Fourteen-year follow up of a girl with primary systemic carnitine deficiency due to a carnitine transporter defect and OCTN2 mutation

Primary systemic carnitine deficiency is an inborn error of fatty acid oxidation attributable to a defect in the cellular uptake of carnitine. This disorder is autosomal recessive in inheritance, and is due to a defect in the plasmalemmal high-affinity carnitine transporter expressed in heart, kidney, muscle, fibroblasts and lymphoblasts. Plasma and tissue concentrations of carnitine are low, urinary excretion of carnitine is high and dicarboxylic aciduria is absent. Patients most commonly present with cardiomyopathy with or without weakness, recurrent hypoglycaemic hypoketotic encephalopathy and failure to thrive. A rapid and dramatic improvement follows the institution of oral carnitine supplementation. Studies of carnitine uptake in fibroblasts have demonstrated a defect in the specific, high-affinity, low-concentration, carrier-mediated uptake mechanism. Molecular analysis of the 10 exons of the OCTN2 gene, encoding the high-affinity carnitine transporter, have demonstrated diverse mutations. We report a patient with primary systemic carnitine deficiency, who was diagnosed at 4.5 years of age and who has been monitored for 14 years. The diagnosis was confirmed by carnitine uptake studies in cultured skin fibroblasts in our proband and her parents. The molecular analysis of this patient revealed a single nucleotide deletion of g.7081C in exon 5 of the OCTN2 gene resulting in a frame shift at Arg282Asp and leading to a predicted truncated protein of 294 amino acids, which was homozygous. Treatment with L-carnitine improved her cardiac function, strength and somatic growth. Now, at 18.5 years of age this girl is entirely asymptomatic, with excellent academic performance, on continuing high-dose oral carnitine therapy, which maintains her plasma carnitine in the low normal range.