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Entry
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- *607008 - ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN; ACADM
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607008</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607008">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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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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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000117054;t=ENST00000370841" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=34" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607008" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000117054;t=ENST00000370841" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000016,NM_001127328,NM_001286042,NM_001286043,NM_001286044" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000016" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607008" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=08447&isoform_id=08447_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/ACADM" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/113017,177964,187433,553529,4557231,7542837,13529233,57997529,119626804,119626805,119626806,187960098,189069176,194375021,194375079,194377254,194382108,221045280,332367456,554506554,554506556,554506558,957948811,957948814,957948817" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P11310" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=34" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000117054;t=ENST00000370841" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACADM" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=ACADM" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+34" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/ACADM" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:34" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/34" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000370841.9&hgg_start=75724709&hgg_end=75763679&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:89" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:89" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/acadm" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607008[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607008[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/ACADM/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000117054" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ACADM" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ACADM" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ACADM" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://research.cchmc.org/LOVD2/home.php?select_db=ACADM" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ACADM&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA24425" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:89" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0035811.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:87867" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ACADM#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:87867" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/34/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002585/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=34" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00019406;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00019406 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00020366;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00020366 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00020812;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00020812 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1945" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:607008" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:34" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=ACADM&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 128596003<br />
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<strong>ICD10CM:</strong> E71.311<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607008
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN; ACADM
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE; MCAD; MCADH
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ACADM" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ACADM</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/1/727?start=-3&limit=10&highlight=727">1p31.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:75724709-75763679&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:75,724,709-75,763,679</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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<a href="/geneMap/1/727?start=-3&limit=10&highlight=727">
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1p31.1
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Acyl-CoA dehydrogenase, medium chain, deficiency of
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<a href="/entry/201450"> 201450 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/607008" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607008" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p><a href="#26" class="mim-tip-reference" title="Matsubara, Y., Kraus, J. P., Yang-Feng, T. L., Francke, U., Rosenberg, L. E., Tanaka, K. <strong>Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1.</strong> Proc. Nat. Acad. Sci. 83: 6543-6547, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3462713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3462713</a>] [<a href="https://doi.org/10.1073/pnas.83.17.6543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3462713">Matsubara et al. (1986)</a> stated that 5 acyl-CoA dehydrogenases had been reported: short-chain (<a href="/entry/606885">606885</a>), medium-chain (<a href="https://enzyme.expasy.org/EC/1.3.99.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.3.99.3</a>), and long-chain (<a href="/entry/609576">609576</a>) acyl-CoA dehydrogenases; isovaleryl-CoA dehydrogenase (<a href="/entry/243500">243500</a>); and 2-methyl branched-chain acyl-CoA dehydrogenase. The first 3 catalyze the initial reaction in the beta-oxidation of fatty acids, while the last 2 catalyze the dehydrogenation of branched short-chain acyl-CoAs in the metabolism of the branched-chain amino acids. All 5 may have evolved from a common ancestral gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3462713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By screening a liver cDNA library with the rat pre-medium-chain acyl-CoA dehydrogenase cDNA, <a href="#26" class="mim-tip-reference" title="Matsubara, Y., Kraus, J. P., Yang-Feng, T. L., Francke, U., Rosenberg, L. E., Tanaka, K. <strong>Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1.</strong> Proc. Nat. Acad. Sci. 83: 6543-6547, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3462713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3462713</a>] [<a href="https://doi.org/10.1073/pnas.83.17.6543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3462713">Matsubara et al. (1986)</a> cloned a partial human MCAD cDNA. The MCAD enzyme is a homotetramer with a molecular mass of about 45 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3462713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Kelly, D. P., Kim, J.-J., Billadello, J. J., Hainline, B. E., Chu, T. W., Strauss, A. W. <strong>Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.</strong> Proc. Nat. Acad. Sci. 84: 4068-4072, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3035565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3035565</a>] [<a href="https://doi.org/10.1073/pnas.84.12.4068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3035565">Kelly et al. (1987)</a> determined the MCAD mRNA nucleotide sequence from 2 overlapping cDNA clones isolated from human liver and placenta cDNA libraries, respectively. The sequence encodes a 421-amino acid protein with characteristics of mitochondrial protein transit peptides. The protein shows 88% sequence identity with porcine MCAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3035565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The MCAD gene contains 12 exons (<a href="#43" class="mim-tip-reference" title="Zhang, Z. F., Kelly, D. P., Kim, J.-J., Zhou, Y., Ogden, M. L., Whelan, A. J., Strauss, A. W. <strong>Structural organization and regulatory regions of the human medium-chain acyl-CoA dehydrogenase gene.</strong> Biochemistry 31: 81-89, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1731887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1731887</a>] [<a href="https://doi.org/10.1021/bi00116a013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1731887">Zhang et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1731887" 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>Medium-chain acyl-CoA dehydrogenase catalyzes the initial reaction in the beta-oxidation of C4 to C12 straight-chain acyl-CoAs (<a href="#26" class="mim-tip-reference" title="Matsubara, Y., Kraus, J. P., Yang-Feng, T. L., Francke, U., Rosenberg, L. E., Tanaka, K. <strong>Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1.</strong> Proc. Nat. Acad. Sci. 83: 6543-6547, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3462713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3462713</a>] [<a href="https://doi.org/10.1073/pnas.83.17.6543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3462713">Matsubara et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3462713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#26" class="mim-tip-reference" title="Matsubara, Y., Kraus, J. P., Yang-Feng, T. L., Francke, U., Rosenberg, L. E., Tanaka, K. <strong>Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1.</strong> Proc. Nat. Acad. Sci. 83: 6543-6547, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3462713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3462713</a>] [<a href="https://doi.org/10.1073/pnas.83.17.6543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3462713">Matsubara et al. (1986)</a> mapped the ACADM gene to 1p31 by Southern analysis of DNA from hybrid cells and by in situ hybridization. <a href="#20" class="mim-tip-reference" title="Kidd, J. R., Matsubara, Y., Castiglione, C. M., Tanaka, K., Kidd, K. K. <strong>The locus for the medium-chain acyl-CoA dehydrogenase gene on chromosome 1 is highly polymorphic.</strong> Genomics 6: 89-93, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1968047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1968047</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90451-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1968047">Kidd et al. (1990)</a> demonstrated extensive polymorphism in ACADM. With linkage studies, they showed that the ACADM locus is proximal to PGM1 (<a href="/entry/171900">171900</a>). Since the latter locus has been assigned to 1p22.1 by somatic cell studies, these results are in conflict with the assignment of ACADM to 1p31 by in situ hybridization. The authors suggested that the somatic cell localization of PGM1 may be incorrect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1968047+3462713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By use of a backcross with Mus spretus, <a href="#4" class="mim-tip-reference" title="Bahary, N., Zorich, G., Pachter, J. E., Leibel, R. L., Friedman, J. M. <strong>Molecular genetic linkage maps of mouse chromosomes 4 and 6.</strong> Genomics 11: 33-47, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684952</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90099-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1684952">Bahary et al. (1991)</a> assigned the homologous gene to chromosome 8 in the mouse. However, <a href="#37" class="mim-tip-reference" title="Tolwani, R. J., Farmer, S. C., Johnson, K. R., Davisson, M. T., Kurtz, D. M., Hinsdale, M. E., Cresci, S., Kelly, D. P., Wood, P. A. <strong>Structure and chromosomal location of the mouse medium-chain acyl-CoA dehydrogenase-encoding gene and its promoter.</strong> Gene 170: 165-171, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666240</a>] [<a href="https://doi.org/10.1016/0378-1119(95)00882-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8666240">Tolwani et al. (1996)</a> mapped the Acadm gene to the distal end of mouse chromosome 3. They showed that sequences previously localized to chromosome 8 represent a pseudogene, and identified an additional pseudogene on chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1684952+8666240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#18" class="mim-tip-reference" title="Kelly, D. P., Kim, J.-J., Billadello, J. J., Hainline, B. E., Chu, T. W., Strauss, A. W. <strong>Nucleotide sequence of medium-chain acyl-CoA dehydrogenase mRNA and its expression in enzyme-deficient human tissue.</strong> Proc. Nat. Acad. Sci. 84: 4068-4072, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3035565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3035565</a>] [<a href="https://doi.org/10.1073/pnas.84.12.4068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3035565">Kelly et al. (1987)</a> performed blot hybridization of RNA prepared from cultured skin fibroblasts from a patient with MCAD deficiency (ACADMD; <a href="/entry/201450">201450</a>) and showed that mRNA was present and of similar size to MCAD mRNA derived from control fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3035565" 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 9 patients with MCAD deficiency, <a href="#27" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Miyabayashi, S., Tada, K., Coates, P. M. <strong>Molecular lesion in patients with medium-chain acyl-CoA dehydrogenase deficiency. (Letter)</strong> Lancet 335: 1589 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1972503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1972503</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1972503">Matsubara et al. (1990)</a> identified a homozygous 985A-G transition in the MCAD gene, which resulted in a lys304-to-glu substitution (K304E; <a href="#0001">607008.0001</a>) in the mature protein. These patients were unrelated, suggesting a high incidence of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. <a href="#27" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Miyabayashi, S., Tada, K., Coates, P. M. <strong>Molecular lesion in patients with medium-chain acyl-CoA dehydrogenase deficiency. (Letter)</strong> Lancet 335: 1589 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1972503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1972503</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1972503">Matsubara et al. (1990)</a> found this point mutation in 31 of 34 (91%) mutant MCAD alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1972503" 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="#45" class="mim-tip-reference" title="Zschocke, J., Schulze, A., Lindner, M., Fiesel, S., Olgemoller, K., Hoffmann, G. F., Penzien, J., Ruiter, J. P. N., Wanders, R. J. A., Mayatepek, E. <strong>Molecular and functional characterization of mild MCAD deficiency.</strong> Hum. Genet. 108: 404-408, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409868</a>] [<a href="https://doi.org/10.1007/s004390100501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409868">Zschocke et al. (2001)</a> characterized the molecular defect in 4 patients with mild MCAD deficiency. In routine neonatal screening on the fifth day of life, they had been found to have abnormal acylcarnitine profiles indicative of MCAD deficiency. Two were of German origin and the other 2 were born to different consanguineous Turkish parents. In all 4, the clinical course and routine laboratory investigations up to the age of 6 months were unremarkable. Enzyme studies showed residual MCAD activities between those with classic MCAD deficiency and heterozygotes. In 2 cases, ACADM gene analysis revealed compound heterozygosity for the common K304E mutation (<a href="#0001">607008.0001</a>) and the Y42H mutation (<a href="#0011">607008.0011</a>), which they designated Y67H. In the 2 children of consanguineous parents, homozygosity was found for the gly267-to-arg mutation (G267R; <a href="#0003">607008.0003</a>) and the S220L mutation (<a href="#0012">607008.0012</a>), respectively. As in other metabolic disorders, the distinction between 'normal' and 'disease' in MCAD deficiency is blurred into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11409868" 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="#39" class="mim-tip-reference" title="Wilcken, B., Wiley, V., Hammond, J., Carpenter, K. <strong>Screening newborns for inborn errors of metabolism by tandem mass spectrometry.</strong> New Eng. J. Med. 348: 2304-2312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788994</a>] [<a href="https://doi.org/10.1056/NEJMoa025225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788994">Wilcken et al. (2003)</a> reported on the use of electrospray tandem mass spectrometry to screen newborns for 31 inborn errors affecting the metabolism of the urea cycle, amino acids, and organic acids and fatty acid oxidation in a 4-year period in Australia. The rate of inborn errors, excluding PKU, was 15.7 per 100,000 births, as compared with adjusted rates of 8.6 to 9.5 per 100,000 births in the 4 preceding 4-year cohorts. The rate of detection was increased specifically for MCAD deficiency and other disorders of fatty acid oxidation, as compared with the 16-year period before the implementation of neonatal screening for these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788994" 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="Maier, E. M., Gersting, S. W., Kemter, K. F., Jank, J. M., Reindl, M., Messing, D. D., Truger, M. S., Sommerhoff, C. P., Muntau, A. C. <strong>Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening.