MCAD

**Pathophysiology:** MCAD catalyzes the first step of beta-oxidation for medium-chain (C6–C12) fatty acids in mitochondria. Deficiency (autosomal recessive; ACADM gene on chromosome 1p31; most common mutation c.985A>G, K304E, in people of Northern European descent) blocks fatty acid oxidation. This causes: (1) impaired acetyl-CoA production, so reduced ketogenesis (hypoketosis); (2) reduced NADH/FADH2 and acetyl-CoA, so impaired gluconeogenesis (acetyl-CoA normally activates pyruvate carboxylase), leading to hypoglycemia; (3) accumulation of medium-chain acyl-CoAs, which are shunted to carnitine esters (octanoylcarnitine, C8) and dicarboxylic acids.

**Clinical presentation:** Typically between 3 months and 3 years of age, triggered by fasting, prolonged intervals between feeds, or illness (gastroenteritis, febrile infection) that raises energy demand. Features include vomiting, lethargy, seizures, coma, hypoketotic hypoglycemia, hepatomegaly/hepatic dysfunction, mild hyperammonemia, and elevated transaminases. It can mimic Reye syndrome and may cause SIDS-like sudden death. Patients are usually well between episodes.

**Diagnosis:** Newborn screening by tandem mass spectrometry shows elevated C8 (octanoylcarnitine, also C6 and C10:1) acylcarnitines. Urine organic acids show dicarboxylic aciduria (adipic, suberic, sebacic acids) and hexanoylglycine/suberylglycine. Urine ketones are low or absent during hypoglycemia. Confirm with ACADM genetic testing. Serum free carnitine is often low (secondary carnitine deficiency).

**Management:** Avoid fasting (frequent feeds, with a bedtime snack and cornstarch in older children). During illness or poor oral intake, give IV dextrose (D10) to stop lipolysis. Carnitine supplementation is sometimes used, though evidence is limited. Avoid prolonged fasting and high-fat intake (MCT oil).

**High-yield associations and comparisons:** - Hypoketotic hypoglycemia is the hallmark of fatty acid oxidation defects. This contrasts with hyperketotic hypoglycemia seen in glycogen storage disorders and ketotic hypoglycemia, and with the high ketones of DKA. - Primary carnitine deficiency (OCTN2 defect) causes hypoketotic hypoglycemia, cardiomyopathy, and skeletal myopathy. - LCHAD/VLCAD deficiency are more likely to cause cardiomyopathy, rhabdomyolysis, and arrhythmias. MCAD generally spares the heart. - Jamaican vomiting sickness (hypoglycin A from unripe ackee fruit) inhibits acyl-CoA dehydrogenases and produces a similar picture. - Medium-chain triglycerides (MCT oil) are contraindicated in MCAD deficiency. - Pearl: The key board stem is an infant or toddler who becomes lethargic or hypoglycemic after a prolonged fast or gastroenteritis, with low ketones and dicarboxylic aciduria. The answer is MCAD deficiency.