MCAD DEFICIENCY: INSIGHTS ON NOVEL MUTATIONS IN THE ACADM GENE

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of mitochondrial β-oxidation, characterized by hypoglycemic crisis under fasting or stress conditions, leading to lethargy, seizures, brain damage or even death. This report aims to improve the knowledge of this as dangerous as it is treatable metabolic disorder included in the expanded newborn screening (NBS) panel. Biochemical acylcarnitines data obtained through NBS by LC-MS/MS were confirmed by molecular analysis of the ACADM gene and by RT-PCR analysis and in silico predictions of altered MCAD protein structures. Among 324.000 screened newborns we identified 14 MCADD patients bearing eight known and the following three new mutations: p.Gly85Arg, p.Val119Asp and p.Gly275*. In silico analysis predicted for p.Gly275* a high degree of potential alternative splicing for ACADM mRNA, confirmed by RT-PCR and sequencing analysis. These findings confirm the rising incidence of MCADD due to the efficacy of NBS. Our molecular data reveal that the “common” Lys329Glu mutation only accounts for 32% of the defective alleles identified by NBS, while in clinically diagnosed patients it accounted for 90% of them. Finally, in silico analysis proved to be useful for clarifying the pathogenetic mechanism of any new mutation including nonsense variants.