Primary carnitine deficiency.

Carnitine deficiency can be defined as a decrease of intracellular carnitine, leading to an accumulation of acyl-CoA esters and an inhibition of acyl-transport via the mitochondrial inner membrane. This may cause disease by the following processes. A. Inhibition of the mitochondrial oxidation of long-chain fatty acids during fasting causes heart or liver failure. The latter may cause encephalopathy by hypoketonaemia, hypoglycaemia and hyperammonaemia. B. Increased acyl-CoA esters inhibit many enzymes and carriers. Long-chain acyl-CoA affects mitochondrial oxidative phosphorylation at the adenine nucleotide carrier, and also inhibits other mitochondrial enzymes such as glutamate dehydrogenase, carnitine acetyltransferase and NAD(P) transhydrogenase. C. Accumulation of triacylglycerols in organs increases stress susceptibility by an exaggerated response to hormonal stimuli. D. Decreased mitochondrial acetyl-export lowers acetylcholine synthesis in the nervous system. Primary carnitine deficiency can be defined as a genetic defect in the transport or biosynthesis of carnitine. Until now only defects at the level of carnitine transport have been discovered. The most severe form of primary carnitine deficiency is the consequence of a lesion of the carnitine transport protein in the brush border membrane of the renal tubules. This defect causes cardiomyopathy or hepatic encephalopathy usually in combination with skeletal myopathy. In a patient with cardiomyopathy and without myopathy, we found that carnitine transport at the level of the small intestinal epithelial brush border was also inhibited. The patient was cured by carnitine supplementation. Muscle carnitine increased, but remained too low. This suggests that carnitine transport in muscle is also inhibited. Carnitine transport in fibroblasts was normal, which disagrees with literature reports for similar patients.