIDEMIA II; GA2<br />
GLUTARIC ACIDURIA II<br />
GA II<br />
ETHYLMALONIC-ADIPICACIDURIA; EMA
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
GLUTARIC ACIDEMIA IIA, INCLUDED; GA2A, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
ETFA DEFICIENCY, INCLUDED<br />
GLUTARIC ACIDEMIA IIB, INCLUDED; GA2B, INCLUDED<br />
ETFB DEFICIENCY, INCLUDED<br />
GLUTARIC ACIDEMIA IIC, INCLUDED; GA2C, INCLUDED<br />
ETFDH DEFICIENCY, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 22886006; &nbsp;
<strong>ICD10CM:</strong> E71.313; &nbsp;
<strong>ORPHA:</strong> 26791, 394529, 394532; &nbsp;
<strong>DO:</strong> 0060358; &nbsp;
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
4q32.1
</span>
</td>
<td>
<span class="mim-font">
Glutaric acidemia IIC
</span>
</td>
<td>
<span class="mim-font">
231680
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ETFDH
</span>
</td>
<td>
<span class="mim-font">
231675
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
15q24.2-q24.3
</span>
</td>
<td>
<span class="mim-font">
Glutaric acidemia IIA
</span>
</td>
<td>
<span class="mim-font">
231680
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ETFA
</span>
</td>
<td>
<span class="mim-font">
608053
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
19q13.41
</span>
</td>
<td>
<span class="mim-font">
Glutaric acidemia IIB
</span>
</td>
<td>
<span class="mim-font">
231680
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ETFB
</span>
</td>
<td>
<span class="mim-font">
130410
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because MADD, also known as glutaric acidemia II or glutaric aciduria II, can be caused by mutations in at least 3 different genes: ETFA (608053), ETFB (130410), and ETFDH (231675). These genes are all involved in electron transfer in the mitochondrial respiratory chain. The disorders resulting from defects in these 3 genes are referred to as glutaric acidemia IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotypes.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1; 231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). </p><p>The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by Frerman and Goodman, 2001).</p><p>Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Neonatal Onset</em></strong></p><p>
In the son of healthy parents from the same small town in Turkey, Przyrembel et al. (1976) described fatal neonatal acidosis and hypoglycemia with a strong 'sweaty feet' odor. Large amounts of glutaric acid were found in the blood and urine. The defect was tentatively located to the metabolism of a range of acyl-CoA compounds. A possibly identically affected child died earlier. </p><p>Lehnert et al. (1982), Bohm et al. (1982), and others described malformations with multiple acyl-CoA dehydrogenation deficiency: congenital polycystic kidneys, characteristic facies, etc. </p><p>Typical clinical features of the disorder are respiratory distress, muscular hypotonia, sweaty feet odor, hepatomegaly, and death often in the neonatal period. Of the 12 previously reported cases reviewed by Niederwieser et al. (1983), 7 died in the first 5 days of life and only 2 patients survived to ages 5 and 19 years. </p><p>Harkin et al. (1986) described apparently characteristic and perhaps pathognomonic, cytoplasmic, homogeneous, and moderately electron-dense membrane-limited bodies in the central nervous system and renal tissues of a female patient who died at age 5 days. The kidneys were enlarged with numerous cortical cysts. Selective proximal tubular damage leads to glycosuria and generalized amino aciduria. The patient came from an inbred Louisiana Cajun community and had a sib who also died in the newborn period. </p><p>Patients with severe deficiency of the ETF dehydrogenase type have distinctive congenital malformations, whereas those with ETF deficiency do not; the severity of the metabolic block, rather than its location, and the resulting profound acidosis in utero may disturb normal morphogenesis. Colevas et al. (1988) described the pathologic findings in 2 cases. The pattern of lesions, in particular the striking localization of renal dysplasia to the medulla, suggested that the malformations may be the consequence of an accumulation of toxic metabolites that is not corrected by placental transfer. Other malformations included cerebral pachygyria, pulmonary hypoplasia, and facial dysmorphism. Lipid accumulation was demonstrated in the liver, heart, and renal tubular epithelium, all tissues that use fatty acids as a primary source of energy. </p><p>Wilson et al. (1989) found reports of malformations in 8 of 16 cases. The anomalies included macrocephaly, large anterior fontanel, high forehead, flat nasal bridge, telecanthus, and malformed ears. Abnormalities such as hypotonia, cerebral gliosis, heterotopias, hepatomegaly, hepatic periportal necrosis, polycystic kidneys, and genital defects