</strong> Hum. Molec. Genet. 18: 1612-1623, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19224950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19224950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19224950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19224950">Maier et al. (2009)</a> analyzed the impact of 10 ACADM mutations (see, e.g., <a href="#0001">607008.0001</a> and <a href="#0011">607008.0011</a>) on conformation, stability and enzyme kinetics of the corresponding mutant proteins. Partial to total rescue of aggregation by overexpression of GroES (HSPE1; <a href="/entry/600141">600141</a>) and GroEL (HSPD1; <a href="/entry/118190">118190</a>) suggested protein misfolding as a pathogenic mechanism. Catalytic function varied from high residual activity to markedly decreased activity or substrate affinity. Mutations mapping to the beta-domain of the protein predisposed to severe destabilization. In silico structural analysis of the affected amino acid residues revealed involvement in functionally relevant networks. <a href="#25" class="mim-tip-reference" title="Maier, E. M., Gersting, S. W., Kemter, K. F., Jank, J. M., Reindl, M., Messing, D. D., Truger, M. S., Sommerhoff, C. P., Muntau, A. C. <strong>Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening.</strong> Hum. Molec. Genet. 18: 1612-1623, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19224950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19224950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19224950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19224950">Maier et al. (2009)</a> concluded that protein misfolding with loss-of-function is the common molecular basis in MCAD deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19224950" 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="Suhre, K., Shin, S.-Y., Petersen, A.-K., Mohney, R. P., Meredith, D., Wagele, B., Altmaier, E., CARDIoGRAM, Deloukas, P., Erdmann, J., Grundberg, E., Hammond, C. J., and 22 others. <strong>Human metabolic individuality in biomedical and pharmaceutical research.</strong> Nature 477: 54-60, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21886157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21886157</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21886157[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21886157">Suhre et al. (2011)</a> reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. <a href="#35" class="mim-tip-reference" title="Suhre, K., Shin, S.-Y., Petersen, A.-K., Mohney, R. P., Meredith, D., Wagele, B., Altmaier, E., CARDIoGRAM, Deloukas, P., Erdmann, J., Grundberg, E., Hammond, C. J., and 22 others. <strong>Human metabolic individuality in biomedical and pharmaceutical research.</strong> Nature 477: 54-60, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21886157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21886157</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21886157[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21886157">Suhre et al. (2011)</a> identified <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs211718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs211718</a> in the ACADM gene as associated with hexanoylcarnitine/oleate ratio with a p value of 2.2 x 10(-71). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21886157" 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="#36" class="mim-tip-reference" title="Tajima, G., Hara, K., Tsumura, M., Kagawa, R., Okada, S., Sakura, N., Hata, I., Shigematsu, Y., Kobayashi, M. <strong>Screening of MCAD deficiency in Japan: 16 years' experience of enzymatic and genetic evaluation.</strong> Molec. Genet. Metab. 119: 322-328, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27856190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27856190</a>] [<a href="https://doi.org/10.1016/j.ymgme.2016.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27856190">Tajima et al. (2016)</a> sequenced the ACADM gene in a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of MCAD deficiency. The most prevalent mutation was a 4-bp deletion (c.449_452delCTGA; <a href="#0016">607008.0016</a>) identified in 25 ACADM alleles of 22 subjects from 19 families. Other prevalent mutations in this cohort included R17H, G362E, R53C, and R281S. These 5 mutations accounted for 60% of the mutations identified in this patient cohort. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27856190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Andresen, B. S., Bross, P., Udvari, S., Kirk, J., Gray, G., Kmoch, S., Chamoles, N., Knudsen, I., Winter, V., Wilcken, B., Yokota, I., Hart, K., Packman, S., Harpey, J. P., Saudubray, J. M., Hale, D. E., Bolund, L., Kolvraa, S., Gregersen, N. <strong>The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?</strong> Hum. Molec. Genet. 6: 695-707, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158144</a>] [<a href="https://doi.org/10.1093/hmg/6.5.695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9158144">Andresen et al. (1997)</a> determined the frequency of 14 known and 7 previously unknown non-G985 mutations in the MCAD gene in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. They showed that none of the non-G985 mutations is prevalent. In 14 families in which they identified both disease-causing mutations, they correlated the mutations with clinical/biochemical data and found that a genotype/phenotype correlation in MCAD deficiency is not straightforward. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9158144" 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 class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77931234 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77931234;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77931234?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77931234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77931234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003769 OR RCV000077895 OR RCV001526621 OR RCV002251863 OR RCV002512722 OR RCV003430631" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003769, RCV000077895, RCV001526621, RCV002251863, RCV002512722, RCV003430631" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003769...</a>
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<p>This mutation has also been called LYS329GLU (K329E), based on the precursor protein.</p><p>In 9 patients with MCAD deficiency (ACADMD; <a href="/entry/201450">201450</a>), <a href="#27" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Miyabayashi, S., Tada, K., Coates, P. M. <strong>Molecular lesion in patients with medium-chain acyl-CoA dehydrogenase deficiency. (Letter)</strong> Lancet 335: 1589 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1972503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1972503</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1972503">Matsubara et al. (1990)</a> identified an A-to-G transition in the ACADM gene, which resulted in the substitution of lysine (AAA) by glutamic acid (GAA) at residue 329 (K304E) of the enzyme. These patients were unrelated, suggesting a high instance of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. <a href="#27" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Miyabayashi, S., Tada, K., Coates, P. M. <strong>Molecular lesion in patients with medium-chain acyl-CoA dehydrogenase deficiency. (Letter)</strong> Lancet 335: 1589 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1972503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1972503</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1972503">Matsubara et al. (1990)</a> found this point mutation in 31 of 34 (91%) mutant MCAD alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1972503" 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 3 patients with MCAD deficiency, <a href="#41" class="mim-tip-reference" title="Yokota, I., Indo, Y., Coates, P. M., Tanaka, K. <strong>Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency: an A-to-G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation.</strong> J. Clin. Invest. 86: 1000-1003, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2394825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2394825</a>] [<a href="https://doi.org/10.1172/JCI114761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2394825">Yokota et al. (1990)</a> demonstrated an A-to-G transition at position 985 (G985) of the coding region of the ACADM gene, which resulted in a lys304-to-glu (K304E) substitution in the mature protein. Since no appropriate restriction sites for detecting this point mutation were found, they devised an ingenious PCR-based method for demonstrating the G985 mutation. In studies of 9 MCAD deficient patients, homozygosity for this mutation was found in all; in contrast, all 8 controls lacked the mutation. All the patients were Caucasian. In a later study, <a href="#41" class="mim-tip-reference" title="Yokota, I., Indo, Y., Coates, P. M., Tanaka, K. <strong>Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency: an A-to-G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation.</strong> J. Clin. Invest. 86: 1000-1003, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2394825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2394825</a>] [<a href="https://doi.org/10.1172/JCI114761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2394825">Yokota et al. (1990)</a> found that the mutation introduces a new NcoI restriction site. Genomic DNA from 11 unrelated MCAD patients was homozygous for the G985 transition as indicated by complete cleavage of PCR-amplified fragments by NcoI. The high prevalence of this mutation in Caucasians and the similarity between the mutations described by <a href="#41" class="mim-tip-reference" title="Yokota, I., Indo, Y., Coates, P. M., Tanaka, K. <strong>Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency: an A-to-G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation.</strong> J. Clin. Invest. 86: 1000-1003, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2394825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2394825</a>] [<a href="https://doi.org/10.1172/JCI114761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2394825">Yokota et al. (1990)</a> and <a href="#27" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Miyabayashi, S., Tada, K., Coates, P. M. <strong>Molecular lesion in patients with medium-chain acyl-CoA dehydrogenase deficiency. (Letter)</strong> Lancet 335: 1589 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1972503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1972503</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1972503">Matsubara et al. (1990)</a> suggested that the distinction may lie simply in the numbering of residues and that in fact the investigators had described the same mutation. (Residue 304 in the mature human MCAD corresponds to residue 329 in the preprotein.) <a href="#41" class="mim-tip-reference" title="Yokota, I., Indo, Y., Coates, P. M., Tanaka, K. <strong>Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency: an A-to-G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation.</strong> J. Clin. Invest. 86: 1000-1003, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2394825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2394825</a>] [<a href="https://doi.org/10.1172/JCI114761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2394825">Yokota et al. (1990)</a> stated that only 3 patients overlapped in their study and that of <a href="#27" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Miyabayashi, S., Tada, K., Coates, P. M. <strong>Molecular lesion in patients with medium-chain acyl-CoA dehydrogenase deficiency. (Letter)</strong> Lancet 335: 1589 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1972503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1972503</a>] [<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1972503">Matsubara et al. (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2394825+1972503" 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 Dutch MCAD-deficient patient described by <a href="#13" class="mim-tip-reference" title="Duran, M., Hofkamp, M., Rhead, W. J., Saudubray, J. M., Wadman, S. K. <strong>Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency.</strong> Pediatrics 78: 1052-1057, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3786030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3786030</a>]" pmid="3786030">Duran et al. (1986)</a>, <a href="#19" class="mim-tip-reference" title="Kelly, D. P., Whelan, A. J., Ogden, M. L., Alpers, R., Zhang, Z., Bellus, G., Gregersen, N., Dorland, L., Strauss, A. W. <strong>Molecular characterization of inherited medium-chain acyl-CoA dehydrogenase deficiency.</strong> Proc. Nat. Acad. Sci. 87: 9236-9240, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2251268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2251268</a>] [<a href="https://doi.org/10.1073/pnas.87.23.9236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2251268">Kelly et al. (1990)</a> found an A-to-G change at nucleotide 985 of the MCAD mRNA coding region, resulting in substitution of glutamic acid for lysine at amino acid 304 of the mature protein. In addition to the point mutation, a significant proportion of the index patient's MCAD mRNA contained a variety of deletions and insertions as a result of exon skipping and intron retention. The missplicing occurred in multiple regions throughout the MCAD mRNA. Analysis of regions where missplicing occurred most frequently did not reveal a mutation in the splice acceptor or donor sites. That the lys304-to-glu mutation was pathogenic was supported by the fact that the change was not found in any wildtype MCAD mRNAs. Using a PCR-based test on consecutive Guthrie spots, <a href="#5" class="mim-tip-reference" title="Blakemore, A. I. F., Singleton, H., Pollitt, R. J., Engel, P. C., Kolvraa, S., Gregersen, N., Curtis, D. <strong>Frequency of the G985 MCAD mutation in the general population. (Letter)</strong> Lancet 337: 298-299, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671131</a>] [<a href="https://doi.org/10.1016/0140-6736(91)90907-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1671131">Blakemore et al. (1991)</a> studied the frequency of the G985 MCAD mutation in the neonatal population of the Trent (England) health region. Although no homozygotes were found, 6 of 410 newborns were heterozygous for the mutation, representing a carrier frequency of 1 in 68. This suggests that the frequency of homozygotes should be about 1 in 18,500 births. Since about 15% of mutations are other than the G985 mutation, the total carrier frequency may be 1 in 58, with the total population frequency 1 in 13,400. <a href="#14" class="mim-tip-reference" title="Gregersen, N., Andresen, B. S., Bross, P., Winter, V., Rudiger, N., Engst, S., Christensen, E., Kelly, D., Strauss, A. W., Kolvraa, S., Bolund, L., Ghisla, S. <strong>Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329-to-glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli.</strong> Hum. Genet. 86: 545-551, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1902818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1902818</a>] [<a href="https://doi.org/10.1007/BF00201539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1902818">Gregersen et al. (1991)</a> found the same mutation in homozygous form in 12 of 13 patients with MCAD deficiency. <a href="#14" class="mim-tip-reference" title="Gregersen, N., Andresen, B. S., Bross, P., Winter, V., Rudiger, N., Engst, S., Christensen, E., Kelly, D., Strauss, A. W., Kolvraa, S., Bolund, L., Ghisla, S. <strong>Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329-to-glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli.</strong> Hum. Genet. 86: 545-551, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1902818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1902818</a>] [<a href="https://doi.org/10.1007/BF00201539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1902818">Gregersen et al. (1991)</a> later reported that 15 of 16 patients with MCAD deficiency were homozygous for the G985 mutation. The same 15 who were homozygous for G985 were also homozygous for the haplotype 112, suggesting founder effect. <a href="#21" class="mim-tip-reference" title="Kolvraa, S., Gregersen, N., Blakemore, A. I. F., Schneidermann, A. K., Winter, V., Andresen, B. S., Curtis, D., Engel, P. C., Pricille, D., Rhead, W., Bolund, L. <strong>The most common mutation causing medium-chain acyl-CoA dehydrogenase deficiency is strongly associated with a particular haplotype in the region of the gene.</strong> Hum. Genet. 87: 425-428, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1679031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1679031</a>] [<a href="https://doi.org/10.1007/BF00197161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1679031">Kolvraa et al. (1991)</a> found the G985 mutation in 31 of 32 disease-causing alleles. In at least 30 of the 31 alleles carrying this G985 mutation, a specific RFLP haplotype was found. In contrast, the same haplotype was present in only 23% of normal alleles. The findings were interpreted as consistent with a strong founder effect. <a href="#8" class="mim-tip-reference" title="Curtis, D., Blakemore, A. I. F., Engel, P. C., Macgregor, D., Besley, G., Kolvraa, S., Gregersen, N. <strong>Heterogeneity for mutations in medium chain acyl-CoA dehydrogenase deficiency in the UK population.</strong> Clin. Genet. 40: 283-286, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1756601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1756601</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03097.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1756601">Curtis et al. (1991)</a> studied 21 affected children from 18 families in the U.K. In 14 families the children were homozygous for the G985 mutation. In 3 families the children were compound heterozygotes for G985 and another unknown mutation. In 1 family the affected child did not carry the G985 on either chromosome. It was calculated that the carrier incidence of the G985 mutation is 1 in 68. