title: Medium-chain acyl-CoA deficiency: outlines from newborn screening, in silico predictions, and molecular studies.
abstract: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of fatty acid oxidation characterized by hypoglycemic crisis under fasting or during stress conditions, leading to lethargy, seizures, brain damage, or even death. Biochemical acylcarnitines data obtained through newborn screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were confirmed by molecular analysis of the medium-chain acyl-CoA dehydrogenase (ACADM) gene. Out of 324.000 newborns screened, we identified 14 MCADD patients, in whom, by molecular analysis, we found a new nonsense c.823G>T (p.Gly275∗) and two new missense mutations: c.253G>C (p.Gly85Arg) and c.356T>A (p.Val119Asp). Bioinformatics predictions based on both phylogenetic conservation and functional/structural software were used to characterize the new identified variants. Our findings confirm the rising incidence of MCADD whose existence is increasingly recognized due to the efficacy of an expanded newborn screening panel by LC-MS/MS making possible early specific therapies that can prevent possible crises in at-risk infants. We noticed that the "common" p.Lys329Glu mutation only accounted for 32% of the defective alleles, while, in clinically diagnosed patients, this mutation accounted for 90% of defective alleles. Unclassified variants (UVs or VUSs) are especially critical when considering screening programs. The functional and pathogenic characterization of genetic variants presented here is required to predict their medical consequences in newborns.
authors.affiliation: Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Viale Pieraccini 24, 50139 Florence, Italy ; Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Viale Pieraccini 24, 50139 Florence, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Catarzi
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.forename: Janita
authors.initials: J
authors.lastname: Thusberg
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Tonin
authors.forename: Sabrina
authors.initials: S
authors.lastname: Malvagia
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pasquini
authors.forename: Catia
authors.initials: C
authors.lastname: Cavicchi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferri
authors.forename: Maria A
authors.initials: MA
authors.lastname: Donati
authors.forename: Federico
authors.initials: F
authors.lastname: Baronio
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D005820:Genetic Testing / Q000706:statistics & numerical data*; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007558:Italy / Q000453:epidemiology; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D015997:Neonatal Screening / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D018570:Risk Assessment; D012680:Sensitivity and Specificity
chemical_list: D042964:Acyl-CoA Dehydrogenase