Primary carnitine deficiency

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. 

CO Free carnitine Primary carnitine deficiency, CPTl... 

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. 

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. 

Wang Y, Ye J, Ganapathy V, Longo N. Mutations in the organic cation/camitine transporter OCTN2 in primary carnitine deficiency. Proc Natl Acad Sci USA 1999 96(5) 2356-2360. 

Mayatepek E, Nezu J, Tamai I, Oku A, Katsura M, Shimane M et al. Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency. Hum Mutat 2000 15(1) 118. 

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. 

Generalized carnitine deficiency, in its primary form and inherited as an autosomal recessive trait, is due to a defect of the specific high-affinity, low-concentration, carrier-mediated carnitine-uptake mechanism. The defect has been documented in cultured fibroblasts and muscle cultures, but the same uptake system is probably shared by heart and kidney, thus explaining the cardiomyopathy and the excessive leakage of carnitine into the urine. Oral L-carnitine supplementation results in dramatic improvement in cardiac function [4,8]. 

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). 

Myopathic carnitine acyltransferase (CAT/CPT) deficiency, primary etiology myopathic... 

There are two recognized types of carnitine deficiency—primary and secondary. 

Primary carnitine deficiency arises from inherited deficiency ofCPT-i or CPT-ii, both of which are rare disorders showing autosomal recessive inheritance. 

In 1955, Fritz determined that carnitine plays an essential role in fatty acid -oxidation (FAO), and in 1973 the first two clinically relevant disorders affecting this pathway were described primary carnitine deficiency by Engel and Angelini, and carnitine palmitoyltransferase (CPT) type II (CPT-II) deficiency by DiMauro and DiMauro [6, 7]. To date, more than 20 different enzyme deficiency states affecting fatty acid transport and mitochondrial / -oxidaLion have been described [8] and additional enzymes involved in this pathway are still being discovered [9, 10]. 

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. 

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. 

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