About this condition
MCADD — Medium-Chain Acyl-CoA Dehydrogenase Deficiency
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited disorder of fatty acid β-oxidation, affecting approximately 1 in 10,000-20,000 newborns in European-ancestry populations. MCADD is caused by autosomal recessive pathogenic variants in ACADM (chromosome 1p31.1), encoding the mitochondrial enzyme that catalyzes the initial step of medium-chain fatty acid β-oxidation. When the body's glucose reserves are depleted during fasting or illness, energy production shifts to fatty acid oxidation — MCADD patients cannot complete this metabolic switch, leading to accumulation of medium-chain acyl-CoAs and hypoketotic hypoglycemia.
Before newborn screening, MCADD presented as a catastrophic metabolic crisis — sudden hypoketotic hypoglycemia, encephalopathy, hepatic failure, and cardiac arrhythmia — typically triggered by an intercurrent illness (gastroenteritis, respiratory infection) in which the infant or child could not maintain oral caloric intake. Approximately 20-25% of undiagnosed MCADD patients died during their first metabolic crisis, and many survivors suffered permanent neurological damage. Newborn screening using tandem mass spectrometry (detecting elevated octanoylcarnitine, C8) has reduced MCADD mortality by over 90%.
The common European ACADM variant p.Lys329Glu (c.985A>G, formerly K304E) accounts for approximately 80% of mutant alleles and produces classic severe MCADD with very low residual enzyme activity. Other ACADM variants — particularly p.Tyr67His and several mild missense variants — produce partial enzyme deficiency with higher residual activity and lower metabolic crisis risk. Genotype-phenotype correlation directly affects management: classic homozygous K329E patients require strict fasting avoidance protocols lifelong, while patients compound heterozygous for a mild allele may tolerate longer fasting intervals and require less restrictive dietary management.
Newborn screening detects both classic severe and mild MCADD — but cannot distinguish between them. The specific ACADM genotype determines whether strict or relaxed fasting avoidance protocols are appropriate, reducing unnecessary anxiety in mild cases.
- Gene locus
- ACADM (1p31.1)