were considered reminiscent of the anomalies in Zellweger syndrome, but elevations of glutaric, ethylmalonic, adipic, and isovaleric acids were considered distinctive for glutaric aciduria type II. Wilson et al. (1989) described a unique ultrastructural change in the glomerular basement membrane which they suggested may represent an early stage in renal cyst formation and provide a diagnostic criterion for glutaric aciduria II when enzyme studies are unavailable. </p><p>Poplawski et al. (1999) reported a family in which an unexplained neonatal death had occurred. Twelve years after the death, they retrospectively diagnosed multiple acyl-CoA-dehydrogenase deficiency by demonstrating an abnormal acyl-carnitine profile in the child's archived neonatal screening card, using tandem mass spectrometry. </p><p>Angle and Burton (2008) reported 3 unrelated infants with genetically confirmed MADD who experienced sudden acute life-threatening events in the first year of life, resulting in death in 2 infants. All had been correctly diagnosed via a newborn screening protocol. Each developed cardiopulmonary arrest concurrent with metabolic stress or limited caloric intake, including vomiting, upper respiratory infection, and rotaviral diarrhea. Although only 1 patient had a documented arrhythmia, Angle and Burton (2008) suggested that an intrinsic abnormality of myocardial function due to altered energy production may have played a role. The authors emphasized the importance of aggressive nutritional management in infants with MADD. </p><p><strong><em>Later Onset</em></strong></p><p>
Hypoglycemia caused by inborn errors of metabolism, including disturbances of organic-acid metabolism, usually appear during infancy or childhood. Thus, the case reported by Dusheiko et al. (1979) was unusual. A 19-year-old woman had episodic vomiting, severe hypoglycemia, and fatty infiltration of the liver. The parents were not related. One of her sisters, at age 7, developed nausea, vomiting, and a 'stale' odor to the breath, and died after 3 days in hypoglycemic coma. At age 10, a second sister was found to have jaundice, hepatomegaly, and hypoglycemia after an acute febrile illness. She recovered from that illness but died 'in her sleep' 2 years later. Excess amounts of glutaric and ethylmalonic acids were found in the urine, consistent with defective dehydrogenation of isovaleryl CoA and butyryl CoA, respectively. These organic acids plus others are excreted in the urine in excess in Jamaican vomiting sickness, caused by the ingestion of unripe akee. Unripe akee contains the toxin hypoglycin, which inhibits several acyl CoA dehydrogenases. Cultured fibroblasts in the patient of Dusheiko et al. (1979) showed reduced ability to oxidize radiolabeled butyrate and lysine. </p><p>Mongini et al. (1992) reported a 25-year-old woman who complained of episodes of muscle weakness, nausea and vomiting since the age of 10 years. She had been born with bilateral cataracts and strabismus. Muscle biopsy showed free fatty acid accumulation. Low-fat diet reduced the episodes of muscle weakness. </p><p>Horvath et al. (2006) reported 3 unrelated patients with myopathy associated with coenzyme Q10 deficiency: a 32-year-old German woman who developed proximal muscle weakness during pregnancy; a 29-year-old Turkish man who developed difficulty walking and premature fatigue; and a 6-year-old Hungarian boy who had exercise intolerance and generalized hypotonia. All patients had significantly increased serum creatine kinase, increased serum lactate, myopathic changes on EMG, and hypo- or areflexia. None had myoglobinuria, ataxia, or seizures. Muscle biopsies showed lipid storage myopathy, respiratory chain complex deficiencies, and CoQ10 levels below 50% of normal. All 3 patients showed marked improvement after 3 to 6 months of oral CoQ10 supplementation. Gempel et al. (2007) reported follow-up on the patients reported by Horvath et al. (2006). The German woman had developed abnormal liver enzymes and recurrence of muscle weakness, and laboratory studies showed increased multiple acyl-CoA derivatives in serum. The Turkish man had proximal muscle weakness with scapular winging and waddling gait, and laboratory studies were consistent with MADD. Gempel et al. (2007) also reported 5 patients from 3 additional consanguineous families with late-onset MADD manifest as childhood-onset muscle weakness, muscle pain, and increased serum creatine kinase. All 7 patients responded favorably to riboflavin and/or coenzyme Q supplementation. Muscle biopsies showed a myopathy with lipid accumulation and small vacuoles; only 2 patients had ragged-red fibers. All had a decrease of respiratory complex I+III and II+III activity, and all had decreased muscle CoQ10 levels. Molecular analysis identified biallelic pathogenic mutations in the ETFDH gene in all patients (see, e.g., 