MCAD deficiency

MCAD deficiency is the most common inherited disorder of fatty acid oxidation. Normally, during prolonged fasting, fatty acids are mobilized and undergo β-oxidation in mitochondria to generate acetyl-CoA, ketone bodies, and energy, sparing glucose. MCAD catalyzes the first step in oxidation of medium-chain (C6-C12) fatty acids. Deficiency leads to accumulation of medium-chain acyl-carnitines and dicarboxylic acids, and failure to produce ketones and glucose (via limited hepatic gluconeogenesis substrate and inhibited glycogenolysis regulation) during fasting stress.

Pathophysiology: Autosomal recessive; most common mutation is c.985A>G in ACADM gene on chromosome 1p31. This leads to impaired enzyme folding/function, reducing β-oxidation flux, especially problematic during high energy demand/fasting states when glucose stores are depleted and the body would normally shift to fatty acid oxidation and ketogenesis.

Clinical presentation: Often asymptomatic until a triggering event (viral illness, prolonged fasting, decreased caloric intake) precipitates a metabolic crisis. Presents with vomiting, lethargy, hypoketotic hypoglycemia, hepatomegaly, and can progress to seizures, coma, or sudden death—historically misdiagnosed as SIDS. Episodes typically occur between 3 months and 2 years of age (after the frequent feeding of early infancy transitions to overnight fasting).

Diagnosis: Newborn screening via tandem mass spectrometry detects elevated octanoylcarnitine (C8) and related medium-chain acylcarnitines. Urine organic acids show medium-chain dicarboxylic aciduria (hexanoylglycine, suberylglycine). Confirmatory genetic testing for ACADM mutations.

Management: Avoidance of prolonged fasting, especially during illness; frequent feeding; IV dextrose during illness/metabolic crisis to suppress lipolysis and provide glucose; carnitine supplementation is sometimes used, though efficacy is debated. Emergency letter/protocol for illness management to prevent decompensation. Prognosis excellent with early diagnosis and management; newborn screening has drastically reduced mortality.

Key associations for boards: Think MCAD deficiency when you see hypoketotic hypoglycemia (low glucose AND low ketones—contrast with normal fasting response with elevated ketones), especially after fasting/illness in a young child, or history of unexplained infant death in siblings.