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The Scientific World Journal
Volume 2013, Article ID 625824, 8 pages
http://dx.doi.org/10.1155/2013/625824
Research Article

Medium-Chain Acyl-CoA Deficiency: Outlines from Newborn Screening, In Silico Predictions, and Molecular Studies

1Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Viale Pieraccini 24, 50139 Florence, Italy
2Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, Viale Pieraccini 24, 50139 Florence, Italy
3Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA
4Newborn Screening Biochemistry and Pharmacology Laboratory, Clinic of Paediatric Neurology, A. Meyer Children’s Hospital, Viale Pieraccini 24, 50139 Florence, Italy
5Metabolic Disorders Unit, Neuroscience Department, A. Meyer Children’s Hospital, Viale Pieraccini 24, 50139 Florence, Italy
6Department of Pediatrics, University of Bologna, Via Massarenti 13, 40138 Bologna, Italy
7Pediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, Viale Pieraccini 24, 50139 Florence, Italy

Received 19 August 2013; Accepted 12 September 2013

Academic Editors: G. Briassoulis and R. Gorodischer

Copyright © 2013 Serena Catarzi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.