Defects in activation and transport of fatty acids

The oxidation of long-chain fatty acids in mitochondria plays an important role in energy production, especially in skeletal muscle, heart and liver. Long-chain fatty acids, activated to their CoA esters in the cytosol, are s huttled across the barrier of the inner mitochondrial membrane by the carni tine cycle. This pathway includes four steps, mediated by a plasma membrane carnitine transporter, two carnitine palmitoyltransferases (CPT I and CPT II) and a carnitine-acylcarnitine translocase. Defects in activation and up take of fatty acids affect these four steps: CPT II deficiency leads to eit her exercise-induced rhabdomyolysis in adults or hepatocardiomuscular sympt oms in neonates and children. The three other disorders of the carnitine cy cle have an early onset. Hepatic CPT I deficiency is characterized by recur rent episodes of Reye-like syndrome, whereas severe muscular and cardiac si gns are associated with episodes of fasting hypoglycaemia in defects of car nitine transport and translocase. Convenient metabolic investigations for r eaching the diagnosis of carnitine cycle disorders are determination of pla sma free and total carnitine concentrations, determination of plasma acylca rnitine profile by tandem mass spectrometry and in vitro fatty acid oxidati on studies, particularly in fresh lymphocytes. Application of the tools of molecular biology has greatly aided the understanding of the carnitine palm itoyltransferase enzyme system and confirmed the existence of different rel ated genetic diseases. Mutation analysis of CPT II defects has given some c lues for correlation of genotype and phenotype. The first molecular analyse s of hepatic CPT I and translocase deficiencies were recently reported.