ACADM – Medium-chain Acyl-CoA Dehydrogenase Deficiency

ACADM encodes the mitochondrial enzyme MCAD, which catalyzes the initial dehydrogenation step in fatty acid β-oxidation. Biallelic pathogenic variants in ACADM cause medium-chain acyl-CoA dehydrogenase deficiency (MCADD; [MONDO:0008721]), an autosomal recessive metabolic disorder characterized by hypoketotic hypoglycemia, vomiting, lethargy, seizures, and risk of sudden death during catabolic stress. Early identification and management, including avoidance of prolonged fasting and carnitine supplementation, are critical to prevent life-threatening decompensation.

Genetic evidence for the ACADM–MCADD association is definitive: over 150 unrelated probands have been reported with biallelic ACADM variants, most commonly the c.985A>G (p.Lys329Glu) allele, accounting for ~80–90% of pathogenic alleles ([PMID:2394825], [PMID:1902818]). Homozygosity or compound heterozygosity for c.985A>G has been demonstrated in multiple families worldwide, and unusual deletions (e.g., c.1102_1105del (p.Ala369fs), c.449_452del (p.Thr150ArgfsTer4)) and missense variants (e.g., c.158G>A (p.Arg53His), c.843A>T (p.Arg281Ser)) further expand the variant spectrum in diverse populations ([PMID:1356169], [PMID:15915086]). Segregation of pathogenic alleles with disease has been observed in at least ten affected kindreds.

Functional assays consistently demonstrate that MCAD variants result in enzyme instability and loss of activity. The prevalent p.Lys329Glu mutant fails to form stable tetramers and is degraded in patient fibroblasts ([PMID:1594327]); co-expression with GroEL/GroES chaperonins can partially rescue folding but not restore full activity ([PMID:8104486]). Rare missense changes such as p.Arg53His disrupt a conserved salt-bridge critical for catalysis and oligomer assembly ([PMID:8102510]). Splice-site mutations (e.g., c.217-2A>G) lead to complete mRNA missplicing and nonsense-mediated decay, abolishing MCAD expression and correlating with neonatal lethality ([PMID:15171999]).

Genotype-phenotype correlations reveal that classic c.985A>G homozygotes exhibit the most severe biochemical profiles and clinical crises, whereas certain variants (e.g., c.199T>C (p.Tyr67His)) retain residual enzyme activity (~25–50%) and may present with mild or subclinical phenotypes, occasionally escaping newborn screening thresholds ([PMID:11349232]). Nevertheless, any biallelic combination of ACADM pathogenic alleles confers risk under fasting or febrile stress, underscoring the need for risk-stratified management.

Integration of extensive case series, segregation studies, and in vitro/in vivo functional investigations establishes a definitive gene-disease relationship between ACADM and MCADD. The molecular mechanism involves loss-of-function through protein misfolding, impaired tetramerization, or absent protein due to aberrant splicing. Prospective newborn screening coupled with molecular diagnosis informs timely initiation of dietary and supportive therapies, significantly reducing morbidity and mortality.

Key Take-home: Biallelic ACADM variants cause MCADD via enzyme loss-of-function; definitive diagnosis relies on genetic testing of ACADM and functional confirmation, enabling targeted management to prevent metabolic crises.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1990 • Molecular characterization of inherited medium-chain acyl-CoA dehydrogenase deficiency. PMID:2251268
• The Journal of Clinical Investigation • 1990 • Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency. An A to G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation. PMID:2394825
• Pediatric research • 1992 • Immunochemical characterization of variant medium-chain acyl-CoA dehydrogenase in fibroblasts from patients with medium-chain acyl-CoA dehydrogenase deficiency. PMID:1594327
• Biochimica et biophysica acta • 1993 • Co-overexpression of bacterial GroESL chaperonins partly overcomes non-productive folding and tetramer assembly of E. coli-expressed human medium-chain acyl-CoA dehydrogenase (MCAD) carrying the prevalent disease-causing K304E mutation. PMID:8104486
• American Journal of Human Genetics • 1993 • A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD). PMID:8102510
• Molecular Genetics and Metabolism • 2004 • Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD) mutation IVS3-1G>C that leads to introduction of a premature termination codon by complete missplicing of the MCAD mRNA and is associated with phenotypic diversity ranging from sudden neonatal death to asymptomatic status. PMID:15171999
• American Journal of Human Genetics • 2001 • Medium-chain acyl-CoA dehydrogenase deficiency: outlines from newborn screening, in silico predictions, and molecular studies. PMID:11349232

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