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3786030+1902818+2251268+1756601+1679031+1671131" 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 study of 55 MCAD-deficient patients, <a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">Yokota et al. (1991)</a> reported that the G985 allele was found in homozygous state in 44 and in heterozygous state in 10; one patient did not carry this mutant allele, indicating that the prevalence of the G985 allele was 89.1%. They identified 5 other types of mutations: one each in 3 of the compound heterozygotes and 2 in the single non-G985 patient. A RFLP study of 12 G985-homozygotes showed that all 24 alleles fell into a single haplotype. All of 41 patients for whom information was available were Caucasians. Of 29 patients whose country of origin was specified, 19 were from the British Isles and 5 from Germany. <a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">Yokota et al. (1991)</a> interpreted these data to indicate that the G985 mutation may have occurred in a single person in an ancient Germanic tribe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684086" 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="#11" class="mim-tip-reference" title="Ding, J.-H., Roe, C. R., Iafolla, A. K., Chen, Y.-T. <strong>Medium-chain acyl-coenzyme A dehydrogenase deficiency and sudden infant death. (Letter)</strong> New Eng. J. Med. 325: 61-62, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2046713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2046713</a>] [<a href="https://doi.org/10.1056/NEJM199107043250113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2046713">Ding et al. (1991)</a> analyzed DNA from 7 infants who had died suddenly of unexpected causes, i.e., cases of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>). These cases were identified through the diagnosis of MCAD deficiency in subsequent, live sibs. Mutational analysis performed on postmortem fixed tissue showed the A-to-G mutation at nucleotide 985 in homozygous form in all 7 probands and in heterozygous form in all parents. The fixed tissues had been stored for as long as 18 years. <a href="#30" class="mim-tip-reference" title="Miller, M. E., Brooks, J. G., Forbes, N., Insel, R. <strong>Frequency of medium-chain acyl-CoA dehydrogenase deficiency G-985 mutation in sudden infant death syndrome.</strong> Pediat. Res. 31: 305-307, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570195</a>] [<a href="https://doi.org/10.1203/00006450-199204000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570195">Miller et al. (1992)</a> extracted DNA from autopsy tissues of 67 victims of SIDS in Monroe County, N.Y., who died between 1984 and 1989. Using the PCR/NcoI digestion method, they found no G985 homozygotes and 3 (4.5%) G985 heterozygotes. In 70 newborn controls, they found no G985 homozygotes and 1 (1.4%) heterozygote. They doubted that the G985 mutation is strongly associated with SIDS. <a href="#34" class="mim-tip-reference" title="Opdal, S. H., Vege, A., Saugstad, O. D., Rognum, T. O. <strong>Is the medium-chain acyl-CoA dehydrogenase G985 mutation involved in sudden infant death in Norway? (Letter)</strong> Europ. J. Pediat. 154: 166-167, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7720752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7720752</a>] [<a href="https://doi.org/10.1007/BF01991929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7720752">Opdal et al. (1995)</a> found no case of the G985 mutation among 133 cases of SIDS, 6 cases of borderline SIDS, and 30 cases of infectious death in Norway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7720752+2046713+1570195" 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="Leung, K.-C., Hammond, J. W., Chabra, S., Carpenter, K. H., Potter, M., Wilcken, B. <strong>A fatal neonatal case of medium-chain acyl-coenzyme A dehydrogenase deficiency with homozygous A-to-G(985) transition.</strong> J. Pediat. 121: 965-968, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1447668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1447668</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)80353-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1447668">Leung et al. (1992)</a> described an affected neonate in whom lethargy and hypotonia developed at 46 hours of age and death followed 10 hours later. They claimed that neonatal presentation had been ignored or discounted in literature reviews. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1447668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Tada, K., Ikeda, H., Ye-Qi, Y., Danks, D. M., Green, A., McCabe, E. R. B. <strong>Prevalence of K329E mutation in medium-chain acyl-CoA dehydrogenase gene determined from Guthrie cards.</strong> Lancet 338: 552-553, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1678810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1678810</a>] [<a href="https://doi.org/10.1016/0140-6736(91)91110-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1678810">Matsubara et al. (1991)</a> determined the prevalence of the K304E mutation by study of dried blood spots on Guthrie cards obtained in neonatal screening programs. Twelve carriers were identified among 479 newborn babies in Britain, 5 among 353 in Australia, 5 among 536 in North America, but none among 500 samples in Japan. <a href="#14" class="mim-tip-reference" title="Gregersen, N., Andresen, B. S., Bross, P., Winter, V., Rudiger, N., Engst, S., Christensen, E., Kelly, D., Strauss, A. W., Kolvraa, S., Bolund, L., Ghisla, S. <strong>Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329-to-glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli.</strong> Hum. Genet. 86: 545-551, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1902818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1902818</a>] [<a href="https://doi.org/10.1007/BF00201539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1902818">Gregersen et al. (1991)</a> described a PCR-based assay suitable for use with Guthrie spots. See <a href="#29" class="mim-tip-reference" title="Matsubara, Y., Narisawa, K., Tada, K. <strong>Medium-chain acyl-CoA dehydrogenase deficiency: molecular aspects.</strong> Europ. J. Pediat. 151: 154-159, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1601002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1601002</a>] [<a href="https://doi.org/10.1007/BF01954373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1601002">Matsubara et al. (1992)</a> for a review. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1902818+1601002+1678810" 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="#42" class="mim-tip-reference" title="Yokota, I., Saijo, T., Vockley, J., Tanaka, K. <strong>Impaired tetramer assembly of variant medium-chain acyl-coenzyme A dehydrogenase with a glutamate or aspartate substitution for lysine 304 causing instability of the protein.</strong> J. Biol. Chem. 267: 26004-26010, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1361190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1361190</a>]" pmid="1361190">Yokota et al. (1992)</a> estimated that 90% of MCAD cases involve a substitution of lysine-329 in the precursor (lysine-304 in the mature protein). <a href="#42" class="mim-tip-reference" title="Yokota, I., Saijo, T., Vockley, J., Tanaka, K. <strong>Impaired tetramer assembly of variant medium-chain acyl-coenzyme A dehydrogenase with a glutamate or aspartate substitution for lysine 304 causing instability of the protein.</strong> J. Biol. Chem. 267: 26004-26010, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1361190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1361190</a>]" pmid="1361190">Yokota et al. (1992)</a> used site-directed mutagenesis to produce 3 variant cDNAs encoding variant precursor MCAD with glutamate, aspartate, or arginine substituted for lys329. They carried out in vitro expression studies of the cDNAs, and incubated the translation products with isolated rat liver mitochondria. K329E precursor was imported into mitochondria and processed into the mature subunit as efficiently as wildtype, but 10 minutes after import markedly more K329E eluted as a monomer than did wildtype, and the amount of K329E tetramer formed was distinctly less than wildtype at any point up to 60 minutes after import, indicating that the assembly of K329E was defective. After further incubation, K304E decayed more rapidly than did wildtype, indicating a reduced stability. In similar studies K329R behaved like the wildtype, while K329D closely resembled K329E, indicating that a basic residue at 304 is essential for tetramer formation and intramitochondrial stability of mature MCAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1361190" 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="#15" class="mim-tip-reference" title="Gregersen, N., Winter, V., Curtis, D., Deufel, T., Mack, M., Hendrickx, J., Willems, P. J., Ponzone, A., Parrella, T., Ponzone, R., Ding, J.-H., Zhang, W., Chen, Y. T., Kahler, S., Roe, C. R., Kolvraa, S., Schneiderman, K., Andresen, B. S., Bross, P., Bolund, L. <strong>Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe.</strong> Hum. Hered. 43: 342-350, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7904584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7904584</a>] [<a href="https://doi.org/10.1159/000154157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7904584">Gregersen et al. (1993)</a> found that the frequency of G985 heterozygotes in Caucasians in North Carolina is 1 in 84 (there are many Scottish-Irish in North Carolina), which is 5- to-10-fold higher than the frequency found in non-Caucasian Americans. They also found a complete association of the G985 mutation in 17 families with a certain haplotype. The frequency of G985 mutation carriers was 1 in 68 to 1 in 101 in newborns in the United Kingdom and Denmark, but 1 in 333 in Italy. They interpreted this as indicating a founder effect in northwestern Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7904584" 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 prevalence of carriers of 1 in 55 was estimated by <a href="#9" class="mim-tip-reference" title="de Vries, H. G., Niezen-Koning, K., Kliphuis, J. W., Smit, G. P. A., Scheffer, H., ten Kate, L. P. <strong>Prevalence of carriers of the most common medium-chain acyl-CoA dehydrogenase (MCAD) deficiency mutation (G985A) in The Netherlands.</strong> Hum. Genet. 98: 1-2, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8682492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8682492</a>] [<a href="https://doi.org/10.1007/s004390050149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8682492">de Vries et al. (1996)</a> on the basis of study of Guthrie cards of newborns. Comparably, the glu510-to-gln mutation of the HADHA gene (<a href="/entry/600890#0001">600890.0001</a>) is responsible for some 87% of cases of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (<a href="#16" class="mim-tip-reference" title="IJlst, L., Ruiter, J. P. N., Hoovers, J. M. N., Jakobs, M. E., Wanders, R. J. A. <strong>Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.</strong> J. Clin. Invest. 98: 1028-1033, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8770876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8770876</a>] [<a href="https://doi.org/10.1172/JCI118863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8770876">IJlst et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8770876+8682492" 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="#38" class="mim-tip-reference" title="Wang, S. S., Fernhoff, P. M., Hannon, W. H., Khoury, M. J. <strong>Medium chain acyl-CoA dehydrogenase deficiency: human genome epidemiology review.</strong> Genet. Med. 1: 332-339, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11263545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11263545</a>] [<a href="https://doi.org/10.1097/00125817-199911000-00004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11263545">Wang et al. (1999)</a> provided data on the frequency of the K304E mutation in 20 countries. Of patients clinically diagnosed with MCADD, 81% had been identified retrospectively as homozygous for K304E, and 18% were compound heterozygotes for K304E. The frequency varied from 1 in 6,400 in Birmingham, England, and 1 in 10,000 in Finland to 1 in 442,000 in Italy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11263545" 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 newborns, <a href="#3" class="mim-tip-reference" title="Andresen, B. S., Dobrowolski, S. F., O'Reilly, L., Muenzer, J., McCandless, S. E., Frazier, D. M., Udvari, S., Bross, P., Knudsen, I., Banas, R., Chace, D. H., Engel, P., Naylor, E. W., Gregersen, N. <strong>Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.</strong> Am. J. Hum. Genet. 68: 1408-1418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11349232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11349232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11349232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11349232">Andresen et al. (2001)</a> found compound heterozygosity for a 199T-C transition in exon 3 of the ACADM gene, causing a tyr42-to-his substitution. This mutation had never been observed in clinically manifest disease, but was present in a large proportion of the acylcarnitine-positive samples. Overexpression Screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are widely used for screening for MCAD deficiency. <a href="#3" class="mim-tip-reference" title="Andresen, B. S., Dobrowolski, S. F., O'Reilly, L., Muenzer, J., McCandless, S. E., Frazier, D. M., Udvari, S., Bross, P., Knudsen, I., Banas, R., Chace, D. H., Engel, P., Naylor, E. W., Gregersen, N. <strong>Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.</strong> Am. J. Hum. Genet. 68: 1408-1418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11349232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11349232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11349232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11349232">Andresen et al. (2001)</a> performed mutation analysis in blood spots from 930,078 neonates in the U.S. and found a frequency of MCAD deficiency of 1 in 15,001. Mutation analysis showed that the frequency of the 985A-G mutant allele in newborns with a positive acylcarnitine profile was much lower than that observed in clinically affected patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11349232" 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 4 asymptomatic sibs, <a href="#1" class="mim-tip-reference" title="Albers, S., Levy, H. L., Irons, M., Strauss, A. W., Marsden, D. <strong>Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.</strong> J. Inherit. Metab. Dis. 24: 417-418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486912</a>] [<a href="https://doi.org/10.1023/a:1010533408635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486912">Albers et al. (2001)</a> reported compound heterozygosity for an arg256-to-thr substitution (<a href="#0013">607008.0013</a>) with K304E. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Bodman, M., Smith, D., Nyhan, W. L., Naviaux, R. K. <strong>Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.</strong> Arch. Neurol. 58: 811-814, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11346377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11346377</a>] [<a href="https://doi.org/10.1001/archneur.58.5.811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11346377">Bodman et al. (2001)</a> reported a 12-month-old child who presented with viral infections and lethargy and was found to be homozygous for the 985A-G mutation. Family history revealed that his father had experienced episodes of hypoglycemic shock, and genetic analysis showed that he also was homozygous for the mutation. The authors noted that the carrier frequency for the mutation is as common as 1 in 55 persons, which predicts a homozygote frequency of 1 in 12,000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11346377" 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="#31" class="mim-tip-reference" title="Nichols, M. J., Saavedra-Matiz, C. A., Pass, K. A., Caggana, M. <strong>Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985A-G mutation in the New York state population.</strong> Am. J. Med. Genet. 146A: 610-619, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18241067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18241067</a>] [<a href="https://doi.org/10.1002/ajmg.a.32192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18241067">Nichols et al. (2008)</a> found that the K304E mutation accounted for only 47.5% of mutant ACADM alleles in New York state over an 18-month period of newborn screening. The frequency was lower than that reported by others, possibly reflecting the mixed ethnic composition of the New York population. Y42H (<a href="#0011">607008.0011</a>) was the second most common mutation, accounting for 7.5% of mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18241067" 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 meta-regression analysis of 43 studies reporting the frequency of the c.985A-G mutation in over 10 million individuals, <a href="#23" class="mim-tip-reference" title="Leal, J., Ades, A. E., Wordsworth, S., Dezateux, C. <strong>Regional differences in the frequency of the c.985A-G ACADM mutation: findings from a meta-regression of genotyping and screening studies.</strong> Clin. Genet. 