Defective urinary carnitine transport in heterozygotes for primary carnitine deficiency

Purpose: Primary carnitine deficiency is an autosomal recessive disorder ca used by defective carnitine transport and manifests as nonketotic hypoglyce mia or skeletal or heart myopathy. Methods: To define the mechanisms produc ing partially reduced plasma carnitine levels in the parents of affected pa tients, we examined carnitine transport in vivo and in the fibroblasts of a new patient and his heterozygous parents. Results: Kinetic analysis of car nitine transport in fibroblasts revealed an absence of saturable carnitine transport in the proband's cells and a partially impaired carnitine transpo rt in fibroblasts from both parents, whose cells retained normal K-m values toward carnitine (6-9 mu M) but reduced V-max. At steady state, normal fib roblasts accumulated carnitine to a concentration that was up to 80 times t he extracellular value (0.5 mu M). By contrast, cells from the proband had minimal carnitine accumulation, and cells from both parents had intermediat e values of carnitine accumulation. Plasma carnitine levels were slightly b elow normal in both heterozygous, yet clinically normal, parents and in the paternal grandfather and the maternal grandmother. To define the mechanism producing partially decreased carnitine levels, we studied urinary carniti ne losses in heterozygous parents compared with controls. Urinary losses in creased linearly (P < 0.05) with plasma carnitine levels in normal controls . When urinary carnitine losses were normalized to plasma carnitine levels, a significant difference was observed between controls and heterozygous in dividuals (P < 0.01). Conclusions: These results indicate that fibroblasts from heterozygotes for primary carnitine deficiency have a decreased capaci ty to accumulate carnitine and that heterozygotes have increased urinary lo sses, which may contribute to their reduced plasma carnitine levels.