Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy

Evidence is emerging that primary systemic carnitine deficiency, a potentially lethal but eminently treatable inborn error of fatty acid oxidation, involves a cellular defect in the uptake of carnitine. We present four unrelated children with primary carnitine-responsive cardiomyopathy, weakness (with or without hypoketotic hypoglycemic encephalopathy), low serum and/or tissue carnitine concentrations, and severe renal carnitine leak. Di-carboxylic acids were absent in the urine of three children who were tested, and all four had a rapid and dramatic improvement in cardiac function, strength, and somatic growth after carnitine therapy. We studied carnitine uptake in cultured skin fibroblasts from all four children and seven of the eight healthy nonconsanguinous parents. [³H]L-carnitine uptake was evaluated in vitro under linear time kinetics. Substrate concentrations were varied from 0.1 to 1000 µM. Physiologic uptake was determined at carnitine concentrations between 0.1 and 50 µM. Nonspecific uptake was determined at a concentration of 10 mM. The four patients had negligible uptake throughout the physiologic range, implying a marked deficiency in the specific high-affinity, low-concentration, carrier-mediated uptake mechanism. At a concentration of 5 µmol/L, the mean velocity of uptake in the four patients was 2% of control values. Their parents showed intermediate maximal rates of carnitine uptake ranging from 13 to 44% of control V_max values, but normal Km values, suggesting that the hetero-zygotes had a reduced number of normal functioning carnitine transporters. The observed reduction in V_max values for the parents supports an autosomal recessive inheritance pattern and may be a more sensitive indicator of heterozygosity than serum carnitine concentrations. We conclude that carnitine uptake studies in cultured skin fibroblasts are important for diagnosis, screening of siblings and heterozygote parents, understanding pathogenesis, and investigating the molecular basis of this disease. Given the frequent history of previously unexplained sibling deaths in these familes, early identification of presymptomatic siblings and oral institution of carnitine prophylaxis may decrease immediate and long-term morbidity and mortality.