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At a glance

A disorder that is caused by decreased carnitine concentrations in plasma and tissues preventing mitochondria from adequate β-oxidation. The disorder can manifest with cardiomyopathy, encephalopathy, and myopathy.

Synonyms

Systemic Carnitine Deficiency; Primary Carnitine Deficiency; Carnitine Uptake Deficiency; Deficiency of Plasma-membrane Carnitine Transporter.

Incidence

For primary defects, the incidence is as high as 1:40,000 live births in Japan, whereas in other parts of the world it is in the range of 1:20,000-120,000. The highest prevalence of 1:300 has recently been reported from the Danish archipelago of the Faroe Islands. The incidence for secondary causes is unknown.

Genetic inheritance

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 chromosome 5q33.1. SLC22A5, also known as OCTN2 (organic cation/carnitine transporter 2) gene, encodes for the high-affinity carnitine transporter OCTN2. Heterozygotes for primary carnitine deficiency have a higher risk of late-onset cardiac hypertrophy than healthy individuals.

Pathophysiology

Carnitine (β-hydroxy-γ-trimethyl-aminobutyric acid) is derived from diet, but is also endogenously synthesized from lysine (in meat and dairy products) 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. The biologic effects of carnitine deficiency do not manifest unless the carnitine levels are at least below 20% of normal. Carnitine is required for intracellular esterification of long-chain fatty acids, and its absence inhibits their entry into the mitochondria across the inner mitochondrial membrane. Carnitine deficiency leads to decreased energy production from β-oxidation of long-chain fatty acids and ketone bodies during fasting or stress. Thus, tissues have to rely on energy production from glucose, but the demands exceed the hepatic capacity for glucose synthesis. 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 (eg, 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 (eg, medium-chain ☞Acyl-CoA dehydrogenase deficiency), in preterm infants, especially those receiving total parenteral nutrition without carnitine supplementation, ☞De Toni-Debré-Fanconi Syndrome, and in patients taking certain medications (eg, valproic acid, cyclosporine, pivampicillin, pivmecillinam, or zidovudine) (see also “Pharmacological implications”).

Diagnosis

Ideally, newborns are diagnosed through the newborn screening ...

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