Carnitine Transport Defect Primary Generalized Carnitine Deficiency

Carnitine fails to be taken up in muscle, heart, and kidney but not liver, leading to insufficient carnitine to support fatty acid oxidation. ^ Ihe kidney fails to conserve carnitine by reabsorption, resulting in very low plasma carnitine levels, which then causes decreased passive diffusion into liver, impairing ketogenesis. Accumulating acyl-CoA compounds become substrates for peroxisomal beta- oxidation, which produces medium-chain fatty acids and dicarboxylic acids, which do not require carnitine for mitochondrial entry. They are then completely oxidized in mitochondria, which is the reason for lack of dicarboxylicaciduria in disorders of the high-affinity carnitine transporter. Treatment with L-carnitine restores plasma levels to normal (40 to 60 pM) but not skeletal muscle. Muscle function can be restored, however, with less than 10 percent normal muscle carnitine levels. This is a rare disorder, and the exact incidence is unknown. Ihere are two major types of presentation, an early one (3 months to 2% years) with nonketotic hypoglycemia, and a later one (1 to 7 years) with cardiomyopathy. Ihe nonketotic hypoglycemia in the early presentation is accompanied by hyperammonemia and elevated alanine and aspartate aminotransferase levels, which may present after a short fast, particularly if the patient is being fed a carnitine-free formula. Ihe cardiomyopathy in the later presentation is progressive, with cardiac decompensation and respiratory distress, and is often accompanied by skeletal muscle weakness. Mild to moderate anemia, nonresponsive to iron, may be present. Very low plasma carnitine levels (<10 pM) and absent dicarboxylicaciduria are practically pathognomonic of a carnitine transporter defect. Ihe differential diagnosis includes carnitine deficiencies secondary to other disorders of the carnitine cycle, in which medium and long-chain acylcarnitines that accumulate from the metabolic block may induce a defect in tissue uptake of free carnitine. In this primary disorder the diagnosis is established by measuring carnitine uptake by fibroblasts and leukocytes (<10 percent of control rates). In the nonketotic hypoglycemia presentation, management involves the intravenous use of glucose and the long-term oral administration of L-carnitine at 100 to 120 mg/kg/day in two to three divided doses. Oral L-carnitine doses can be higher in the cardiomyopathy presentation, up to 175 mg/kg/day.

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