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A disorder that results from decreased carnitine concentrations in plasma and tissues preventing mitochondria from adequate beta oxidation. Primary and secondary defects have been described. The manifestations are cardiomyopathy, encephalopathy, and myopathy.

Systemic Carnitine Deficiency; Primary Carnitine Deficiency.

For primary defects, the incidence is as high as 1 in 40,000 live births (Japan). The incidence for secondary causes is unknown.

Autosomal recessive. Evidence exists that primary carnitine deficiency is caused by mutations in the SLC22A5 (solute carrier family 22 [organic cation transporter] member 5) gene, which has been mapped to 5q33.1. SLC22A5 is also called OCTN2 (organic cation/carnitine transporter 2) gene. Heterozygotes for primary carnitine deficiency have a higher risk of late-onset cardiac hypertrophy than normal individuals.

Carnitine is derived from diet, but is also endogenously synthesized from lysine in the liver and kidneys. It is taken up from the plasma into peripheral tissues by a high-affinity, sodium-dependent carnitine cotransporter. Primary carnitine deficiency results from a decreased function of this cotransporter, leading to low intracellular and high urine carnitine levels. Biologic effects of carnitine deficiency do not occur unless the carnitine levels are at least below 20% of the norm. Carnitine is required for intracellular esterification of long-chain fatty acids, and its absence inhibits their entry into mitochondria. Beta oxidation of long-chain fatty acids and ketone bodies and energy production are consequently impaired. Carnitine further plays a role in increasing the ratio between free and acylated coenzyme A (acyl-CoA) by binding and assisting in the elimination of acyl residues. The resulting intramitochondrial accumulation of acyl-CoA esters in carnitine deficiency affects the pathways of the intermediary metabolism (e.g., Krebs cycle, pyruvate oxidation), which all require CoA. Low muscle carnitine levels in the presence of normal serum levels characterize myopathic carnitine deficiency, which is limited to the muscle only. It seems to result from a defect in the muscle carnitine transporter. Secondary carnitine deficiency may be seen in organic acidemia, disorders of fatty acid oxidation (e.g., medium-chain acyl-CoA dehydrogenase deficiency), in preterm infants, especially those receiving total parenteral nutrition without carnitine supplementation, Fanconi renal tubulopathy, and in patients taking valproic acid (decreased renal tubular reabsorption of carnitine) or zidovudine.

Both primary and secondary carnitine deficiency may present as sudden death. Older children frequently present with symptoms of heart failure as a result of progressive cardiomyopathy that typically does not respond to diuretic therapy or inotropic agents. Symptoms may progress rapidly. Younger children may present with hypoglycemic and hypoketotic encephalopathy, which may be triggered by fasting or intercurrent illness. A skin biopsy can be used to confirm reduced carnitine transport in fibroblasts that express the transporter, which is diagnostic of primary deficiency. Muscle biopsy may be required for diagnosis of secondary disorders.

Most commonly the disorder affects the heart (progressive cardiomyopathy with cardiomegaly), but it also affects the central nervous system (encephalopathy with lethargy, somnolence, coma, ...

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