Medium Chain Acyl-CoA Dehydrogenase Deficiency via the ACADM Gene

Medium chain acyl-CoA dehydrogenase deficiency (MCADD, OMIM #201450) is a defect in the catabolism of fatty acids within the mitochondria. Currently, the majority of new patients are identified through tandem mass spectrometry in neonatal screening. Patients who are identified clinically typically present within the first two years of life with an episode of lethargy and vomiting accompanied by hypoketotic hypoglycemia, which is commonly triggered by a viral infection. Some patients also have hepatomegaly and acute liver disease. These symptoms may progress to seizures, coma, and death. If MCADD is diagnosed early, most mortality and morbidity can be prevented through relatively simple measures, such as frequent feedings to avoid any extended periods of fasting (Wilcken et al. Lancet 369:37-42, 2007). MCADD is one of the most common monogenic metabolic disorders with an incidence of about 1 in 15,000 newborns in the United States. A significant fraction of sudden infant death victims have MCADD (Boles et al. J Pediatr 132:924-933, 1998).

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive disease. Medium chain acyl-CoA dehydrogenase, encoded by the ACADM gene, catalyzes the first step in the breakdown of fatty acids with 4-12 carbon atoms. For patients with Northern European ancestry, one missense variant in exon 11 (c.985A>G, p.Lys304Glu) is predominant, comprising up to about 76% of alleles in individuals with MCAD deficiency. This variant tends to cause particularly severe disease. At least 90 other causative missense, frameshift, splicing, and nonsense variants as well as gross deletions have been described throughout the length of the gene; most are private variants. Individuals who are compound heterozygous for the p.Lys304Glu variant, or homozygous for other variants in the ACADM gene, tend to have less severe disease. It appears that diagnosis by tandem mass spectrometry is more sensitive than diagnosis by other clinical features and may identify subclinical cases (Andresen et al. Am J Hum Genet 68:1408-18, 2001; Maier et al. Hum Mut 25:443-52, 2005; Matern and Rinaldo, GeneReviews, 2005; and Waddell et al. Mol Genet Metab 87:32-9, 2006).

Sensitivity of this test appears to be high. Approximately 50% of patients are homozygous for the p.Lys304Glu variant, and 40% of affected individuals are heterozygous for this variant (Matern and Rinaldo, GeneReviews, 2012).

This test provides full coverage of all coding exons of the ACADM gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).