acyl-CoA dehydrogenase

**Reaction:** Acyl-CoA + FAD → trans-Δ2-enoyl-CoA + FADH2. Electrons from FADH2 pass to electron transfer flavoprotein (ETF), then ETF-ubiquinone oxidoreductase, then CoQ in the electron transport chain. This is the first of 4 repeating β-oxidation steps: (1) dehydrogenation by acyl-CoA dehydrogenase (FAD→FADH2), (2) hydration by enoyl-CoA hydratase, (3) oxidation by 3-hydroxyacyl-CoA dehydrogenase (NAD+→NADH), (4) thiolysis by β-ketothiolase, which releases acetyl-CoA and a chain shortened by 2 carbons.

**Isoforms (chain-length specific):** SCAD (short, C4–C6), MCAD (medium, C6–C12), LCAD (long), and VLCAD (very long, C14–C20, on the inner mitochondrial membrane). Very-long-chain fatty acids (>C22) and branched-chain fatty acids undergo initial peroxisomal oxidation. Fatty acids enter mitochondria through the carnitine shuttle (CPT-I, the rate-limiting step, is inhibited by malonyl-CoA).

**MCAD deficiency (the high-yield disease):** - Autosomal recessive. It is the most common fatty acid oxidation disorder. The most common mutation is ACADM K304E. - Presents in infancy or early childhood, often after fasting or during a viral illness with poor oral intake. Features are vomiting, lethargy, seizures, and coma. - Labs: hypoketotic hypoglycemia (the body can't make ketones from fatty acids and relies on glucose), elevated liver enzymes, hyperammonemia, and metabolic acidosis in some cases. Urine shows dicarboxylic acids (from ω-oxidation) and low ketones. Plasma acylcarnitine profile shows elevated C6–C10 (especially C8 octanoylcarnitine). Urine organic acids show hexanoylglycine and suberylglycine. - Management: avoid fasting, give frequent feeds, and give IV dextrose during acute episodes. Newborn screening uses tandem mass spectrometry. Untreated, it can cause sudden infant death or cerebral edema. - Differential for hypoketotic hypoglycemia: other FAO disorders (VLCAD, LCHAD, CPT-I and CPT-II deficiency, primary carnitine deficiency), hyperinsulinism, and exogenous insulin.

**Related associations:** - Primary carnitine deficiency: decreased carnitine uptake causes hypoketotic hypoglycemia and cardiomyopathy. - VLCAD deficiency: cardiomyopathy, hypotonia, and rhabdomyolysis. - Jamaican vomiting sickness: hypoglycin A from unripe ackee fruit inhibits acyl-CoA dehydrogenases, causing hypoglycemia. - Multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia type II): ETF or ETF-QO defect. - Odd-chain fatty acids yield propionyl-CoA, which enters the TCA cycle as succinyl-CoA via propionyl-CoA carboxylase (biotin), methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase (B12). - Riboflavin (B2) is the precursor of FAD, the cofactor for this enzyme. - Do not confuse acyl-CoA dehydrogenase (FAD) with 3-hydroxyacyl-CoA dehydrogenase (NAD+).