85: 253-259, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23574375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23574375</a>] [<a href="https://doi.org/10.1111/cge.12157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23574375">Leal et al. (2014)</a> found significant variation in the frequency of the mutation across regions. The proportion of individuals homozygous for the mutation was highest in western Europe (4.1 per 100,000), followed by the New World, including the United States, Canada, and Australia (3.2), southern Europe (1.2), and eastern Europe (0.9). No cases with the mutation were identified in Asia or the Middle East. The findings were consistent with a founder effect originating in northern Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23574375" 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 class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1225471006 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1225471006;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1225471006?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1225471006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1225471006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Spanish patient with MCAD deficiency (ACADMD; <a href="/entry/201450">201450</a>), who was previously described by <a href="#10" class="mim-tip-reference" title="Del Valle, J. A., Garcia, M. J., Merinero, B., Perez Cerda, C., Roman, F., Jimenez, A., Ugarte, M., Martinez Pardo, M., Ludena, C., Camarero, C., Duran, M., Wadman, S. K. <strong>A new patient with dicarboxylic aciduria suggestive of medium-chain acyl-CoA dehydrogenase deficiency presenting as Reye's syndrome.</strong> J. Inherit. Metab. Dis. 7: 62-64, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6434827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6434827</a>] [<a href="https://doi.org/10.1007/BF01805804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6434827">Del Valle et al. (1984)</a>, Yokota et al. (<a href="#41" class="mim-tip-reference" title="Yokota, I., Indo, Y., Coates, P. M., Tanaka, K. <strong>Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency: an A-to-G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation.</strong> J. Clin. Invest. 86: 1000-1003, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2394825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2394825</a>] [<a href="https://doi.org/10.1172/JCI114761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2394825">1990</a>, <a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">1991</a>) found compound heterozygosity for the mutation listed here as <a href="#0001">607008.0001</a> and an apparently rare mutant allele consisting of a 13-bp tandem repeat from position 999 (T) to 1011 (C) in the MCAD cDNA sequence, causing a premature stop codon at the 5-prime end of the second set of the repeat (after tyr337). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2394825+1684086+6434827" 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="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003771 OR RCV000185665 OR RCV003415641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003771, RCV000185665, RCV003415641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003771...</a>
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<p><a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">Yokota et al. (1991)</a> found a G-to-A transition at position 799 in the ACADM gene in 2 of 110 mutant alleles studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684086" 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="0004" class="mim-anchor"></a>
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<strong>.0004 MCAD DEFICIENCY</strong>
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ACADM, ILE375THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434275;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434275?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003772" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003772" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003772</a>
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<p><a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">Yokota et al. (1991)</a> found a T-to-C transition at position 1124 in the ACADM gene as the responsible mutation in 1 of 110 mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684086" 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="0005" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0005 MCAD DEFICIENCY</strong>
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</h4>
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ACADM, CYS244ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434276 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434276;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003773" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003773" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003773</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In 1 patient out of 55 with MCAD deficiency (<a href="/entry/201450">201450</a>), <a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">Yokota et al. (1991)</a> found compound heterozygosity in the ACADM gene, with 1 allele having a transition from T-to-C at position 730, resulting in substitution of arginine for cysteine-244. Thus this allele represented only 1 out of 110 studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684086" 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="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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ACADM, MET149ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434277 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434277;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434277?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003774 OR RCV000723823 OR RCV003398435" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003774, RCV000723823, RCV003398435" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003774...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a study of 55 patients with MCAD deficiency (ACADMD; <a href="/entry/201450">201450</a>), <a href="#40" class="mim-tip-reference" title="Yokota, I., Coates, P. M., Hale, D. E., Rinaldo, P., Tanaka, K. <strong>Molecular survey of a prevalent mutation, (985)A-to-G transition, and identification of five infrequent mutations in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.</strong> Am. J. Hum. Genet. 49: 1280-1291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684086</a>]" pmid="1684086">Yokota et al. (1991)</a> found a G-to-A transition at position 447 in the ACADM gene in 1 of 110 mutant alleles. The mutation resulted in substitution of isoleucine for methionine-149. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684086" 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>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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ACADM, 4-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906297 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906297;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003775 OR RCV000077877 OR RCV003924798 OR RCV004601087" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003775, RCV000077877, RCV003924798, RCV004601087" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003775...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p><a href="#12" class="mim-tip-reference" title="Ding, J.-H., Yang, B.-Z., Bao, Y., Roe, C. R., Chen, Y.-T. <strong>Identification of a new mutation in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.</strong> Am. J. Hum. Genet. 50: 229-233, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1729890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1729890</a>]" pmid="1729890">Ding et al. (1992)</a> found a deletion of nucleotides 1102-1105, inclusive, from MCAD cDNA. The patient was a compound heterozygote for this allele and the lys329-to-glu mutation (<a href="#0001">607008.0001</a>). The 4-bp deletion came from paternal Welsh ancestry. <a href="#17" class="mim-tip-reference" title="Kelly, D. P., Hale, D. E., Rutledge, S. L., Ogden, M. L., Whelan, A. J., Zhang, Z., Strauss, A. W. <strong>Molecular basis of inherited medium-chain acyl-CoA dehydrogenase deficiency causing sudden child death.</strong> J. Inherit. Metab. Dis. 15: 171-180, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1356169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1356169</a>] [<a href="https://doi.org/10.1007/BF01799626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1356169">Kelly et al. (1992)</a> identified the same 4-bp deletion in compound heterozygous state with the same lys329-to-glu mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1356169+1729890" 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="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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ACADM, 6-BP DEL, GLY90 AND CYS91
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864621963 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864621963;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs864621963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs864621963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003776" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003776" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003776</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant with MCAD deficiency (ACADMD; <a href="/entry/201450">201450</a>), <a href="#44" class="mim-tip-reference" title="Ziadeh, R., Hoffman, E. P., Finegold, D. N., Hoop, R. C., Brackett, J. C., Strauss, A. W., Naylor, E. W. <strong>Medium chain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies.</strong> Pediat. Res. 37: 675-678, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7603790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7603790</a>] [<a href="https://doi.org/10.1203/00006450-199505000-00021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7603790">Ziadeh et al. (1995)</a> demonstrated compound heterozygosity for the common lys329-to-glu mutation (<a href="#0001">607008.0001</a>) and a previously undescribed mutation: a deletion of 6 amino acids which removed gly90 and cys91 from the MCAD protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7603790" 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>
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<div>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434278 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434278;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434278?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003777 OR RCV000077891" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003777, RCV000077891" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003777...</a>
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<p>MCAD deficiency (ACADMD; <a href="/entry/201450">201450</a>) typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Most cases (approximately 80%) are homozygous for the lys329-to-glu mutation in the ACADM gene (<a href="#0001">607008.0001</a>). <a href="#7" class="mim-tip-reference" title="Brackett, J. C., Sims, H. F., Steiner, R. D., Nunge, M., Zimmerman, E. M., deMartinville, B., Rinaldo, P., Slaugh, R., Strauss, A. W. <strong>A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.</strong> J. Clin. Invest. 94: 1477-1483, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7929823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7929823</a>] [<a href="https://doi.org/10.1172/JCI117486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7929823">Brackett et al. (1994)</a> reported 4 compound heterozygous individuals from 2 unrelated families with the lys329-to-glu mutation on 1 allele and a novel G-to-A transition at nucleotide 583 as the second mutant allele. These patients presented with MCAD deficiency in the first week of life. The expressed 583G-A mutant protein lacked enzymatic activity. The novel mutation was associated with severe MCAD deficiency causing hypoglycemia or sudden unexpected neonatal death. The mutation predicts a change from glycine, a neutral amino acid with no side chain, to arginine, a positively charged residue with a bulky side chain, at amino acid 195 (G170R) of the precursor protein (residue 170 of the mature protein). This amino acid is conserved as a small neutral amino acid (glycine or alanine) in every known acyl-CoA dehydrogenase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7929823" 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 class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434279 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434279;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#2" class="mim-tip-reference" title="Andresen, B. S., Bross, P., Udvari, S., Kirk, J., Gray, G., Kmoch, S., Chamoles, N., Knudsen, I., Winter, V., Wilcken, B., Yokota, I., Hart, K., Packman, S., Harpey, J. P., Saudubray, J. M., Hale, D. E., Bolund, L., Kolvraa, S., Gregersen, N. <strong>The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?</strong> Hum. Molec. Genet. 6: 695-707, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158144</a>] [<a href="https://doi.org/10.1093/hmg/6.5.695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9158144">Andresen et al. (1997)</a> studied 52 families with MCAD deficiency (<a href="/entry/201450">201450</a>) not caused by homozygosity for the K304E mutation (<a href="#0001">607008.0001</a>) and found 7 new mutations in the ACADM gene. One of these was a 577A-G point mutation resulting in a thr168-to-ala amino acid substitution in the mature protein. The patient and his father had previously been reported to be heterozygous for a 13-bp insertion mutation in exon 11; the mother was found to be heterozygous for the 577A-G mutation. The steady-state amounts of MCADH mRNA from both mutant alleles were found to be decreased. <a href="#22" class="mim-tip-reference" title="Kuchler, B., Abdel-Ghany, A.-G., Bross, P., Nandy, A., Rasched, I., Ghisla, S. <strong>Biochemical characterization of a variant human medium-chain acyl-CoA dehydrogenase with a disease-associated mutation localized in the active site.</strong> Biochem. J. 337: 225-230, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9882619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9882619</a>]" pmid="9882619">Kuchler et al. (1999)</a> stated that what set the T168A mutation apart from all other previously known mutations was that it constituted the first case of a modification within the active site of the protein. Thr168 is located in contact with the FAD cofactor and forms a hydrogen-bond with the flavin N(5) position. This is the point of entry of the substrate-derived hydride during catalysis, so that it is conceivable that the modification affects the chemistry of catalysis. <a href="#22" class="mim-tip-reference" title="Kuchler, B., Abdel-Ghany, A.-G., Bross, P., Nandy, A., Rasched, I., Ghisla, S. <strong>Biochemical characterization of a variant human medium-chain acyl-CoA dehydrogenase with a disease-associated mutation localized in the active site.</strong> Biochem. J. 337: 225-230, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9882619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9882619</a>]" pmid="9882619">Kuchler et al. (1999)</a> investigated these aspects and reported on some of the properties of the mutant protein in comparison with those of wildtype MCADH and K304E-MCADH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9158144+9882619" 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 class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434280;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434280?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003780 OR RCV000185668 OR RCV002512723" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003780, RCV000185668, RCV002512723" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003780...</a>