231675.0007 and 231675.0008), thus confirming the diagnosis of MADD. Gempel et al. (2007) concluded that MADD due to ETFDH mutations can result in isolated myopathy with secondary coenzyme Q10 deficiency. </p><p>Liang et al. (2009) reported 4 Taiwanese patients from 3 unrelated families with MADD due to mutations in the ETFDH gene (231675.0003-231675.0005). There was marked phenotypic variability, even between 2 affected sibs with the same genotype. The first patient was a 27-year-old woman who had exercise intolerance since early childhood. In her teens, she developed several episodes of acute pancreatitis. At age 19, she developed dysphagia with progressive weakness of neck and proximal limb muscles, and later had a more severe episode of muscle weakness with acute respiratory failure, but no metabolic acidosis and hypoketotic hypoglycemia. Serum creatine kinase was elevated, and muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. Urinary profile was consistent with MADD. Her older sister had a milder phenotype, with 2 bouts of muscle weakness and difficulty climbing stairs and combing her hair. She never had metabolic crisis, hypoketotic hypoglycemia, or respiratory failure. Laboratory studies showed low serum carnitine, increased serum acylcarnitine levels, and elevated glutaric, ethylmalonic, 2-hydroxylglutaric, 3-methylglutaconic, and lactic acids in urine. Both patients responded well to riboflavin and carnitine treatment. The third patient developed exercise intolerance, dysphagia, poor head control, and limb weakness at age 14 years, and was wheelchair-bound by age 16. He had neck and proximal muscle weakness with wasting, lordosis, winged scapula, and absent tendon reflexes. He did not have metabolic acidosis or hypoketotic hypoglycemia. Pulmonary function tests demonstrated a severe restrictive ventilatory defect. Muscle biopsy showed increased lipid droplets predominantly in type 1 fibers. He also responded well to riboflavin and carnitine treatment. The last patient was a 10-year-old girl who was a slow runner since childhood. She had an upper respiratory tract infection followed by progressive proximal muscle weakness. A few days after discharge from the hospital, her condition rapidly deteriorated and she developed fatal cardiopulmonary failure associated with marked metabolic acidosis, hyperammonemia, and hypoglycemia. </p><p>Lan et al. (2010) reported 7 Han Taiwanese patients with genetically confirmed MADD. The patients were identified retrospectively by review of muscle biopsies ascertained for lipid storage myopathy, and all were asymptomatic when recruited. The age at diagnosis ranged from 7 to 43 years, and the patients' ages at the time of the report were between 22 and 44 years. All had a history of episodic myalgia and limb weakness predominantly affecting the proximal muscles during an acute stage of myopathy. Four had dysphagia and 2 had respiratory failure. Serum creatine kinase was increased during the acute attacks. Three had 1 episode, whereas 4 had recurrent episodes. Four patients had extramuscular features, including encephalopathy, seizures, hypoglycemia, and heart failure in 1; vomiting and cardiac arrhythmia in 1; encephalopathy, liver function impairment and lactic acidosis in 1; and vomiting and liver function impairment in 1. All except 1 regained normal muscle strength after the acute stage. Trigger factors in some patients included prolonged fasting and exercise. Blood analysis showed increased acylcarnitines ranging from C8 to C16. Genetic analysis showed that 6 of the patients were homozygous for an A84T mutation in the ETFDH gene (231675.0003), and 1 was compound heterozygous for A84T and R175H (231675.0006). This patient also had a heterozygous substitution in the PNPLA2 gene (609059), which was not thought to contribute to the phenotype. </p><p>Lalani et al. (2005) reported a boy who presented at 11.5 years of age with exercise intolerance and ragged-red fibers identified on muscle histology. Muscle CoQ10 was reduced (46% of normal) and complex I, I+III, and II+III activity was decreased. He was originally diagnosed with primary muscle coenzyme Q10 deficiency (607426), and treatment with CoQ10 supplementation resulted in significant clinical improvement. However, he presented again at age 23 with relapse of muscle weakness, myalgia, and extreme fatigue. Laboratory studies showed elevated creatine kinase, aspartate transaminase, and alanine transaminase, and ultrasound showed signs of fatty liver disease. Acylcarnitine profile in blood demonstrated elevation of C14-C18 species, and urine organic acids showed elevation in ethylmalonic acid, isovaleric acid, glutaric acid, and hexanoyl glycine. A diagnosis of MADD was confirmed by direct gene sequencing, and he was started on riboflavin and ubiquinol in place of ubiquinone. After 4 months of treatment, the patient experienced improvement of symptoms and had normalization of laboratory values. