Carnitine transporter deficiency

Carnitine (total) P, B u Carnitine transporter deficiency GA-I (12), MCAD, VLCAD, LCHAD... 

Lahjouji, K., G. A. Mitchell, and I. A. Qureshi. Carnitine transport by organic cation transporters and systemic carnitine deficiency. Mol. Genet. Metab. 2001, 73, 287-297. 

Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genet 1999 21(1) 91 94. 

Tang NL, Ganapathy V, Wu X, Hui J, Seth P, Yuen PM et al. Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum Mol Genet 1999 8(4) 655-660. 

The genetically determined defect of membrane carnitine transport is the only known condition that fulfills the criteria for primary carnitine deficiency [4, 9]. This condition, like the other conditions involving the carnitine cycle, is not associated with dicarboxylic aciduria. It is... 

J. Nezu, I. Tamai, A. Oku, R. Ohashi, H. Yabuuchi, N. Hashimoto, H. Nikaido, Y. Sai, A. Koizumi, Y. Shoji, G. Takada, T. Matsuishi, M. Yoshino, H. Kato, T. Ohura, G. Tsujimoto, J. Hayakawa, M. Shimane, and A. Tsuji. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21 91-94 (1999). 

Children with a primary deficiency of the carnitine transporter present with acute episodes of hypoglycaemia leading to loss of consciousness during even a short fast. (See Chapter 9 for a role of carnitine) in the Krebs cycle. 

Cederbaum SD, Koo-McCoy S, Tein I, Hsu BYL, Ganguly A, Vilain E, Dipple K, Cvitanovic-Sojat L, Stanley C. Carnitine membrane transporter deficiency a long-term follow up and OCTN2 mutation in the first documented case of primary carnitine deficiency. Mol Genet Metab 2002 77 195-201. 

Wang Y, Ye J, Ganapathy Y, Longo N. Mutations in the organic cation/ carnitine transporter OCTN2 in primary carnitine deficiency. PNAS 1999 96 2356-2360. 

Carnitine is present in biological systems as both carnitine and acylcarnitines generated in tissues (see next section). Carnitine deficiency may be a primary defect due to a genetic defect in carnitine transport systems or may be secondary to other metabolic derangements. Normal carnitine homeostasis requires reabsorption of carnitine in the renal tubule via a specific transport protein. This same transport protein is responsible for the accumulation of carnitine in heart and skeletal muscle. If this transport system is not functional, then carnitine cannot reach tissues, and primary carnitine... 

Stanley CA.Treem WR, Hale D, et al. A genetic defect in carnitine transport causing primary carnitine deficiency. Prog Clin Biol Res 321 457-464,1990. 

TreemWR, Stanley CA, Finegold DN, et al. Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle and fibroblasts. N Engl J Med 319 1331-1336,1988. 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

Carnitine translocase deficiency and glucose 6-phosphate transporter deficiency. 

A. Carnitine is required for the transport of fatty acids into mitochondria where they undergo 3-oxidation. If carnitine is deficient, fatty acids accumulate. 

Lahjouji. K., Mitchell, G.A., and Qureshi, l.A. (2001) Carnitine transport by organic cation tr ansporters and systemic carnitine deficiency. Molecular Genetics and Metabolism. 73 (4), IXl-lSn. 

Carnitine translocase deficiency and glucose 6-phosphate transporter deficiency. For an explanation, see text. Section 22.5. 

Primary carnitine deficiency results from a defect in the carnitine transporter within the plasma membrane resulting in the inability to reabsorb carnitine and in significant loss of urinary carnitine. As a result, extremely low serum... 

In the heart, fatty acid oxidation defects can cause cardiomyopathy. The cardiomyopathy is usually associated with a degree of hypertrophy. Cardiomyopathy is typical for severe fatty acid oxidation defects of long-chain fatty acids. Cardiomyopathy in those with carnitine transporter defect is typically dilated in nature without hypertrophy. Severe ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes) occur in fatty acid oxidation defects. They are frequent in severe fatty acid oxidation defects of long-chain fatty acids and particularly prominent in camitine-acylcamitine translocase deficiency but can also occur in MCAD deficiency during decompensation. Atrioventricular block can occur but is rare. 

Waber, L.J., Valle, D., Neill, C, DiMauro, S., and Shug, A., Carnitine deficiency presenting as familial cardiomyopathy a treatable defect in carnitine transport. J. Pediatr., 101, 700-705, 1982. 

Hepatic steatosis usually is a result of excessive administration of carbohydrates and/or lipids, but deficiencies of carnitine, choline, and essential fatty acids also may contribute. Hepatic steatosis can be minimized or reversed by avoiding overfeeding, especially from dextrose and lipids.35,38 Carnitine is an important amine that transports long-chain triglycerides into the mitochondria for oxidation, but carnitine deficiency in adults is extremely rare and is mostly a problem in premature infants and patients receiving chronic dialysis. Choline is an essential amine required for synthesis of cell membrane components such as phospholipids. Although a true choline deficiency is rare, preliminary studies of choline supplementation to adult patients PN caused reversal of steatosis. 

Wang, Y., et al. Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency lack of genotype-phenotype correlation. Hum. Mutat. 2000, 16, 401-407. 

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