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<p>This mutation has also been called TYR67HIS (Y67H).</p><p>In 7 newborns with MCAD deficiency (<a href="/entry/201450">201450</a>), <a href="#3" class="mim-tip-reference" title="Andresen, B. S., Dobrowolski, S. F., O'Reilly, L., Muenzer, J., McCandless, S. E., Frazier, D. M., Udvari, S., Bross, P., Knudsen, I., Banas, R., Chace, D. H., Engel, P., Naylor, E. W., Gregersen, N. <strong>Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.</strong> Am. J. Hum. Genet. 68: 1408-1418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11349232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11349232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11349232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11349232">Andresen et al. (2001)</a> identified a new mutation in the ACADM gene, a 199T-C change resulting in a tyr42-to-his (Y42H) substitution. Although this mutation had never been observed in patients with clinically manifest disease, it was present in a large proportion of the acylcarnitine-positive samples. The Y42H mutation was found to have a carrier frequency of 1 in 500 in the general population, and overexpression experiments showed that it is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. In all cases in which haplotyping was performed, the 199T-C mutation was found on the same haplotype, indicating a common origin of the mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11349232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with MCAD deficiency, <a href="#45" class="mim-tip-reference" title="Zschocke, J., Schulze, A., Lindner, M., Fiesel, S., Olgemoller, K., Hoffmann, G. F., Penzien, J., Ruiter, J. P. N., Wanders, R. J. A., Mayatepek, E. <strong>Molecular and functional characterization of mild MCAD deficiency.</strong> Hum. Genet. 108: 404-408, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409868</a>] [<a href="https://doi.org/10.1007/s004390100501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409868">Zschocke et al. (2001)</a> found the same mutation, which they called a tyr67-to-his mutation. The mutation was found in compound heterozygosity with the K329E mutation (<a href="#0001">607008.0001</a>) in both patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11409868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro studies, <a href="#33" class="mim-tip-reference" title="O'Reilly, L., Bross, P., Corydon, T. J., Olpin, S. E., Hansen, J., Kenney, J. M., McCandless, S. E., Frazier, D. M., Winter, V., Gregersen, N., Engel, P. C., Andresen, B. S. <strong>The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive.</strong> Europ. J. Biochem. 271: 4053-4063, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15479234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15479234</a>] [<a href="https://doi.org/10.1111/j.1432-1033.2004.04343.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15479234">O'Reilly et al. (2004)</a> determined that the Y42H mutation compromised enzyme activity to only a minor degree. Substrate binding, interaction with the natural electron acceptor, and binding of the prosthetic group FAD were only slightly affected by the Y42H mutation. However, thermostability of the Y42H variant was decreased compared to wildtype protein but not to the same degree as that of the K304E variant. The findings suggested that Y42H is a temperature-sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15479234" 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="#31" class="mim-tip-reference" title="Nichols, M. J., Saavedra-Matiz, C. A., Pass, K. A., Caggana, M. <strong>Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985A-G mutation in the New York state population.</strong> Am. J. Med. Genet. 146A: 610-619, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18241067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18241067</a>] [<a href="https://doi.org/10.1002/ajmg.a.32192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18241067">Nichols et al. (2008)</a> found that Y42H was the second (7.5%) most common ACADM mutation in New York state over an 18-month period of newborn screening. K304E was most common, accounting for 47.5% of mutant ACADM alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18241067" 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 class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434281;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434281?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003781 OR RCV000077894" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003781, RCV000077894" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003781...</a>
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<p>This mutation has also been called SER245LEU (S245L), based on the precursor protein.</p><p>In a patient with MCAD deficiency (<a href="/entry/201450">201450</a>), <a href="#45" class="mim-tip-reference" title="Zschocke, J., Schulze, A., Lindner, M., Fiesel, S., Olgemoller, K., Hoffmann, G. F., Penzien, J., Ruiter, J. P. N., Wanders, R. J. A., Mayatepek, E. <strong>Molecular and functional characterization of mild MCAD deficiency.</strong> Hum. Genet. 108: 404-408, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409868</a>] [<a href="https://doi.org/10.1007/s004390100501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409868">Zschocke et al. (2001)</a> found a homozygous C-to-T transition at nucleotide 734 in exon 9 of the ACADM gene, resulting in a ser220-to-leu (S220L) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11409868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 MCAD DEFICIENCY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434282;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434282?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003779" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003779" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003779</a>
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<p><a href="#1" class="mim-tip-reference" title="Albers, S., Levy, H. L., Irons, M., Strauss, A. W., Marsden, D. <strong>Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.</strong> J. Inherit. Metab. Dis. 24: 417-418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486912</a>] [<a href="https://doi.org/10.1023/a:1010533408635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486912">Albers et al. (2001)</a> reported a G-to-C transversion at nucleotide 842 in the ACADM gene, resulting in an arg256-to-thr substitution. This mutation was found in compound heterozygosity with the lys304-to-glu mutation (<a href="#0001">607008.0001</a>) in 4 asymptomatic sibs, ranging in age from 1 to 9 years, with MCAD deficiency (<a href="/entry/201450">201450</a>). The proband was identified because of expanded newborn screening using tandem mass spectrometry. <a href="#1" class="mim-tip-reference" title="Albers, S., Levy, H. L., Irons, M., Strauss, A. W., Marsden, D. <strong>Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.</strong> J. Inherit. Metab. Dis. 24: 417-418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486912</a>] [<a href="https://doi.org/10.1023/a:1010533408635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486912">Albers et al. (2001)</a> suggested that this mutation may have a mild or benign clinical phenotype and that it is important to screen older unscreened sibs of all infants diagnosed by expanded newborn screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 MCAD DEFICIENCY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434283 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434283;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121434283?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121434283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003782 OR RCV000185674 OR RCV003230894 OR RCV003924799" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003782, RCV000185674, RCV003230894, RCV003924799" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003782...</a>
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<p><a href="#3" class="mim-tip-reference" title="Andresen, B. S., Dobrowolski, S. F., O'Reilly, L., Muenzer, J., McCandless, S. E., Frazier, D. M., Udvari, S., Bross, P., Knudsen, I., Banas, R., Chace, D. H., Engel, P., Naylor, E. W., Gregersen, N. <strong>Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.</strong> Am. J. Hum. Genet. 68: 1408-1418, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11349232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11349232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11349232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11349232">Andresen et al. (2001)</a> initially reported the 362C-T mutation in the ACADM gene in a baby with MCAD deficiency (<a href="/entry/201450">201450</a>) identified in a U.S. MS/MS newborn screening program and demonstrated that the encoded T96I mutant ICAD protein had a low but detectable level of enzyme activity. Thereafter the same mutation was identified in 2 additional newborns and in 3 patients with clinically manifest disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11349232" 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="Nielsen, K. B., Sorensen, S., Cartegni, L., Corydon, T. J., Doktor, T. K., Schroeder, L. D., Reinert, L. S., Elpeleg, O., Krainer, A. R., Gregersen, N., Kjems, J., Andresen, B. S. <strong>Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer.</strong> Am. J. Hum. Genet. 80: 416-432, 2007. Note: Erratum: Am. J. Hum. Genet. 80: 816 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273963">Nielsen et al. (2007)</a> showed that mRNA from alleles with the 362C-T mutation displayed a high level of exon 5 skipping. Exon 5 skipping led to a shifted reading frame, resulting in a premature termination codon in exon 6, indicating that the decreased amount of MCAD mRNA from the 362C-T allele is a result of nonsense-mediated decay (NMD). The authors went on to demonstrate that the MCAD 362C-T mutation disrupts an exonic splicing enhancer (ESE). They concluded that the MCAD ESE is functionally similar to the ESE of SMN1 (<a href="/entry/600354">600354</a>). Further studies demonstrated that the negative effect of the 362C-T mutation is antagonized by a flanking polymorphic 351A-C synonymous variation (<a href="#0015">607008.0015</a>). In conclusion, <a href="#32" class="mim-tip-reference" title="Nielsen, K. B., Sorensen, S., Cartegni, L., Corydon, T. J., Doktor, T. K., Schroeder, L. D., Reinert, L. S., Elpeleg, O., Krainer, A. R., Gregersen, N., Kjems, J., Andresen, B. S. <strong>Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer.</strong> Am. J. Hum. Genet. 80: 416-432, 2007. Note: Erratum: Am. J. Hum. Genet. 80: 816 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273963">Nielsen et al. (2007)</a> reported a novel mechanism by which a presumed neutral polymorphic variant, 351C, in an exon can protect against disease-causing splicing mutations. This could be a common mode by which SNPs affect gene expression, but, under normal conditions, such occurrences would be underestimated because the involved ESS elements would be unmasked only when the mutation in cis inactivates the antagonizing ESE element. <a href="#32" class="mim-tip-reference" title="Nielsen, K. B., Sorensen, S., Cartegni, L., Corydon, T. J., Doktor, T. K., Schroeder, L. D., Reinert, L. S., Elpeleg, O., Krainer, A. R., Gregersen, N., Kjems, J., Andresen, B. S. <strong>Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer.</strong> Am. J. Hum. Genet. 80: 416-432, 2007. Note: Erratum: Am. J. Hum. Genet. 80: 816 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273963">Nielsen et al. (2007)</a> suggested that this mechanism may also play an important role in evolution, since substitutions that inactivate such ESS elements would neutralize the restrictions put on splicing-inactivating mutations elsewhere in the exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 MCAD DEFICIENCY, MODIFIER OF</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74090726 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74090726;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74090726?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74090726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74090726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003783 OR RCV000077887 OR RCV000211524 OR RCV003230894 OR RCV004713188" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003783, RCV000077887, RCV000211524, RCV003230894, RCV004713188" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003783...</a>
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<p><a href="#32" class="mim-tip-reference" title="Nielsen, K. B., Sorensen, S., Cartegni, L., Corydon, T. J., Doktor, T. K., Schroeder, L. D., Reinert, L. S., Elpeleg, O., Krainer, A. R., Gregersen, N., Kjems, J., Andresen, B. S. <strong>Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer.</strong> Am. J. Hum. Genet. 80: 416-432, 2007. Note: Erratum: Am. J. Hum. Genet. 80: 816 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273963">Nielsen et al. (2007)</a> identified a neutral polymorphic variant in exon 5 of the ACADM gene, 351A-C, that inactivates the exonic splicing silencer (ESS) and, while this has no effect on splicing itself, makes splicing immune to deleterious mutations in the ESE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273963" 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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ACADM, 4-BP DEL, 449CTGA (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204642;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs786204642</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786204642 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204642;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786204642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786204642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000169427 OR RCV000723370" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169427, RCV000723370" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169427...</a>
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<p>In a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of the disorder (ACADMD; <a href="/entry/201450">201450</a>), <a href="#36" class="mim-tip-reference" title="Tajima, G., Hara, K., Tsumura, M., Kagawa, R., Okada, S., Sakura, N., Hata, I., Shigematsu, Y., Kobayashi, M. <strong>Screening of MCAD deficiency in Japan: 16 years' experience of enzymatic and genetic evaluation.</strong> Molec. Genet. Metab. 119: 322-328, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27856190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27856190</a>] [<a href="https://doi.org/10.1016/j.ymgme.2016.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27856190">Tajima et al. (2016)</a> found that the most prevalent mutation was a 4-bp deletion (c.449_452delCTGA) in the ACADM gene, predicted to result in a frameshift and premature termination (Thr150Argfs). The mutation, which was found by direct sequencing of the gene, was identified in 25 ACADM alleles of 22 individuals from 19 families. Analyses in patient lymphocytes showed that the mutation resulted in abolished ACADM enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27856190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Albers2001" class="mim-anchor"></a>
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<strong>Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.</strong>
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[<a href="https://doi.org/10.1023/a:1010533408635" target="_blank">Full Text</a>]
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<a id="Andresen1997" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158144</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9158144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/6.5.695" target="_blank">Full Text</a>]
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<a id="Andresen2001" class="mim-anchor"></a>
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Andresen, B. S., Dobrowolski, S. F., O'Reilly, L., Muenzer, J., McCandless, S. E., Frazier, D. M., Udvari, S., Bross, P., Knudsen, I., Banas, R., Chace, D. H., Engel, P., Naylor, E. W., Gregersen, N.
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<strong>Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.</strong>
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Am. J. Hum. Genet. 68: 1408-1418, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11349232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11349232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11349232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11349232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/320602" target="_blank">Full Text</a>]
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<a id="Bahary1991" class="mim-anchor"></a>
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Bahary, N., Zorich, G., Pachter, J. E., Leibel, R. L., Friedman, J. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684952</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90099-z" target="_blank">Full Text</a>]
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<a id="Blakemore1991" class="mim-anchor"></a>
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Blakemore, A. I. F., Singleton, H., Pollitt, R. J., Engel, P. C., Kolvraa, S., Gregersen, N., Curtis, D.
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<strong>Frequency of the G985 MCAD mutation in the general population. (Letter)</strong>
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Lancet 337: 298-299, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671131</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0140-6736(91)90907-7" target="_blank">Full Text</a>]
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<a id="Bodman2001" class="mim-anchor"></a>
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Bodman, M., Smith, D., Nyhan, W. L., Naviaux, R. K.
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Arch. Neurol. 58: 811-814, 2001.
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[<a href="https://doi.org/10.1001/archneur.58.5.811" target="_blank">Full Text</a>]
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Brackett, J. C., Sims, H. F., Steiner, R. D., Nunge, M., Zimmerman, E. M., deMartinville, B., Rinaldo, P., Slaugh, R., Strauss, A. W.
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[<a href="https://doi.org/10.1172/JCI117486" target="_blank">Full Text</a>]
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<a id="Curtis1991" class="mim-anchor"></a>
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<div class="">
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Curtis, D., Blakemore, A. I. F., Engel, P. C., Macgregor, D., Besley, G., Kolvraa, S., Gregersen, N.
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[<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03097.x" target="_blank">Full Text</a>]
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<a id="de Vries1996" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1007/s004390050149" target="_blank">Full Text</a>]
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<a id="Del Valle1984" class="mim-anchor"></a>
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Del Valle, J. A., Garcia, M. J., Merinero, B., Perez Cerda, C., Roman, F., Jimenez, A., Ugarte, M., Martinez Pardo, M., Ludena, C., Camarero, C., Duran, M., Wadman, S. K.
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<strong>A new patient with dicarboxylic aciduria suggestive of medium-chain acyl-CoA dehydrogenase deficiency presenting as Reye's syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6434827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6434827</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6434827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01805804" target="_blank">Full Text</a>]
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<a id="Ding1991" class="mim-anchor"></a>
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Ding, J.-H., Roe, C. R., Iafolla, A. K., Chen, Y.-T.