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>By fusion of isovaleric acidemia (243500) cells with those of GA II, Dubiel et al. (1983) showed that these disorders are genetically distinct, since complementation was observed. In both disorders, isovaleryl-CoA dehydrogenation is blocked. The defect in GA II is in one of the proteins involved in the transfer of electrons from acyl-CoA dehydrogenases to coenzyme Q of the mitochondrial electron transport chain. Sarcosinemia and sarcosinuria are also observed in this disorder (Goodman et al., 1980; Gregersen et al., 1980). </p><p>Ikeda et al. (1985) concluded that defective synthesis of ETFA was the fundamental defect in 3 cell lines from patients with severe MADD.</p><p>Moon and Rhead (1987) detected 2 complementation groups in cell lines from patients with severe multiple acyl-CoA dehydrogenation disorder. This was consistent with the different defects in glutaric aciduria IIA and glutaric aciduria IIB. The metabolic block in the cell lines from the latter disorder was 3 times more severe than the former, as assayed by oxidation of radiolabelled palmitate. No intragenic complementation was observed within either group. Complementation was started after polyethylene glycol fusion. </p><p>Onkenhout et al. (2001) determined the fatty acid composition of liver, skeletal muscle, and heart obtained postmortem from patients with deficiency of 1 of 3 types of acyl-CoA dehydrogenase: medium-chain (MCAD; 607008), multiple (MADD), and very long-chain (VLCADD; 201475). Increased amounts of multiple unsaturated fatty acids were found exclusively in the triglyceride fraction. They could not be detected in the free fatty acid or phospholipid fractions. Onkenhout et al. (2001) concluded that intermediates of unsaturated fatty acid oxidation that accumulate as a consequence of MCADD, MADD, and VLCADD are transported to the endoplasmic reticulum for esterification into neutral glycerolipids. The pattern of accumulation is characteristic for each disease, which makes fatty acid analysis of total lipid of postmortem tissues a useful tool in the detection of mitochondrial fatty acid oxidation defects in patients who have died unexpectedly. </p><p>Riboflavin-responsive multiple acylcoenzyme A dehydrogenase deficiency is characterized by, among other features, a decrease in fatty acid beta-oxidation capacity. Muscle uncoupling protein-3 (UCP3; 602044) is upregulated under conditions that either increase the levels of circulating free fatty acid and/or decrease fatty acid beta-oxidation. Using a relatively large cohort of 7 MADD patients, Russell et al. (2003) studied the metabolic disturbances of this disease and determined if they might increase UCP3 expression. Biochemical and molecular tests demonstrated decreases in fatty acid beta-oxidation and in the activities of respiratory chain complexes I (see 157655) and II (see 600857). These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acid/acylCoA. The authors considered MADD an optimal model to study the hypothesis that UCP3 is involved in the outward translocation of an excess of fatty acid from the mitochondria and to show that, in humans, the effects of fatty acid on UCP3 expression are direct and independent of fatty acid beta-oxidation. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Mantagos et al. (1979) proved autosomal recessive inheritance of MADD by demonstration of partial enzyme deficiency in each parent of a female patient. </p><p>Niederwieser et al. (1983) reported the case of the son of consanguineous Jewish parents who died at age 7 months. In a note added in proof, they described the prenatal diagnosis of an affected female of the same parentage, indicating autosomal recessive inheritance. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Costa et al. (1996) noted that a number of subclinical deficiencies caused by malabsorption could be misdiagnosed as inherited mitochondrial fatty acid oxidation defects. They suggested that in the presence of organic acid profiles reminiscent of a defect in the beta-oxidation pathway or a profile reminiscent of glutaric aciduria type II, a possible digestive disorder should be ruled out. </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
