Disorders of the carnitine cycle and detection by newborn screening

Carnitine is necessary for transport of long-chain fatty acids into mitochondria, to enter the beta-oxidation cycle. Four carnitine cycle defects have been described. The carnitine transporter mediates carnitine transport across the plasma membrane. Symptoms include hypoketotic hypoglycaemia and cardiomyopathy. Some affected subjects are asymptomatic. Newborn screening detects very low levels of free carnitine in some but not all. Carnitine palmitoyltransferase type IA (CPTI) transports long-chain fatty acyl-CoAs across the outer mitochondrial membrane. Affected infants have hypoketotic hypoglycaemia with catabolic stress, but otherwise remain well. Newborn screening tests reveal elevated free carnitine, (elevated C0/C16+C18). Sensitivity is unclear and confirmation needs leukocyte or fibroblast assays. Carnitine-acylcarnitine translocase transfers fatty acylcarnitines across the inner mitochondrial membrane. The most common presentation is sudden death in the first days. Carnitine palmitoyltransferase type II (CPTII) converts long-chain acylcarnitines to long-chain acylCoAs for beta-oxidation. Severe deficiency is lethal. Newborn screening for both disorders reveals elevated palmitoylcarnitine and enzymology or mutation analysis is needed for diagnosis. Late-onset CPTII is the most common disorder, presenting as muscle pain and rhabdomyolysis on severe exercise. All 4 disorders can be detected by newborn screening, with variable sensitivity. Late-onset CPTII probably cannot be detected. Carnitine transporter, CPTI and late-onset CPTII have proven treatment strategies.