Carnitine Deficiency

Carnitine is a naturally occurring hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and derived from meat and dairy products in the diet. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation. Carnitine binds acyl residues and helps in their elimination, decreasing the number of acyl residues conjugated with coenzyme A (CoA) and increasing the ratio between free and acylated CoA.

Carnitine deficiency is a metabolic state in which carnitine concentrations in plasma and tissues are less than the levels required for normal function of the organism. Biologic effects of low carnitine levels may not be clinically significant until they reach less than 10-20% of normal. Carnitine deficiency may be primary or secondary.Primary carnitine deficiency is caused by a deficiency in the plasma membrane carnitine transporter, with urinary carnitine wasting causing systemic carnitine depletion. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for beta-oxidation and energy production, and the production of ketone bodies (which are used by the brain) also is impaired.

Regulation of the intramitochondrial free CoA also is affected, with accumulation of acyl-CoA esters in the mitochondria. This, in turn, affects the pathways of intermediary metabolism that require CoA (eg, Krebs cycle, pyruvate oxidation, amino acid metabolism, mitochondrial and peroxisomal beta oxidation).

The 3 areas of involvement include (1) the cardiac muscle, which is affected by progressive cardiomyopathy (by far, the most common form of presentation), (2) the central nervous system, which is affected by encephalopathy caused by hypoketotic hypoglycemia, and (3) the skeletal muscle, which is affected by myopathy.

Muscle carnitine deficiency (restricted to muscle) is characterized by depletion of carnitine levels in muscle with normal serum concentrations. Evidence indicates that the causal factor is a defect in the muscle carnitine transporter.

In secondary carnitine deficiency, which is caused by other metabolic disorders (eg, fatty acid oxidation disorders, organic acidemias), carnitine depletion may be secondary to the formation of acylcarnitine adducts and the inhibition of carnitine transport in renal cells by acylcarnitines.

In disorders of fatty acid oxidation, excessive lipid accumulation occurs in muscle, heart, and liver, with cardiac and skeletal myopathy and hepatomegaly. Long-chain acylcarnitines also are toxic and may have an arrhythmogenic effect, causing sudden cardiac death.

Encephalopathy may be caused by the decreased availability of ketone bodies associated with hypoglycemia. Preterm newborns also may be at risk for developing carnitine deficiency because immature renal tubular function combined with impaired carnitine biosynthesis renders them strictly dependent on exogenous supplies to maintain normal plasma carnitine levels.

Valproic acid may cause an acquired type of secondary carnitine deficiency by directly impairing renal tubular reabsorption of carnitine. The effect on carnitine uptake and the existence of an underlying inborn error involving energy metabolism may be fatal; in other cases, it may primarily affect the muscle, causing weakness.