Disorders of carnitine transport and the carnitine cycle

Abstract

Carnitine plays an essential role in the transfer of long-chain fatty acids across the inner mitochondrial membrane. This transfer requires enzymes and transporters that accumulate carnitine within the cell (OCTN2 carnitine transporter), conjugate it with long chain fatty acids (carnitine palmitoyl transferase 1, CPT1), transfer the acylcarnitine across the inner plasma membrane (carnitine-acylcarnitine translocase, CACT), and conjugate the fatty acid back to Coenzyme A for subsequent beta oxidation (carnitine palmitoyl transferase 2, CPT2). Deficiency of the OCTN2 carnitine transporter causes primary carnitine deficiency, characterized by increased losses of carnitine in the urine and decreased carnitine accumulation in tissues. Patients can present with hypoketotic hypoglycemia and hepatic encephalopathy, or with skeletal and cardiac myopathy. This disease responds to carnitine supplementation. Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia. The heart and the muscle, which express a genetically distinct form of CPT1, are usually unaffected. These patients can have elevated levels of plasma carnitine. CACT deficiency presents in most cases in the neonatal period with hypoglycemia, hyperammonemia, and cardiomyopathy with arrhythmia leading to cardiac arrest. Plasma carnitine levels are extremely low. Deficiency of CPT2 present more frequently in adults with rhabdomyolysis triggered by prolonged exercise. More severe variants of CPT2 deficiency present in the neonatal period similarly to CACT deficiency associated or not with multiple congenital anomalies. Treatment for deficiency of CPT1, CPT2, and CACT consists in a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from carnitine, carnitine supplements, and avoidance of fasting and sustained exercise.

Fig. 1. Fatty acid oxidation during fasting

Fig. 2. The carnitine cycle in fatty acid oxidation

FATP: Fatty Acid Transporter Protein; FA: Fatty Acid; CPT-1: Carnitine Palmitoyl Tansferase-1; CPT-2: Carnitine Palmitoyl Tansferase-2; CACT: Carnitine Acyl Carnitine Translocase. Modified from [Scaglia and Longo, 1999].

Fig. 3. Mutations in the OCTN2 carnitine transporter in primary carnitine deficiency

Fig. 4. Plasma acylcarnitine profiles from a normal control (top) and a patient with CACT deficiency

The acylcarnitine profiles were obtained at time of diagnosis (7 days of age) and after therapy with medium chain triglycerides and carnitine supplements (1 and 5.5 months of age). Note the progressive decline in C16 and C18:1 and the increase in medium-chain acylcarnitines (C6—C10) reflecting treatment with medium-chain triglycerides (from [Iacobazzi et al., 2004b].