title: Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.
abstract: Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.
authors.affiliation: Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Smith
authors.forename: Cheryl
authors.initials: C
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: McHugh
authors.forename: Dimitar
authors.initials: D
authors.lastname: Gavrilov
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Raymond
authors.forename: Piero
authors.initials: P
authors.lastname: Rinaldo
authors.forename: Silvia
authors.initials: S
authors.lastname: Tortorelli
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: W Edward
authors.initials: WE
authors.lastname: Highsmith
authors.forename: Devin
authors.initials: D
authors.lastname: Oglesbee
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D056726:Genetic Association Studies; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D005838:Genotype; D005998:Glycine / Q000031:analogs & derivatives / Q000652:urine; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology* / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D015997:Neonatal Screening; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C024571:N-caproylglycine; D042964:Acyl-CoA Dehydrogenase; C008698:octanoylcarnitine; D002331:Carnitine; D005998:Glycine