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<strong>Medium-chain acyl-coenzyme A dehydrogenase deficiency and sudden infant death. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2046713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2046713</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2046713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199107043250113" target="_blank">Full Text</a>]
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<a id="Ding1992" class="mim-anchor"></a>
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Ding, J.-H., Yang, B.-Z., Bao, Y., Roe, C. R., Chen, Y.-T.
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<strong>Identification of a new mutation in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.</strong>
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Am. J. Hum. Genet. 50: 229-233, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1729890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1729890</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1729890" 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="Duran1986" class="mim-anchor"></a>
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Duran, M., Hofkamp, M., Rhead, W. J., Saudubray, J. M., Wadman, S. K.
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<strong>Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency.</strong>
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Pediatrics 78: 1052-1057, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3786030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3786030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3786030" 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="Gregersen1991" class="mim-anchor"></a>
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Gregersen, N., Andresen, B. S., Bross, P., Winter, V., Rudiger, N., Engst, S., Christensen, E., Kelly, D., Strauss, A. W., Kolvraa, S., Bolund, L., Ghisla, S.
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<strong>Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329-to-glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli.</strong>
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Hum. Genet. 86: 545-551, 1991.
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[<a href="https://doi.org/10.1007/BF00201539" target="_blank">Full Text</a>]
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<strong>Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe.</strong>
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[<a href="https://doi.org/10.1159/000154157" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI118863" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01799626" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.84.12.4068" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.87.23.9236" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(90)90451-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00197161" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.12157" target="_blank">Full Text</a>]
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<strong>A fatal neonatal case of medium-chain acyl-coenzyme A dehydrogenase deficiency with homozygous A-to-G(985) transition.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(05)80353-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp079" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.83.17.6543" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(90)91413-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(91)91110-g" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01954373" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-199204000-00001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32192" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/511992" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI114761" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-199505000-00021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390100501" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/12/2021
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Cassandra L. Kniffin - updated : 10/23/2014<br>Ada Hamosh - updated : 9/26/2011<br>George E. Tiller - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 4/7/2008<br>Victor A. McKusick - updated : 2/19/2007<br>Victor A. McKusick - updated : 6/19/2003
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Cassandra L. Kniffin : 6/4/2002
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carol : 04/04/2024
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carol : 08/12/2021<br>carol : 05/21/2020<br>alopez : 12/10/2014<br>carol : 10/24/2014<br>mcolton : 10/24/2014<br>ckniffin : 10/23/2014<br>alopez : 10/5/2011<br>terry : 9/26/2011<br>terry : 9/26/2011<br>wwang : 10/21/2009<br>terry : 10/15/2009<br>wwang : 4/9/2008<br>ckniffin : 4/7/2008<br>carol : 5/3/2007<br>alopez : 2/27/2007<br>terry : 2/19/2007<br>ckniffin : 9/22/2005<br>tkritzer : 7/29/2003<br>carol : 6/25/2003<br>terry : 6/19/2003<br>tkritzer : 5/30/2003<br>terry : 1/2/2003<br>carol : 6/13/2002<br>ckniffin : 6/13/2002<br>ckniffin : 6/13/2002
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<strong>*</strong> 607008
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ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN; ACADM
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<em>Alternative titles; symbols</em>
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MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE; MCAD; MCADH
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ACADM</em></strong>
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<strong>SNOMEDCT:</strong> 128596003;
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<strong>ICD10CM:</strong> E71.311;
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Cytogenetic location: 1p31.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:75,724,709-75,763,679 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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1p31.1
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Acyl-CoA dehydrogenase, medium chain, deficiency of
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201450
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Matsubara et al. (1986) stated that 5 acyl-CoA dehydrogenases had been reported: short-chain (606885), medium-chain (EC 1.3.99.3), and long-chain (609576) acyl-CoA dehydrogenases; isovaleryl-CoA dehydrogenase (243500); and 2-methyl branched-chain acyl-CoA dehydrogenase. The first 3 catalyze the initial reaction in the beta-oxidation of fatty acids, while the last 2 catalyze the dehydrogenation of branched short-chain acyl-CoAs in the metabolism of the branched-chain amino acids. All 5 may have evolved from a common ancestral gene. </p>
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<strong>Cloning and Expression</strong>
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<p>By screening a liver cDNA library with the rat pre-medium-chain acyl-CoA dehydrogenase cDNA, Matsubara et al. (1986) cloned a partial human MCAD cDNA. The MCAD enzyme is a homotetramer with a molecular mass of about 45 kD. </p><p>Kelly et al. (1987) determined the MCAD mRNA nucleotide sequence from 2 overlapping cDNA clones isolated from human liver and placenta cDNA libraries, respectively. The sequence encodes a 421-amino acid protein with characteristics of mitochondrial protein transit peptides. The protein shows 88% sequence identity with porcine MCAD. </p>
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<strong>Gene Structure</strong>
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<p>The MCAD gene contains 12 exons (Zhang et al., 1992). </p>
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<strong>Gene Function</strong>
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<p>Medium-chain acyl-CoA dehydrogenase catalyzes the initial reaction in the beta-oxidation of C4 to C12 straight-chain acyl-CoAs (Matsubara et al., 1986). </p>
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<strong>Mapping</strong>
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<p>Matsubara et al. (1986) mapped the ACADM gene to 1p31 by Southern analysis of DNA from hybrid cells and by in situ hybridization. Kidd et al. (1990) demonstrated extensive polymorphism in ACADM. With linkage studies, they showed that the ACADM locus is proximal to PGM1 (171900). Since the latter locus has been assigned to 1p22.1 by somatic cell studies, these results are in conflict with the assignment of ACADM to 1p31 by in situ hybridization. The authors suggested that the somatic cell localization of PGM1 may be incorrect. </p><p>By use of a backcross with Mus spretus, Bahary et al. (1991) assigned the homologous gene to chromosome 8 in the mouse. However, Tolwani et al. (1996) mapped the Acadm gene to the distal end of mouse chromosome 3. They showed that sequences previously localized to chromosome 8 represent a pseudogene, and identified an additional pseudogene on chromosome 11. </p>
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<strong>Molecular Genetics</strong>
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<p>Kelly et al. (1987) performed blot hybridization of RNA prepared from cultured skin fibroblasts from a patient with MCAD deficiency (ACADMD; 201450) and showed that mRNA was present and of similar size to MCAD mRNA derived from control fibroblasts. </p><p>In 9 patients with MCAD deficiency, Matsubara et al. (1990) identified a homozygous 985A-G transition in the MCAD gene, which resulted in a lys304-to-glu substitution (K304E; 607008.0001) in the mature protein. These patients were unrelated, suggesting a high incidence of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles. </p><p>Zschocke et al. (2001) characterized the molecular defect in 4 patients with mild MCAD deficiency. In routine neonatal screening on the fifth day of life, they had been found to have abnormal acylcarnitine profiles indicative of MCAD deficiency. Two were of German origin and the other 2 were born to different consanguineous Turkish parents. In all 4, the clinical course and routine laboratory investigations up to the age of 6 months were unremarkable. Enzyme studies showed residual MCAD activities between those with classic MCAD deficiency and heterozygotes. In 2 cases, ACADM gene analysis revealed compound heterozygosity for the common K304E mutation (607008.0001) and the Y42H mutation (607008.0011), which they designated Y67H. In the 2 children of consanguineous parents, homozygosity was found for the gly267-to-arg mutation (G267R; 607008.0003) and the S220L mutation (607008.0012), respectively. As in other metabolic disorders, the distinction between 'normal' and 'disease' in MCAD deficiency is blurred into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing. </p><p>Wilcken et al. (2003) reported on the use of electrospray tandem mass spectrometry to screen newborns for 31 inborn errors affecting the metabolism of the urea cycle, amino acids, and organic acids and fatty acid oxidation in a 4-year period in Australia. The rate of inborn errors, excluding PKU, was 15.7 per 100,000 births, as compared with adjusted rates of 8.6 to 9.5 per 100,000 births in the 4 preceding 4-year cohorts. The rate of detection was increased specifically for MCAD deficiency and other disorders of fatty acid oxidation, as compared with the 16-year period before the implementation of neonatal screening for these disorders. </p><p>Maier et al. (2009) analyzed the impact of 10 ACADM mutations (see, e.g., 607008.0001 and 607008.0011) on conformation, stability and enzyme kinetics of the corresponding mutant proteins. Partial to total rescue of aggregation by overexpression of GroES (HSPE1; 600141) and GroEL (HSPD1; 118190) suggested protein misfolding as a pathogenic mechanism. Catalytic function varied from high residual activity to markedly decreased activity or substrate affinity. Mutations mapping to the beta-domain of the protein predisposed to severe destabilization. In silico structural analysis of the affected amino acid residues revealed involvement in functionally relevant networks. Maier et al. (2009) concluded that protein misfolding with loss-of-function is the common molecular basis in MCAD deficiency. </p><p>Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. Suhre et al. (2011) identified rs211718 in the ACADM gene as associated with hexanoylcarnitine/oleate ratio with a p value of 2.2 x 10(-71). </p><p>Tajima et al. (2016) sequenced the ACADM gene in a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of MCAD deficiency. The most prevalent mutation was a 4-bp deletion (c.449_452delCTGA; 607008.0016) identified in 25 ACADM alleles of 22 subjects from 19 families. Other prevalent mutations in this cohort included R17H, G362E, R53C, and R281S. These 5 mutations accounted for 60% of the mutations identified in this patient cohort. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Andresen et al. (1997) determined the frequency of 14 known and 7 previously unknown non-G985 mutations in the MCAD gene in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. They showed that none of the non-G985 mutations is prevalent. In 14 families in which they identified both disease-causing mutations, they correlated the mutations with clinical/biochemical data and found that a genotype/phenotype correlation in MCAD deficiency is not straightforward. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>16 Selected Examples):</strong>
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<strong>.0001 MCAD DEFICIENCY</strong>
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ACADM, LYS304GLU
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SNP: rs77931234,
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gnomAD: rs77931234,
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ClinVar: RCV000003769, RCV000077895, RCV001526621, RCV002251863, RCV002512722, RCV003430631
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<p>This mutation has also been called LYS329GLU (K329E), based on the precursor protein.</p><p>In 9 patients with MCAD deficiency (ACADMD; 201450), Matsubara et al. (1990) identified an A-to-G transition in the ACADM gene, which resulted in the substitution of lysine (AAA) by glutamic acid (GAA) at residue 329 (K304E) of the enzyme. These patients were unrelated, suggesting a high instance of this abnormality among Caucasian patients. The change was not found in 20 healthy Caucasian and 6 healthy Japanese subjects. Matsubara et al. (1990) found this point mutation in 31 of 34 (91%) mutant MCAD alleles. </p><p>In 3 patients with MCAD deficiency, Yokota et al. (1990) demonstrated an A-to-G transition at position 985 (G985) of the coding region of the ACADM gene, which resulted in a lys304-to-glu (K304E) substitution in the mature protein. Since no appropriate restriction sites for detecting this point mutation were found, they devised an ingenious PCR-based method for demonstrating the G985 mutation. In studies of 9 MCAD deficient patients, homozygosity for this mutation was found in all; in contrast, all 8 controls lacked the mutation. All the patients were Caucasian. In a later study, Yokota et al. (1990) found that the mutation introduces a new NcoI restriction site. Genomic DNA from 11 unrelated MCAD patients was homozygous for the G985 transition as indicated by complete cleavage of PCR-amplified fragments by NcoI. The high prevalence of this mutation in Caucasians and the similarity between the mutations described by Yokota et al. (1990) and Matsubara et al. (1990) suggested that the distinction may lie simply in the numbering of residues and that in fact the investigators had described the same mutation. (Residue 304 in the mature human MCAD corresponds to residue 329 in the preprotein.) Yokota et al. (1990) stated that only 3 patients overlapped in their study and that of Matsubara et al. (1990). </p><p>In a Dutch MCAD-deficient patient described by Duran et al. (1986), Kelly et al. (1990) found an A-to-G change at nucleotide 985 of the MCAD mRNA coding region, resulting in substitution of glutamic acid for lysine at amino acid 304 of the mature protein. In addition to the point mutation, a significant proportion of the index patient's MCAD mRNA contained a variety of deletions and insertions as a result of exon skipping and intron retention. The missplicing occurred in multiple regions throughout the MCAD mRNA. Analysis of regions where missplicing occurred most frequently did not reveal a mutation in the splice acceptor or donor sites. That the