ACADM Gene - Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency | NCBI, OMIM, ClinVar

The ACADM gene encodes medium-chain acyl-CoA dehydrogenase (MCAD), a mitochondrial enzyme that catalyzes the initial step of medium-chain fatty acid beta-oxidation. MCAD specifically dehydrogenates acyl-CoA substrates with chain lengths of 4 to 12 carbons. Pathogenic variants in ACADM cause medium-chain acyl-CoA dehydrogenase deficiency (MCADD), an autosomal recessive disorder of fatty acid oxidation. MCADD is one of the most common inborn errors of metabolism detected by newborn screening, with an incidence of approximately 1 in 10,000 to 1 in 20,000 births. The most prevalent pathogenic variant is c.985A>G (p.Lys329Glu), accounting for about 80% of disease alleles in European populations.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Fatty acid beta-oxidation (mitochondrial)

• Metabolic pathways

• PPAR signaling pathway

Medium-chain acyl-CoA dehydrogenase (MCAD) is a homotetrameric mitochondrial flavoprotein of 421 amino acids (43 kDa per subunit). Each subunit binds one FAD cofactor. MCAD catalyzes the alpha,beta-dehydrogenation of medium-chain fatty acyl-CoA thioesters (C4-C12), producing trans-2-enoyl-CoA and reduced FADH2. The enzyme is critical for energy production during fasting. Deficiency leads to accumulation of medium-chain acylcarnitines (especially C6, C8, C10) and dicarboxylic acids. The crystal structure (PDB: 1EGC) reveals a tetrameric arrangement with a central cavity accommodating the acyl-CoA substrate.