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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.
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Systemic Carnitine Deficiency; Primary Carnitine
Deficiency.
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For primary defects, the incidence is as high as 1 in
40,000 live births (Japan). The incidence for secondary causes is unknown.
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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.
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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.
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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.
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Most commonly the disorder affects the heart
(progressive cardiomyopathy with cardiomegaly), but it also affects the
central nervous system (encephalopathy with lethargy, somnolence, coma, ...