medium-chain acyl-CoA dehydrogenase

**Function:** MCAD is a flavoprotein (FAD-dependent) in the mitochondrial matrix. It performs the first (dehydrogenation) step of beta-oxidation for medium-chain fatty acids (C6–C12), converting acyl-CoA to trans-2-enoyl-CoA and generating FADH2 (passes electrons to the ETC via ETF). Beta-oxidation yields acetyl-CoA (for ketogenesis in liver, and TCA cycle), NADH, and FADH2. Medium-chain fatty acids enter mitochondria independent of the carnitine shuttle, but long-chain fatty acids require CPT-I/II.

**Genetics:** Autosomal recessive; ACADM gene on chromosome 1p31. Most common mutation is c.985A>G (K304E) in people of Northern European descent. It is the most common inherited disorder of fatty acid oxidation.

**Pathophysiology:** During fasting or increased energy demand (illness, prolonged exercise, vomiting), the body shifts to fatty acid oxidation. With MCAD deficiency, fatty acids can't be fully oxidized, so: - Ketogenesis is impaired → **hypoketotic hypoglycemia** (low ketones for the degree of hypoglycemia). - Gluconeogenesis is impaired (lack of acetyl-CoA activation of pyruvate carboxylase, and less ATP/NADH from beta-oxidation) → hypoglycemia. - Accumulation of medium-chain acyl-CoAs, which are shunted into medium-chain acylcarnitines (C6, C8, C10:1; especially octanoylcarnitine C8), dicarboxylic acids (omega oxidation), and glycine conjugates (hexanoylglycine, suberylglycine). - Hepatic toxicity (hyperammonemia, elevated transaminases, hepatic steatosis/microvesicular fat), and possible Reye-like syndrome. - Secondary carnitine deficiency.

**Clinical presentation:** Typically 3 months to 3 years of age, triggered by prolonged fasting or a viral illness with decreased intake: vomiting, lethargy, seizures, coma, hypoketotic hypoglycemia, hepatomegaly, sudden infant death (SIDS-like presentation). Infants are normal between episodes. Can present in adulthood (rarely) after alcohol or fasting. Hypoglycemia with low or absent urine ketones is the key clue.

**Diagnosis:** - Newborn screening by tandem mass spectrometry: elevated C8 (octanoylcarnitine) with elevated C6 and C10 acylcarnitines (and increased C8/C10 ratio). - Urine organic acids: dicarboxylic aciduria (adipic, suberic, sebacic acids) without ketonuria; urine acylglycines (hexanoylglycine, suberylglycine). - Confirm with ACADM gene sequencing. - Labs during crisis: low glucose, low/absent ketones, elevated ammonia, elevated AST/ALT, elevated uric acid and lactate possible.

**Management:** - Avoid fasting (frequent feeding, especially in infancy; bedtime complex carbohydrate such as cornstarch for older children). - Acute episodes: IV dextrose (D10) to suppress lipolysis and provide energy. - Carnitine supplementation (controversial) may be used for secondary carnitine deficiency. - Avoid medium-chain triglyceride (MCT) oil and high-fat ketogenic diets. - Sick-day protocols; prognosis excellent when diagnosed by newborn screening.

**High-yield comparisons:** - *Primary carnitine deficiency* (OCTN2/SLC22A5): hypoketotic hypoglycemia plus cardiomyopathy and muscle weakness; treated with carnitine. - *Long-chain (LCHAD)/VLCAD deficiency*: more prominent cardiomyopathy, rhabdomyolysis, and (LCHAD) maternal HELLP/AFLP, retinopathy, neuropathy. - *Jamaican vomiting sickness* (hypoglycin A from unripe ackee fruit) inhibits acyl-CoA dehydrogenases → similar picture. - *Ketotic hypoglycemia* (e.g., glycogen storage disease, ketotic hypoglycemia of childhood) would show ketones; MCAD does not. - *Von Gierke*: hypoglycemia with lactic acidosis, hyperuricemia, hepatomegaly, hyperlipidemia.

**Board pearl:** A toddler with vomiting and lethargy after a viral illness/fasting, hypoglycemia, and *no ketones* → think MCAD deficiency; urine shows dicarboxylic acids; treat with glucose.