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 shuttled across the barrier of the inner mitochondrial membrane by the
carnitine 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 uptake of
fatty acids affect these four steps:
CPT II deficiency leads to either exercise-induced
rhabdomyolysis in adults or hepatocardiomuscular symptoms in neonates and children. The three other disorders of the
carnitine cycle have an early onset. Hepatic
CPT I deficiency is characterized by recurrent episodes of
Reye-like syndrome, whereas severe muscular and cardiac signs are associated with episodes of fasting hypoglycaemia in defects of
carnitine transport and translocase. Convenient metabolic investigations for reaching the diagnosis of
carnitine cycle disorders are determination of plasma free and total
carnitine concentrations, determination of plasma
acylcarnitine profile by tandem mass spectrometry and in vitro
fatty acid oxidation studies, particularly in fresh lymphocytes. Application of the tools of molecular biology has greatly aided the understanding of the
carnitine palmitoyltransferase enzyme system and confirmed the existence of different related
genetic diseases. Mutation analysis of
CPT II defects has given some clues for correlation of genotype and phenotype. The first molecular analyses of hepatic
CPT I and translocase deficiencies were recently reported.