Yamaguchi et al. (1990, 1991) described type II glutaric aciduria due to deficiency of ETFB. The patient had a neonatal onset of intermittent illness without congenital anomalies. The diagnosis was made at the age of 10 months. Subsequently, the parents of the patient of Yamaguchi et al. (1991) had another pregnancy and Yamaguchi et al. (1991) performed prenatal diagnosis by immunochemical procedures on cultured amniocytes and by organic acid analysis of amniotic fluid, using a stable isotope dilution method. They also described the monitoring of the clinical course and metabolite excretion in early infancy when the patient had no symptoms. Glutarate concentration was increased in the cell-free supernatant of the amniotic fluid. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Gregersen et al. (1982) reported successful treatment of a 5 year old with riboflavin. </p><p>Riboflavin-responsive glutaric aciduria type II was reported by Uziel et al. (1995) in a boy who developed gradually progressive spastic ataxia and a leukodystrophy without ever having experienced episodic metabolic crises. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Glutaric aciduria IIA</em></strong></p><p>
Indo et al. (1991), Rhead et al. (1992), and Freneaux et al. (1992) identified mutations in the ETFA gene in patients with GA IIA (e.g., 608053.0001). </p><p><strong><em>Glutaric aciduria IIB</em></strong></p><p>
Colombo et al. (1994) identified mutations in the ETFB gene in patients with GA IIB (e.g., 130410.0001). </p><p><strong><em>Glutaric aciduria IIC</em></strong></p><p>
Beard et al. (1993) identified 5 mutations in the ETFDH gene (e.g., 231675.0001) in 4 patients with GA IIC. All 5 mutations were rare and caused total lack of enzyme activity and antigen.</p><p>In 4 Taiwanese patients from 3 unrelated families with relatively late-onset MADD, Liang et al. (2009) identified homozygous or compound heterozygous mutations in the ETFDH gene (231675.0003-231675.0005). The A84T mutation (231675.0003) was present in all 4 patients. </p><p>In 7 patients from 5 families with late-onset of an isolated myopathy associated with coenzyme Q10 deficiency, Gempel et al. (2007) identified homozygous or compound heterozygous mutations in the ETFDH gene (see, e.g., 231675.0007 and 231675.0008). Two of the patients had previously been reported by Horvath et al. (2006) as having primary coenzyme Q10 deficiency (see, e.g., COQ10D1, 607426). All patients had increased levels of multiple acyl-CoA derivatives, and all showed marked improvement upon treatment with oral CoQ10 and/or riboflavin. Gempel et al. (2007) concluded that MADD due to ETFDH mutations can result in isolated myopathy with secondary coenzyme Q10 deficiency. </p><p>In a patient with late-onset glutaric acidemia IIC, who was originally reported by Lalani et al. (2005) with primary coenzyme Q10 deficiency, Xiao et al. (2020) identified compound heterozygous mutations in the ETFDH gene (231675.0009-231675.0010). Western blot analysis in patient fibroblasts revealed decreased expression of the ETFHD, TFP-alpha (HADHA; 600890), and VLCAD (609575) proteins, and minimally reduced TFP-beta (HADHB 143450) protein. Mitochondrial superoxide was increased in patient fibroblasts, and steady-state ATP levels and maximal respiration-basal respiration were decreased. Xiao et al. (2020) concluded that these studies provided evidence for widespread mitochondrial dysfunction in this patient. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>To examine whether the different clinical forms of MADD can be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, Olsen et al. (2003) investigated the molecular genetic basis for disease development in 9 patients representing the phenotypic spectrum of MADD. They identified and characterized 7 novel and 3 previously reported disease-causing mutations. Studies of these 9 patients yielded results consistent with 3 clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of the disease. Homozygosity for 2 null mutations caused fetal development of congenital anomalies, resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seemed to be sufficient to prevent embryonic development of congenital anomalies, giving rise to type II disease. Studies of an asp128-to-asn mutation of the ETFB gene (D128N; 130410.0003), identified in a patient with type III disease, showed that the residual activity of the enzyme could be rescued up to 59% of that of wildtype activity when ETFB(D128N)-transformed E. coli cells were grown at low temperature. This suggested that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors such as cellular temperature. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>A neonatal lethal form, called 'GA IIA' by Coude et al. (1981), was thought possibly to be X-linked. Coude et al. (1981) reported a pedigree supportive of X-linked inheritance because of the occurrence of a total of 5 proved or presumed cases in 3 sibships related through 5 presumptive carrier females. ('GA IIB' was the designation used by Coude et al. (1981) for a mild form that presented as recurrent hypoglycemia without ketosis and showed a less severe evolution with survival to adulthood.) </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Amendt and Rhead (1986); Gregersen (1985); Jakobs et al. (1984);
Mitchell et al. (1983)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Amendt, B. A., Rhead, W. J.