lys304-to-glu mutation was pathogenic was supported by the fact that the change was not found in any wildtype MCAD mRNAs. Using a PCR-based test on consecutive Guthrie spots, Blakemore et al. (1991) studied the frequency of the G985 MCAD mutation in the neonatal population of the Trent (England) health region. Although no homozygotes were found, 6 of 410 newborns were heterozygous for the mutation, representing a carrier frequency of 1 in 68. This suggests that the frequency of homozygotes should be about 1 in 18,500 births. Since about 15% of mutations are other than the G985 mutation, the total carrier frequency may be 1 in 58, with the total population frequency 1 in 13,400. Gregersen et al. (1991) found the same mutation in homozygous form in 12 of 13 patients with MCAD deficiency. Gregersen et al. (1991) later reported that 15 of 16 patients with MCAD deficiency were homozygous for the G985 mutation. The same 15 who were homozygous for G985 were also homozygous for the haplotype 112, suggesting founder effect. Kolvraa et al. (1991) found the G985 mutation in 31 of 32 disease-causing alleles. In at least 30 of the 31 alleles carrying this G985 mutation, a specific RFLP haplotype was found. In contrast, the same haplotype was present in only 23% of normal alleles. The findings were interpreted as consistent with a strong founder effect. Curtis et al. (1991) studied 21 affected children from 18 families in the U.K. In 14 families the children were homozygous for the G985 mutation. In 3 families the children were compound heterozygotes for G985 and another unknown mutation. In 1 family the affected child did not carry the G985 on either chromosome. It was calculated that the carrier incidence of the G985 mutation is 1 in 68. </p><p>In a study of 55 MCAD-deficient patients, Yokota et al. (1991) reported that the G985 allele was found in homozygous state in 44 and in heterozygous state in 10; one patient did not carry this mutant allele, indicating that the prevalence of the G985 allele was 89.1%. They identified 5 other types of mutations: one each in 3 of the compound heterozygotes and 2 in the single non-G985 patient. A RFLP study of 12 G985-homozygotes showed that all 24 alleles fell into a single haplotype. All of 41 patients for whom information was available were Caucasians. Of 29 patients whose country of origin was specified, 19 were from the British Isles and 5 from Germany. Yokota et al. (1991) interpreted these data to indicate that the G985 mutation may have occurred in a single person in an ancient Germanic tribe. </p><p>Ding et al. (1991) analyzed DNA from 7 infants who had died suddenly of unexpected causes, i.e., cases of sudden infant death syndrome (SIDS; 272120). These cases were identified through the diagnosis of MCAD deficiency in subsequent, live sibs. Mutational analysis performed on postmortem fixed tissue showed the A-to-G mutation at nucleotide 985 in homozygous form in all 7 probands and in heterozygous form in all parents. The fixed tissues had been stored for as long as 18 years. Miller et al. (1992) extracted DNA from autopsy tissues of 67 victims of SIDS in Monroe County, N.Y., who died between 1984 and 1989. Using the PCR/NcoI digestion method, they found no G985 homozygotes and 3 (4.5%) G985 heterozygotes. In 70 newborn controls, they found no G985 homozygotes and 1 (1.4%) heterozygote. They doubted that the G985 mutation is strongly associated with SIDS. Opdal et al. (1995) found no case of the G985 mutation among 133 cases of SIDS, 6 cases of borderline SIDS, and 30 cases of infectious death in Norway. </p><p>Leung et al. (1992) described an affected neonate in whom lethargy and hypotonia developed at 46 hours of age and death followed 10 hours later. They claimed that neonatal presentation had been ignored or discounted in literature reviews. </p><p>Matsubara et al. (1991) determined the prevalence of the K304E mutation by study of dried blood spots on Guthrie cards obtained in neonatal screening programs. Twelve carriers were identified among 479 newborn babies in Britain, 5 among 353 in Australia, 5 among 536 in North America, but none among 500 samples in Japan. Gregersen et al. (1991) described a PCR-based assay suitable for use with Guthrie spots. See Matsubara et al. (1992) for a review. </p><p>Yokota et al. (1992) estimated that 90% of MCAD cases involve a substitution of lysine-329 in the precursor (lysine-304 in the mature protein). Yokota et al. (1992) used site-directed mutagenesis to produce 3 variant cDNAs encoding variant precursor MCAD with glutamate, aspartate, or arginine substituted for lys329. They carried out in vitro expression studies of the cDNAs, and incubated the translation products with isolated rat liver mitochondria. K329E precursor was imported into mitochondria and processed into the mature subunit as efficiently as wildtype, but 10 minutes after import markedly more K329E eluted as a monomer than did wildtype, and the amount of K329E tetramer formed was distinctly less than wildtype at any point up to 60 minutes after import, indicating that the assembly of K329E was defective. After further incubation, K304E decayed more rapidly than did wildtype, indicating a reduced stability. In similar studies K329R behaved like the wildtype, while K329D closely resembled K329E, indicating that a basic residue at 304 is essential for tetramer formation and intramitochondrial stability of mature MCAD. </p><p>Gregersen et al. (1993) found that the frequency of G985 heterozygotes in Caucasians in North Carolina is 1 in 84 (there are many Scottish-Irish in North Carolina), which is 5- to-10-fold higher than the frequency found in non-Caucasian Americans. They also found a complete association of the G985 mutation in 17 families with a certain haplotype. The frequency of G985 mutation carriers was 1 in 68 to 1 in 101 in newborns in the United Kingdom and Denmark, but 1 in 333 in Italy. They interpreted this as indicating a founder effect in northwestern Europe. </p><p>A prevalence of carriers of 1 in 55 was estimated by de Vries et al. (1996) on the basis of study of Guthrie cards of newborns. Comparably, the glu510-to-gln mutation of the HADHA gene (600890.0001) is responsible for some 87% of cases of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (IJlst et al., 1996). </p><p>Wang et al. (1999) provided data on the frequency of the K304E mutation in 20 countries. Of patients clinically diagnosed with MCADD, 81% had been identified retrospectively as homozygous for K304E, and 18% were compound heterozygotes for K304E. The frequency varied from 1 in 6,400 in Birmingham, England, and 1 in 10,000 in Finland to 1 in 442,000 in Italy. </p><p>In 7 newborns, Andresen et al. (2001) found compound heterozygosity for a 199T-C transition in exon 3 of the ACADM gene, causing a tyr42-to-his substitution. This mutation had never been observed in clinically manifest disease, but was present in a large proportion of the acylcarnitine-positive samples. Overexpression Screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are widely used for screening for MCAD deficiency. Andresen et al. (2001) performed mutation analysis in blood spots from 930,078 neonates in the U.S. and found a frequency of MCAD deficiency of 1 in 15,001. Mutation analysis showed that the frequency of the 985A-G mutant allele in newborns with a positive acylcarnitine profile was much lower than that observed in clinically affected patients. </p><p>In 4 asymptomatic sibs, Albers et al. (2001) reported compound heterozygosity for an arg256-to-thr substitution (607008.0013) with K304E. </p><p>Bodman et al. (2001) reported a 12-month-old child who presented with viral infections and lethargy and was found to be homozygous for the 985A-G mutation. Family history revealed that his father had experienced episodes of hypoglycemic shock, and genetic analysis showed that he also was homozygous for the mutation. The authors noted that the carrier frequency for the mutation is as common as 1 in 55 persons, which predicts a homozygote frequency of 1 in 12,000. </p><p>Nichols et al. (2008) found that the K304E mutation accounted for only 47.5% of mutant ACADM alleles in New York state over an 18-month period of newborn screening. The frequency was lower than that reported by others, possibly reflecting the mixed ethnic composition of the New York population. Y42H (607008.0011) was the second most common mutation, accounting for 7.5% of mutant alleles. </p><p>In a meta-regression analysis of 43 studies reporting the frequency of the c.985A-G mutation in over 10 million individuals, Leal et al. (2014) found significant variation in the frequency of the mutation across regions. The proportion of individuals homozygous for the mutation was highest in western Europe (4.1 per 100,000), followed by the New World, including the United States, Canada, and Australia (3.2), southern Europe (1.2), and eastern Europe (0.9). No cases with the mutation were identified in Asia or the Middle East. The findings were consistent with a founder effect originating in northern Europe. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, 13-BP DUP
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<br />
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SNP: rs1225471006,
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gnomAD: rs1225471006,
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ClinVar: RCV000003770, RCV000478348, RCV003914801
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Spanish patient with MCAD deficiency (ACADMD; 201450), who was previously described by Del Valle et al. (1984), Yokota et al. (1990, 1991) found compound heterozygosity for the mutation listed here as 607008.0001 and an apparently rare mutant allele consisting of a 13-bp tandem repeat from position 999 (T) to 1011 (C) in the MCAD cDNA sequence, causing a premature stop codon at the 5-prime end of the second set of the repeat (after tyr337). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, GLY267ARG
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<br />
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SNP: rs121434274,
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gnomAD: rs121434274,
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ClinVar: RCV000003771, RCV000185665, RCV003415641
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Yokota et al. (1991) found a G-to-A transition at position 799 in the ACADM gene in 2 of 110 mutant alleles studied. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, ILE375THR
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<br />
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SNP: rs121434275,
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gnomAD: rs121434275,
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ClinVar: RCV000003772
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Yokota et al. (1991) found a T-to-C transition at position 1124 in the ACADM gene as the responsible mutation in 1 of 110 mutant alleles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, CYS244ARG
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<br />
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SNP: rs121434276,
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ClinVar: RCV000003773
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 1 patient out of 55 with MCAD deficiency (201450), Yokota et al. (1991) found compound heterozygosity in the ACADM gene, with 1 allele having a transition from T-to-C at position 730, resulting in substitution of arginine for cysteine-244. Thus this allele represented only 1 out of 110 studied. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, MET149ILE
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<br />
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SNP: rs121434277,
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gnomAD: rs121434277,
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ClinVar: RCV000003774, RCV000723823, RCV003398435
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a study of 55 patients with MCAD deficiency (ACADMD; 201450), Yokota et al. (1991) found a G-to-A transition at position 447 in the ACADM gene in 1 of 110 mutant alleles. The mutation resulted in substitution of isoleucine for methionine-149. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, 4-BP DEL
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<br />
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SNP: rs387906297,
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ClinVar: RCV000003775, RCV000077877, RCV003924798, RCV004601087
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Ding et al. (1992) found a deletion of nucleotides 1102-1105, inclusive, from MCAD cDNA. The patient was a compound heterozygote for this allele and the lys329-to-glu mutation (607008.0001). The 4-bp deletion came from paternal Welsh ancestry. Kelly et al. (1992) identified the same 4-bp deletion in compound heterozygous state with the same lys329-to-glu mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 MCAD DEFICIENCY</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, 6-BP DEL, GLY90 AND CYS91
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<br />
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SNP: rs864621963,
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ClinVar: RCV000003776
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an infant with MCAD deficiency (ACADMD; 201450), Ziadeh et al. (1995) demonstrated compound heterozygosity for the common lys329-to-glu mutation (607008.0001) and a previously undescribed mutation: a deletion of 6 amino acids which removed gly90 and cys91 from the MCAD protein. </p>
|
|
</span>
|
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</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MCAD DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACADM, GLY170ARG
|
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|
<br />
|
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|
|
SNP: rs121434278,
|
|
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|
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gnomAD: rs121434278,
|
|
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|
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ClinVar: RCV000003777, RCV000077891
|
|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>MCAD deficiency (ACADMD; 201450) typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Most cases (approximately 80%) are homozygous for the lys329-to-glu mutation in the ACADM gene (607008.0001). Brackett et al. (1994) reported 4 compound heterozygous individuals from 2 unrelated families with the lys329-to-glu mutation on 1 allele and a novel G-to-A transition at nucleotide 583 as the second mutant allele. These patients presented with MCAD deficiency in the first week of life. The expressed 583G-A mutant protein lacked enzymatic activity. The novel mutation was associated with severe MCAD deficiency causing hypoglycemia or sudden unexpected neonatal death. The mutation predicts a change from glycine, a neutral amino acid with no side chain, to arginine, a positively charged residue with a bulky side chain, at amino acid 195 (G170R) of the precursor protein (residue 170 of the mature protein). This amino acid is conserved as a small neutral amino acid (glycine or alanine) in every known acyl-CoA dehydrogenase. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
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|
</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MCAD DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
ACADM, THR168ALA
|
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<br />
|
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|
|
SNP: rs121434279,
|
|
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|
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|
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ClinVar: RCV000003778
|
|
