Carnitine deficiency

What would be the consequences of a carnitine deficiency for fatty acid oxidation ... 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

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. 

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. 

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. 

Vaz FM, Scholte HR, Ruiter J, Hus-saarts-Odijk FM, Pereira RR, Schweitzer S et al. Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency. Hum Genet 1999 105 (1/2) 157-161. 

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. 

Carnitine deficiency is a clinically useful term describing a diversity of biochemical disorders affecting fatty acid oxidation. Carnitine deficiency may be tissue-specific or generalized. 

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... 

Glutaric aciduria type II, which is a defect of P-oxida-tion, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although... 

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). 

Cefditoren Cefditoren is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency because use of cefditoren causes renal excretion of carnitine. 

Cefditoren (Spectrac ) [Antibiotic/Cephalosporin-3rd Generation] Uses Acute exacCTbations of chronic bronchitis, pharyngitis, tonsillitis skin Infxns Action 3rd-gen cqjhalosporin -I- ceU wall S5mth Dose Adults Feds >12 y Skin 200 mg PO bid X 10 d Chronic bronchitis, pharyngitis, tonsillitis 400 mg PO bid X 10 d avoid antacids w/in 2 h take w/ meals X in renal impair Caution [B, ] Renal/hqiatic impair Contra C halosporin/PCN allergy, milk protein, or carnitine deficiency Disp Tabs SE HA, N/V/D, cohtis, nephrotox. 

Carnitine deficiency leads to impaired carnitine shuttle activity the resulting decreased LCFA metabolism and accumulation of LCFAs In tissues and wasting of acyl-carnitine in urine can produce cardiomyopathy, skeletal muscle myopathy, encephalopathy, and impaired liver function. 

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. 

Carnitine deficiency may also be secondary to a variety of conditions. 

The answer is D. The most likely diagnosis in this case is CPT-II deficiency, although this is apparently a fairly mild case. The patient s muscle weakness and brown urine (myoglobinuria) are characteristic of this disorder. CPT-I deficiency would most likely manifest as liver dysfunction. A secondary form of carnitine deficiency due to exogenous factors such as malnutrition, infection, or dialysis, is unlikely. MCAD ordinarily manifests within the first 3-5 years of life. The patient s normal stature is inconsistent with Marfan syndrome, which is characterized by tall stature and very long bones in the extremities. 

Not recommended for prolonged therapy as carnitine deficiency may result... 

Monitor for carnitine deficiency, as evidenced by confusion, fatigue, hypoglycemia, and muscle damage... 

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]. 

Acylcarnitine profiles are dependent on the clinical status of the patient at the time of sample collection [56, 57]. It is therefore important to provide the biochemical genetics laboratory with information regarding the clinical context during which the sample was collected. The laboratory must be conscientious of the fact that carnitine deficiency states can be associated with acylcarnitine profiles that lack any acylcarnitine species that are elevated above the reference range. Therefore, it is essential that the complete profiles are reviewed and even borderline elevated acylcarnitines should prompt further follow up in the presence of abnormally low free acetylcar-nitine (Fig. 3.2.2). If clinically indicated, a repeat sample should be collected at least 24 h after L-carnitine supplementation. 

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