This article includes discussion of primary carnitine transporter deficiency, carnitine-responsive cardiomyopathy, OCTN2 deficiency, and primary systemic carnitine deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Primary carnitine transporter deficiency is an autosomal recessive inherited disorder caused by a defect of the plasmalemmal high-affinity carnitine transporter, OCTN2, in the SLC22A5 gene. This formerly lethal disease of childhood is characterized by progressive infantile-onset hypertrophic or dilatative cardiomyopathy, weakness, recurrent hypoglycemic hypoketotic encephalopathy, and failure to thrive. These children have very low plasma and tissue concentrations of primary carnitine with microvesicular lipid storage in muscle, heart, and liver and a severe renal leak of primary carnitine, usually with absence of an abnormal dicarboxylic aciduria. Early diagnosis and treatment with high-dose oral primary carnitine supplementation is critical and lifesaving and reverses the end-stage cardiomyopathy, myopathy, and episodes of hypoglycemia. These individuals may be weaned off their anti-failure cardiac medications, but are lifelong dependent on primary carnitine therapy. Early primary carnitine therapy from birth prevents the development of the disease phenotype, and the author and colleagues have shown through mutational studies that this disease is widely geographically distributed. The carrier frequency is 1% in the Japanese population, and carriers may present with cardiomyopathy as adults, making this a potentially significant risk factor for adult heart disease. Surprisingly, 11 asymptomatic affected mothers of affected children have been identified, suggesting that the expression of the disease may be influenced by multifactorial or epigenetic factors.
Historical note and terminology
Carnitine deficiency was first described in 1973 (Engel and Angelini 1973), and patients were subsequently divided into 2 groups. In 1 group were those with "systemic carnitine deficiency", who had recurrent episodes of hypoglycemic, hypoketotic encephalopathy ("Reye-like" syndrome) beginning in infancy or early childhood, and low concentrations of carnitine in their serum, muscle, and liver. In the other group were patients with "myopathic carnitine deficiency," who had progressive lipid storage myopathy beginning in childhood or later in life, and the carnitine deficiency was confined to skeletal muscle (DiMauro 1979; Angelini et al 1987). In the mid-1970s, improved methods of measuring fatty acid oxidation enzymes allowed many previously diagnosed carnitine deficiency cases to be attributed to a variety of intramitochondrial beta-oxidation defects, with an associated secondary carnitine deficiency (Stanley 1987). For example, many patients initially diagnosed as having systemic carnitine deficiency were found to have medium-chain acyl-CoA dehydrogenase deficiency (Coates et al 1984; Hale et al 1985). Also, certain patients formerly diagnosed as having primary myopathic carnitine deficiency have now been diagnosed as having other defects, such as short-chain acyl-CoA dehydrogenase deficiency (Turnbull et al 1984; Trevisan et al 1985).
The first probable case of a primary carnitine transporter defect was described by Chapoy and colleagues in a 3-year-old boy. He initially presented at 3 months of age with hypoketotic hypoglycemic encephalopathy, hepatomegaly, and cardiomegaly, and was later documented to have less than 5% of plasma, muscle, and liver carnitine concentrations (Chapoy et al 1980). This boy responded dramatically to oral carnitine supplementation, as evidenced by increased muscle strength, relief of cardiomyopathy, partial repletion of carnitine concentrations in plasma and muscle, and complete repletion in the liver. The definition of primary carnitine deficiency, as suggested by Stanley, was subsequently based on the following criteria:
(1) The metabolic disorder is caused directly by inadequate carnitine.
Theoretical causes of primary carnitine deficiency put forward by Rebouche and Engel included:
(1) Defective biosynthesis and dietary intake.
No evidence for defective carnitine biosynthesis (Rebouche and Engel 1980a), defective absorption, or excessive degradation (Rebouche and Engel 1984) was found in several patients with "systemic" carnitine deficiency. However, all of these patients were subsequently found to have medium-chain acyl-CoA dehydrogenase deficiency. In mammals, carnitine degradation is not of any quantitative importance and is primarily accomplished by bacteria in the gut (Bremer 1983).
The first evidence for a defect in the cellular uptake of carnitine was offered in 1988. Eriksson and colleagues documented carnitine deficiency in cultured skin fibroblasts from a 4-year-old girl with cardiomyopathy, and also found intermediate carnitine concentrations in the fibroblasts of the asymptomatic mother (Eriksson et al 1988). Carnitine uptake was studied directly by Treem and colleagues in fibroblasts from an infant girl who was suffering from multiple symptoms; she presented as hypoketotic, with hypoglycemic coma, markedly decreased carnitine concentrations in plasma, liver, and muscle, and normal acyl-CoA dehydrogenase activities (Treem et al 1988). Carnitine administration corrected the defect in fasting ketogenesis and restored normal carnitine concentrations in plasma and liver, but not in muscle. Since then, more than 20 cases have been described, where the cellular defect in carnitine uptake has been documented in cultured skin fibroblasts (Garavaglia et al 1991; Stanley et al 1991).
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