A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report

Mitochondrial fatty acid oxidation defects (FAOD) are rare inherited diseases with clinical presentation ranging from severe outcome to asymptomatic status. Diagnosis of FAOD requires specific investigations including biochemical and genetic studies. The most common FAOD is represented by a deficiency in the activity of the medium-chain acyl-CoA dehydrogenase (MCAD, EC 3.1.2.20) protein, which is coded by the ACADM gene (chromosome 1p31) [1-4]. First reported in 1976 [5] and biochemically characterized in 1982 [6], MCAD deficiency (MCADD) has since been extensively described. Point mutations in the ACADM gene were reported early [7,8] and many mutations have been documented subsequently, in part as a result of the large development of screening strategies [9-18]. As a general rule, these mutations lead to either truncated/absent protein synthesis, or replacement of one amino acid by another with a consequent drop in the activity of the mutant protein. The most common ACADM mutation is c.985A>G, which causes the replacement of a lysine by a glutamate at position 329 of the precursor protein (position 304 of the mature protein) [3,17], being for this reason also referred to as the K329E (or K304E) protein variant. Eighty percent of symptomatic MCADD patients of European origin are homozygous for this mutation, and a further 18% of symptomatic MCADD are associated with the c.985A>G mutation in one allele and a rare mutation in the other allele [1,3,19,20]. Mutations other than c.985A>G may predominate in non-European populations [21,22].MCADD is inherited as an autosomal recessive trait [2,3,23,24]. Like other genetic β-oxidation defects, MCADD may cause in early childhood life-threatening events like hypoketotic/hypoglycaemic comas occurring during the course of catabolic states which disrupt the body energetic production/expense balance (infectious episodes, for instance) [2,3,23,24]. In fact, MCADD may present phenotypically as either a classical (severe) or a mild