What causes secondary carnitine deficiency?

Updated: Dec 13, 2019
  • Author: Fernando Scaglia, MD, FACMG; Chief Editor: Maria Descartes, MD  more...
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Secondary carnitine deficiency, which manifests with a decrease of carnitine levels in plasma or tissues, may be associated with genetically determined metabolic conditions, acquired medical conditions, or iatrogenic states.

Disorders of the carnitine cycle or disorders of fatty acid beta-oxidation can cause secondary carnitine deficiency via several mechanisms. Block in fatty acid oxidation contributes to the accumulation of acyl-CoA intermediates. Transesterification with carnitine leads to the formation of acylcarnitine and the release of free CoA. These acylcarnitines are excreted readily in the urine. They inhibit carnitine uptake at the level of the carnitine transporter in renal cells, causing increased carnitine losses in the urine and systemic secondary depletion of carnitine.

Other genetic conditions that are associated with Fanconi syndrome (eg, Lowe syndrome, cystinosis) may present with secondary carnitine deficiency because of increased renal losses of carnitine. Lysinuric protein intolerance is associated with an increased excretion of lysine in the urine, and the biosynthesis of carnitine needs lysine. Other metabolic disorders (eg, propionic acidemia, methylmalonic acidemia) may also present with secondary carnitine deficiency. Secondary carnitine deficiency may also be observed in respiratory chain defects.

Aminoacidopathies (eg, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, glutaric acidemia type I, 3-hydroxymethylglutaryl-CoA lyase deficiency) also contribute to the accumulation of acyl-CoA intermediates at the site of the metabolic block. This occurs with the formation of acylcarnitine esters, which are transported out of the cell and excreted in the urine. The decreased threshold for carnitine excretion causes low total carnitine levels in plasma and tissue.

Carnitine deficiency has been observed in children with urea cycle defects (eg, ornithine transcarbamylase deficiency, carbamoyl phosphate synthetase deficiency). Whether carnitine deficiency is related to the primary metabolic defect, to the concomitant liver disease observed in the initial presentation, or to benzoate therapy is unclear.

Carnitine deficiency is observed in disorders of the mitochondrial respiratory chain, such as cytochrome c oxidase deficiency, in which the ATP depletion may compromise the energy-dependent carnitine uptake. An interference with carnitine transport occurs in tissues, including renal reabsorption, which explains the low plasma and tissue levels in these patients.

Other inborn errors of metabolism or genetic disorders may cause secondary carnitine deficiency because of impairment of carnitine biosynthesis secondary to increased urinary losses of lysine, which occurs in lysinuric protein intolerance. Increased urinary loss of carnitine associated with Fanconi syndrome may be observed in syndromes such as cystinosis or Lowe syndrome (ie, X-linked oculocerebrorenal syndrome).

Acquired medical conditions may affect carnitine homeostasis. Cirrhosis or chronic renal failure may impair the biosynthesis of carnitine. Diets with low carnitine content (eg, lacto-ovo–vegetarian diet) or malabsorption syndromes may cause secondary carnitine deficiency. It may also be observed in conditions of increased catabolism present in patients with critical illness. Increased losses of carnitine in the urine, which occur in renal tubular acidosis or Fanconi syndrome, may cause secondary carnitine deficiency. Preterm neonates are at risk for developing carnitine deficiency because they have impaired reabsorption of carnitine at the level of the proximal renal tubule and immature carnitine biosynthesis.

In cases of maternal primary carnitine deficiency, few infants were found to have dramatically reduced levels of carnitine in newborn screening. However, these levels rapidly normalized with supplementation. The diagnostic work-up revealed that their mothers had primary carnitine deficiency and were asymptomatic all of their lives, with the mother's disorder being unmasked by low carnitine levels in their infants.

Iatrogenic causes of secondary carnitine deficiency include several drugs associated with secondary carnitine deficiency (eg, valproate, pivampicillin, emetine, zidovudine).

Valproate: Numerous mechanisms have been cited, such as sequestration of CoA by valproic acid and metabolites (causing a secondary disturbance of intermediary metabolism) and direct inhibition of fatty acid oxidation enzymes by valproic acid metabolites. In cultured fibroblasts, valproic acid impairs the plasma membrane carnitine uptake in vitro. This impairment of carnitine uptake may explain serum depletion caused by decreased renal tubular reabsorption of carnitine and muscle depletion caused by decreased muscle uptake.

Zidovudine: Muscle mitochondrial impairment caused by zidovudine in patients with AIDS results in decreased content of muscle carnitine levels caused by decreased carnitine uptake in muscle.

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