carnitine palmitoyltransferase II

**Role in the carnitine shuttle:** - Long-chain fatty acids (LCFAs) are activated to acyl-CoA in the cytosol by fatty acyl-CoA synthetase. - CPT I (CPT-1, on the outer mitochondrial membrane) converts acyl-CoA + carnitine to acylcarnitine. This is the rate-limiting step of fatty acid oxidation. Malonyl-CoA, made by acetyl-CoA carboxylase in the fed state, inhibits CPT I. - Carnitine-acylcarnitine translocase (CACT) moves acylcarnitine across the inner membrane in exchange for free carnitine. - CPT II (inner mitochondrial membrane, matrix side) converts acylcarnitine + CoA back to acyl-CoA + carnitine. The acyl-CoA then enters beta-oxidation, which yields acetyl-CoA, NADH, and FADH2. - Short- and medium-chain fatty acids enter mitochondria independently of the carnitine shuttle.

**CPT II deficiency (autosomal recessive; CPT2 gene on chromosome 1p32):** - Impaired LCFA oxidation leads to energy failure in tissues that rely on fatty acids during prolonged exertion or fasting, mainly skeletal muscle. - Long-chain acylcarnitines accumulate. They are toxic to membranes and cause myocyte injury.

**Clinical forms:** 1. **Myopathic (adult, mild; most common):** - Onset is in adolescence or adulthood. - Episodic muscle pain, weakness, and rhabdomyolysis with myoglobinuria (dark urine) and elevated CK. - Triggers: prolonged exercise, fasting, cold, infection, stress, and valproate. - Often more common in males. - Between attacks, findings are normal. 2. **Severe infantile hepatocardiomuscular form:** - Hypoketotic hypoglycemia, liver failure, cardiomyopathy, and arrhythmias. - Often presents in the first year of life. 3. **Lethal neonatal form:** - Associated with renal cystic dysplasia and brain malformations.

**Diagnosis:** - Elevated long-chain acylcarnitines (C16, C18:1) with a high (C16 + C18:1)/C2 ratio on acylcarnitine profile or newborn screen. - Low CPT II activity in fibroblasts or muscle. - Confirm with genetic testing. The common variant is S113L.

**Treatment and management:** - Avoid fasting and prolonged strenuous exercise. - Eat a high-carbohydrate diet with frequent meals. - Consider medium-chain triglyceride (MCT) supplementation, because MCTs bypass the carnitine shuttle. - Treat rhabdomyolysis with aggressive IV hydration to prevent acute kidney injury.

**High-yield comparisons:** - **Carnitine deficiency (primary):** - Defect in the carnitine transporter OCTN2. - Causes hypoketotic hypoglycemia, cardiomyopathy, and weakness. - Responds to carnitine supplementation. - **CPT I deficiency:** - Mainly hepatic. - Causes hypoketotic hypoglycemia, hepatomegaly, and renal tubular acidosis. - Muscle symptoms are absent. - **MCAD deficiency:** - The most common FAO disorder overall. - Causes hypoketotic hypoglycemia with dicarboxylic aciduria after fasting. - Looks like CPT II only superficially. Rhabdomyolysis is less typical. - **McArdle disease (GSD V):** - Muscle glycogen phosphorylase deficiency. - Causes exercise intolerance, cramps, and myoglobinuria. The "second wind" phenomenon is typical. - Lactate fails to rise with ischemic forearm exercise. - Short bursts of intense exercise are the usual trigger. - CPT II deficiency is instead typically triggered by prolonged, lower-intensity exercise or fasting.

**Board pearl:** A young man develops dark urine and muscle pain after a long run or fast. Blood glucose is normal, CK is elevated, and there is no second-wind phenomenon. This points to CPT II deficiency. Biopsy may show lipid accumulation, though it is often normal between episodes.