Carnitine Deficiency Disorders in Children
- 1 November 2004
- journal article
- review article
- Published by Wiley in Annals of the New York Academy of Sciences
- Vol. 1033 (1), 42-51
- https://doi.org/10.1196/annals.1320.004
Abstract
Mitochondrial oxidation of long-chain fatty acids provides an important source of energy for the heart as well as for skeletal muscle during prolonged aerobic work and for hepatic ketogenesis during long-term fasting. The carnitine shuttle is responsible for transferring long-chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of beta-oxidation. The shuttle consists of three enzymes (carnitine palmitoyltransferase 1, carnitine acylcarnitine translocase, carnitine palmitoyl-transferase 2) and a small, soluble molecule, carnitine, to transport fatty acids as their long-chain fatty acylcarnitine esters. Carnitine is provided in the diet (animal protein) and also synthesized at low rates from trimethyl-lysine residues generated during protein catabolism. Carnitine turnover rates (300-500 micromol/day) are <1% of body stores; 98% of carnitine stores are intracellular (total carnitine levels are 40-50 microM in plasma vs. 2-3 mM in tissue). Carnitine is removed by urinary excretion after reabsorption of 98% of the filtered load; the renal carnitine threshold determines plasma concentrations and total body carnitine stores. Because of its key role in fatty acid oxidation, there has long been interest in the possibility that carnitine might be of benefit in genetic or acquired disorders of energy production to improve fatty acid oxidation, to remove accumulated toxic fatty acyl-CoA metabolites, or to restore the balance between free and acyl-CoA. Two disorders have been described in children where the supply of carnitine becomes limiting for fatty acid oxidation: (1) A recessive defect of the muscle/kidney sodium-dependent, plasma membrane carnitine symporter, which presents in infancy with cardiomyopathy or hypoketotic hypoglycemia; treatment with oral carnitine is required for survival. (2) Chronic administration of pivalate-conjugated antibiotics in which excretion of pivaloyl-carnitine can lead to carnitine depletion; tissue levels may become low enough to limit fatty acid oxidation, although no cases of illness due to carnitine deficiency have been described. There is speculation that carnitine supplements might be beneficial in other settings (such as genetic acyl-CoA oxidation defects--"secondary carnitine deficiency", chronic ischemia, hyperalimentation, nutritional carnitine deficiency), but efficacy has not been documented. The formation of abnormal acylcarnitines has been helpful in expanded newborn screening programs using tandem mass-spectrometry of blood spot acylcarnitine profiles to detect genetic fatty acid oxidation defects in neonates. Carnitine-deficient diets (vegetarian) do not have much effect on carnitine pools in adults. A modest 50% reduction in carnitine levels is associated with hyperalimentation in newborn infants, but is of doubtful significance. The above considerations indicate that carnitine does not become rate-limiting unless extremely low; testing the benefits of nutritional supplements may require invasive endurance studies of fasting ketogenesis or muscle and cardiovascular work.Keywords
This publication has 9 references indexed in Scilit:
- Carnitine membrane transporter deficiency: a long-term follow up and OCTN2 mutation in the first documented case of primary carnitine deficiencyMolecular Genetics and Metabolism, 2002
- Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: Lack of genotype-phenotype correlationHuman Mutation, 2000
- Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiencyProceedings of the National Academy of Sciences of the United States of America, 1999
- The Role of Carnitine Supplementation in Valproic Acid TherapyPEDIATRICS, 1994
- Renal Handling of Carnitine in Secondary Carnitine Deficiency DisordersPediatric Research, 1993
- Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptakeAnnals of Neurology, 1991
- CARNITINE DEFICIENCY INDUCED BY PIVAMPICILLIN AND PIVMECILLINAM THERAPYThe Lancet, 1989
- Primary Carnitine Deficiency Due to a Failure of Carnitine Transport in Kidney, Muscle, and FibroblastsThe New England Journal of Medicine, 1988
- L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia.JCI Insight, 1984