<strong>The multiple acyl-coenzyme A dehydrogenation disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria: mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase, and electron transfer flavoprotein activities in fibroblasts.</strong>
J. Clin. Invest. 78: 205-213, 1986.
[PubMed: 3722376]
[Full Text: https://doi.org/10.1172/JCI112553]
</p>
</li>
<li>
<p class="mim-text-font">
Angle, B., Burton, B. K.
<strong>Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II.</strong>
Molec. Genet. Metab. 93: 36-39, 2008.
[PubMed: 17977044]
[Full Text: https://doi.org/10.1016/j.ymgme.2007.09.015]
</p>
</li>
<li>
<p class="mim-text-font">
Beard, S. E., Spector, E. B., Seltzer, W. K., Frerman, F. E., Goodman, S. I.
<strong>Mutations in electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II (GA2). (Abstract)</strong>
Clin. Res. 41: 271A, 1993.
</p>
</li>
<li>
<p class="mim-text-font">
Bohm, N., Uy, J., Kiebling, M., Lehnert, W.
<strong>Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis.</strong>
Europ. J. Pediat. 139: 60-65, 1982.
[PubMed: 7173260]
[Full Text: https://doi.org/10.1007/BF00442082]
</p>
</li>
<li>
<p class="mim-text-font">
Colevas, A. D., Edwards, J. L., Hruban, R. H., Mitchell, G. A., Valle, D., Hutchins, G. M.
<strong>Glutaric acidemia type II: comparison of pathologic features in two infants.</strong>
Arch. Path. Lab. Med. 112: 1133-1139, 1988.
[PubMed: 3178428]
</p>
</li>
<li>
<p class="mim-text-font">
Colombo, I., Finocchiaro, G., Garavaglia, B., Garbuglio, N., Yamaguchi, S., Frerman, F. E., Berra, B., DiDonato, S.
<strong>Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaricacidemia type II.</strong>
Hum. Molec. Genet. 3: 429-435, 1994.
[PubMed: 7912128]
[Full Text: https://doi.org/10.1093/hmg/3.3.429]
</p>
</li>
<li>
<p class="mim-text-font">
Costa, C. G., Verhoeven, N. M., Kneepkens, C. M. F., Douwes, A. C., Wanders, R. J. A., Tavares De Almeida, I., Duran, M., Jakobs, C.
<strong>Organic acid profiles resembling a beta-oxidation defect in two patients with coeliac disease.</strong>
J. Inherit. Metab. Dis. 19: 177-180, 1996.
[PubMed: 8739959]
[Full Text: https://doi.org/10.1007/BF01799423]
</p>
</li>
<li>
<p class="mim-text-font">
Coude, F. X., Ogier, H., Charpentier, C., Thomassin, G., Checoury, A., Amedee-Manesme, O., Saudubray, J. M., Frezal, J.
<strong>Neonatal glutaric aciduria type II: an X-linked recessive inherited disorder.</strong>
Hum. Genet. 59: 263-265, 1981.
[PubMed: 7199025]
[Full Text: https://doi.org/10.1007/BF00283677]
</p>
</li>
<li>
<p class="mim-text-font">
Dubiel, B., Dabrowski, C., Wetts, R., Tanaka, K.
<strong>Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.</strong>
J. Clin. Invest. 72: 1543-1552, 1983.
[PubMed: 6630517]
[Full Text: https://doi.org/10.1172/JCI111113]
</p>
</li>
<li>
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