CPT-II

**Function / Biochemistry** - Carnitine shuttle: Long-chain fatty acids (LCFAs) are activated to acyl-CoA in the cytosol (acyl-CoA synthetase). CPT-I (carnitine acyltransferase I, outer mitochondrial membrane) converts acyl-CoA + carnitine to acyl-carnitine. This is the RATE-LIMITING step of fatty acid oxidation and is inhibited by malonyl-CoA (made by acetyl-CoA carboxylase in fed state). Acyl-carnitine crosses the inner membrane via CACT (carnitine-acylcarnitine translocase). CPT-II (inner mitochondrial membrane, matrix side) converts acyl-carnitine back to acyl-CoA + free carnitine; acyl-CoA then enters beta-oxidation to produce acetyl-CoA, NADH, FADH2 (and ketone bodies in liver). - Medium- and short-chain fatty acids enter mitochondria independent of the carnitine shuttle.

**Genetics** - CPT2 gene (chromosome 1p32). Autosomal recessive. Common mutation in the myopathic form: S113L.

**Clinical forms** 1. Adult/myopathic form (most common, mild): Recurrent episodes of muscle pain, weakness, rhabdomyolysis with myoglobinuria (dark/tea-colored urine, elevated CK) triggered by prolonged exercise, fasting, cold, infection, or stress. Between episodes, patients are typically normal. More common in males. Hepatic ketogenesis usually preserved, so hypoglycemia is not typical. 2. Severe infantile hepatocardiomuscular form: Hypoketotic hypoglycemia, liver failure, cardiomyopathy, arrhythmias, seizures; often fatal. 3. Lethal neonatal form: Multisystem failure, renal dysgenesis/cystic kidneys, neuronal migration defects.

**Diagnosis** - Elevated long-chain acylcarnitines (C16, C18:1) on plasma acylcarnitine profile/newborn screening (elevated (C16 + C18:1)/C2 ratio); elevated CK during attacks; myoglobinuria. Confirm with enzyme assay (fibroblasts/muscle) or genetic testing. Muscle biopsy may show lipid accumulation but is often normal between episodes.

**Treatment** - Avoid fasting and prolonged strenuous exercise; frequent high-carbohydrate meals; low-fat diet; supplement with medium-chain triglycerides (MCT oil), which bypass the carnitine shuttle. Carnitine supplementation has limited benefit in CPT-II (and can be controversial). Treat rhabdomyolysis with aggressive IV hydration to prevent acute kidney injury.

**High-yield comparisons for boards** - CPT-I deficiency: Hypoketotic hypoglycemia, hepatic dysfunction, elevated free carnitine (acylcarnitines low); renal tubular acidosis may occur. Muscle usually spared. - CPT-II deficiency: Muscle-predominant, rhabdomyolysis, elevated long-chain acylcarnitines. - Primary carnitine deficiency (OCTN2 transporter defect): Hypoketotic hypoglycemia, dilated cardiomyopathy, muscle weakness; low plasma free carnitine; responds to carnitine supplementation. - MCAD deficiency: Most common fatty acid oxidation disorder overall; hypoketotic hypoglycemia after fasting, dicarboxylic aciduria, vomiting, lethargy; elevated C8-C10 acylcarnitines. - McArdle disease (GSD V, myophosphorylase deficiency): Also exercise-induced cramps and myoglobinuria, but with the "second wind" phenomenon, a flat venous lactate response to ischemic forearm test, and subsarcolemmal glycogen accumulation. - Mnemonic: CPT-I = "Intake" to the intermembrane space (rate-limiting, malonyl-CoA inhibited); CPT-II = "Inside" the matrix.

**Pitfalls** - Presents with muscle symptoms after fasting/exercise, differentiating from glycogen storage disease by absence of the second-wind phenomenon and normal lactate rise on ischemic forearm test. - Some medications (e.g., valproate, ibuprofen, diazepam, and statins in susceptible patients) and anesthetics may precipitate attacks in myopathic CPT-II deficiency.