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|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>Andresen et al. (1997) studied 52 families with MCAD deficiency (201450) not caused by homozygosity for the K304E mutation (607008.0001) and found 7 new mutations in the ACADM gene. One of these was a 577A-G point mutation resulting in a thr168-to-ala amino acid substitution in the mature protein. The patient and his father had previously been reported to be heterozygous for a 13-bp insertion mutation in exon 11; the mother was found to be heterozygous for the 577A-G mutation. The steady-state amounts of MCADH mRNA from both mutant alleles were found to be decreased. Kuchler et al. (1999) stated that what set the T168A mutation apart from all other previously known mutations was that it constituted the first case of a modification within the active site of the protein. Thr168 is located in contact with the FAD cofactor and forms a hydrogen-bond with the flavin N(5) position. This is the point of entry of the substrate-derived hydride during catalysis, so that it is conceivable that the modification affects the chemistry of catalysis. Kuchler et al. (1999) investigated these aspects and reported on some of the properties of the mutant protein in comparison with those of wildtype MCADH and K304E-MCADH. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MCAD DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
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<span class="mim-text-font">
|
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ACADM, TYR42HIS
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<br />
|
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|
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SNP: rs121434280,
|
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|
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gnomAD: rs121434280,
|
|
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|
|
ClinVar: RCV000003780, RCV000185668, RCV002512723
|
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|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>This mutation has also been called TYR67HIS (Y67H).</p><p>In 7 newborns with MCAD deficiency (201450), Andresen et al. (2001) identified a new mutation in the ACADM gene, a 199T-C change resulting in a tyr42-to-his (Y42H) substitution. Although this mutation had never been observed in patients with clinically manifest disease, it was present in a large proportion of the acylcarnitine-positive samples. The Y42H mutation was found to have a carrier frequency of 1 in 500 in the general population, and overexpression experiments showed that it is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. In all cases in which haplotyping was performed, the 199T-C mutation was found on the same haplotype, indicating a common origin of the mutant allele. </p><p>In 2 patients with MCAD deficiency, Zschocke et al. (2001) found the same mutation, which they called a tyr67-to-his mutation. The mutation was found in compound heterozygosity with the K329E mutation (607008.0001) in both patients. </p><p>By in vitro studies, O'Reilly et al. (2004) determined that the Y42H mutation compromised enzyme activity to only a minor degree. Substrate binding, interaction with the natural electron acceptor, and binding of the prosthetic group FAD were only slightly affected by the Y42H mutation. However, thermostability of the Y42H variant was decreased compared to wildtype protein but not to the same degree as that of the K304E variant. The findings suggested that Y42H is a temperature-sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures. </p><p>Nichols et al. (2008) found that Y42H was the second (7.5%) most common ACADM mutation in New York state over an 18-month period of newborn screening. K304E was most common, accounting for 47.5% of mutant ACADM alleles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, SER220LEU
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<br />
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SNP: rs121434281,
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gnomAD: rs121434281,
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ClinVar: RCV000003781, RCV000077894
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This mutation has also been called SER245LEU (S245L), based on the precursor protein.</p><p>In a patient with MCAD deficiency (201450), Zschocke et al. (2001) found a homozygous C-to-T transition at nucleotide 734 in exon 9 of the ACADM gene, resulting in a ser220-to-leu (S220L) mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, ARG256THR
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<br />
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SNP: rs121434282,
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gnomAD: rs121434282,
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ClinVar: RCV000003779
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Albers et al. (2001) reported a G-to-C transversion at nucleotide 842 in the ACADM gene, resulting in an arg256-to-thr substitution. This mutation was found in compound heterozygosity with the lys304-to-glu mutation (607008.0001) in 4 asymptomatic sibs, ranging in age from 1 to 9 years, with MCAD deficiency (201450). The proband was identified because of expanded newborn screening using tandem mass spectrometry. Albers et al. (2001) suggested that this mutation may have a mild or benign clinical phenotype and that it is important to screen older unscreened sibs of all infants diagnosed by expanded newborn screening. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, THR96ILE
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<br />
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SNP: rs121434283,
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gnomAD: rs121434283,
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ClinVar: RCV000003782, RCV000185674, RCV003230894, RCV003924799
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Andresen et al. (2001) initially reported the 362C-T mutation in the ACADM gene in a baby with MCAD deficiency (201450) identified in a U.S. MS/MS newborn screening program and demonstrated that the encoded T96I mutant ICAD protein had a low but detectable level of enzyme activity. Thereafter the same mutation was identified in 2 additional newborns and in 3 patients with clinically manifest disease. </p><p>Nielsen et al. (2007) showed that mRNA from alleles with the 362C-T mutation displayed a high level of exon 5 skipping. Exon 5 skipping led to a shifted reading frame, resulting in a premature termination codon in exon 6, indicating that the decreased amount of MCAD mRNA from the 362C-T allele is a result of nonsense-mediated decay (NMD). The authors went on to demonstrate that the MCAD 362C-T mutation disrupts an exonic splicing enhancer (ESE). They concluded that the MCAD ESE is functionally similar to the ESE of SMN1 (600354). Further studies demonstrated that the negative effect of the 362C-T mutation is antagonized by a flanking polymorphic 351A-C synonymous variation (607008.0015). In conclusion, Nielsen et al. (2007) reported a novel mechanism by which a presumed neutral polymorphic variant, 351C, in an exon can protect against disease-causing splicing mutations. This could be a common mode by which SNPs affect gene expression, but, under normal conditions, such occurrences would be underestimated because the involved ESS elements would be unmasked only when the mutation in cis inactivates the antagonizing ESE element. Nielsen et al. (2007) suggested that this mechanism may also play an important role in evolution, since substitutions that inactivate such ESS elements would neutralize the restrictions put on splicing-inactivating mutations elsewhere in the exon. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 MCAD DEFICIENCY, MODIFIER OF</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, 351A-C
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<br />
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SNP: rs74090726,
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gnomAD: rs74090726,
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ClinVar: RCV000003783, RCV000077887, RCV000211524, RCV003230894, RCV004713188
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Nielsen et al. (2007) identified a neutral polymorphic variant in exon 5 of the ACADM gene, 351A-C, that inactivates the exonic splicing silencer (ESS) and, while this has no effect on splicing itself, makes splicing immune to deleterious mutations in the ESE. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0016 MCAD DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACADM, 4-BP DEL, 449CTGA ({dbSNP rs786204642})
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<br />
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SNP: rs786204642,
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ClinVar: RCV000169427, RCV000723370
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of the disorder (ACADMD; 201450), Tajima et al. (2016) found that the most prevalent mutation was a 4-bp deletion (c.449_452delCTGA) in the ACADM gene, predicted to result in a frameshift and premature termination (Thr150Argfs). The mutation, which was found by direct sequencing of the gene, was identified in 25 ACADM alleles of 22 individuals from 19 families. Analyses in patient lymphocytes showed that the mutation resulted in abolished ACADM enzyme activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Albers, S., Levy, H. L., Irons, M., Strauss, A. W., Marsden, D.
|
|
<strong>Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.</strong>
|
|
J. Inherit. Metab. Dis. 24: 417-418, 2001.
|
|
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|
|
[PubMed: 11486912]
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[Full Text: https://doi.org/10.1023/a:1010533408635]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Andresen, B. S., Bross, P., Udvari, S., Kirk, J., Gray, G., Kmoch, S., Chamoles, N., Knudsen, I., Winter, V., Wilcken, B., Yokota, I., Hart, K., Packman, S., Harpey, J. P., Saudubray, J. M., Hale, D. E., Bolund, L., Kolvraa, S., Gregersen, N.
|
|
<strong>The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?</strong>
|
|
Hum. Molec. Genet. 6: 695-707, 1997.
|
|
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|
|
[PubMed: 9158144]
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[Full Text: https://doi.org/10.1093/hmg/6.5.695]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Andresen, B. S., Dobrowolski, S. F., O'Reilly, L., Muenzer, J., McCandless, S. E., Frazier, D. M., Udvari, S., Bross, P., Knudsen, I., Banas, R., Chace, D. H., Engel, P., Naylor, E. W., Gregersen, N.
|
|
<strong>Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency.</strong>
|
|
Am. J. Hum. Genet. 68: 1408-1418, 2001.
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|
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|
|
[PubMed: 11349232]
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[Full Text: https://doi.org/10.1086/320602]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bahary, N., Zorich, G., Pachter, J. E., Leibel, R. L., Friedman, J. M.
|
|
<strong>Molecular genetic linkage maps of mouse chromosomes 4 and 6.</strong>
|
|
Genomics 11: 33-47, 1991.
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|
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|
|
|
[PubMed: 1684952]
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[Full Text: https://doi.org/10.1016/0888-7543(91)90099-z]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Blakemore, A. I. F., Singleton, H., Pollitt, R. J., Engel, P. C., Kolvraa, S., Gregersen, N., Curtis, D.
|
|
<strong>Frequency of the G985 MCAD mutation in the general population. (Letter)</strong>
|
|
Lancet 337: 298-299, 1991.
|
|
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|
|
[PubMed: 1671131]
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[Full Text: https://doi.org/10.1016/0140-6736(91)90907-7]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bodman, M., Smith, D., Nyhan, W. L., Naviaux, R. K.
|
|
<strong>Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.</strong>
|
|
Arch. Neurol. 58: 811-814, 2001.
|
|
|
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|
|
[PubMed: 11346377]
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[Full Text: https://doi.org/10.1001/archneur.58.5.811]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Brackett, J. C., Sims, H. F., Steiner, R. D., Nunge, M., Zimmerman, E. M., deMartinville, B., Rinaldo, P., Slaugh, R., Strauss, A. W.
|
|
<strong>A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.</strong>
|
|
J. Clin. Invest. 94: 1477-1483, 1994.
|
|
|
|
|
|
[PubMed: 7929823]
|
|
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|
|
[Full Text: https://doi.org/10.1172/JCI117486]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Curtis, D., Blakemore, A. I. F., Engel, P. C., Macgregor, D., Besley, G., Kolvraa, S., Gregersen, N.
|
|
<strong>Heterogeneity for mutations in medium chain acyl-CoA dehydrogenase deficiency in the UK population.</strong>
|
|
Clin. Genet. 40: 283-286, 1991.
|
|
|
|
|
|
[PubMed: 1756601]
|
|
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|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.1991.tb03097.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
de Vries, H. G., Niezen-Koning, K., Kliphuis, J. W., Smit, G. P. A., Scheffer, H., ten Kate, L. P.
|
|
<strong>Prevalence of carriers of the most common medium-chain acyl-CoA dehydrogenase (MCAD) deficiency mutation (G985A) in The Netherlands.</strong>
|
|
Hum. Genet. 98: 1-2, 1996.
|
|
|
|
|
|
[PubMed: 8682492]
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|
[Full Text: https://doi.org/10.1007/s004390050149]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Del Valle, J. A., Garcia, M. J., Merinero, B., Perez Cerda, C., Roman, F., Jimenez, A., Ugarte, M., Martinez Pardo, M., Ludena, C., Camarero, C., Duran, M., Wadman, S. K.
|
|
<strong>A new patient with dicarboxylic aciduria suggestive of medium-chain acyl-CoA dehydrogenase deficiency presenting as Reye's syndrome.</strong>
|
|
J. Inherit. Metab. Dis. 7: 62-64, 1984.
|
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|
|
|
[PubMed: 6434827]
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|
|
[Full Text: https://doi.org/10.1007/BF01805804]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ding, J.-H., Roe, C. R., Iafolla, A. K., Chen, Y.-T.
|
|
<strong>Medium-chain acyl-coenzyme A dehydrogenase deficiency and sudden infant death. (Letter)</strong>
|
|
New Eng. J. Med. 325: 61-62, 1991.
|
|
|
|
|
|
[PubMed: 2046713]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199107043250113]
|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ding, J.-H., Yang, B.-Z., Bao, Y., Roe, C. R., Chen, Y.-T.
|
|
<strong>Identification of a new mutation in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.</strong>
|
|
Am. J. Hum. Genet. 50: 229-233, 1992.
|
|
|
|
|
|
[PubMed: 1729890]
|
|
|
|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Duran, M., Hofkamp, M., Rhead, W. J., Saudubray, J. M., Wadman, S. K.
|
|
<strong>Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency.</strong>
|
|
Pediatrics 78: 1052-1057, 1986.
|
|
|
|
|
|
[PubMed: 3786030]
|
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gregersen, N., Andresen, B. S., Bross, P., Winter, V., Rudiger, N., Engst, S., Christensen, E., Kelly, D., Strauss, A. W., Kolvraa, S., Bolund, L., Ghisla, S.
|
|
<strong>Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329-to-glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli.</strong>
|
|
Hum. Genet. 86: 545-551, 1991.
|
|
|
|
|
|
[PubMed: 1902818]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF00201539]
|
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</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Gregersen, N., Winter, V., Curtis, D., Deufel, T., Mack, M., Hendrickx, J., Willems, P. J., Ponzone, A., Parrella, T., Ponzone, R., Ding, J.-H., Zhang, W., Chen, Y. T., Kahler, S., Roe, C. R., Kolvraa, S., Schneiderman, K., Andresen, B. S., Bross, P., Bolund, L.
|
|
<strong>Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe.</strong>
|
|
Hum. Hered. 43: 342-350, 1993.
|
|
|
|
|
|
[PubMed: 7904584]
|
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|
|
|
|
[Full Text: https://doi.org/10.1159/000154157]
|
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
IJlst, L., Ruiter, J. P. N., Hoovers, J. M. N., Jakobs, M. E., Wanders, R. J. A.
|
|
<strong>Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.</strong>
|
|
J. Clin. Invest. 98: 1028-1033, 1996.
|
|
|
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|
|
[PubMed: 8770876]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/12/2021<br>Cassandra L. Kniffin - updated : 10/23/2014<br>Ada Hamosh - updated : 9/26/2011<br>George E. Tiller - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 4/7/2008<br>Victor A. McKusick - updated : 2/19/2007<br>Victor A. McKusick - updated : 6/19/2003
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Cassandra L. Kniffin : 6/4/2002
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