Carnitine deficiency

Carnitine deficiency

This may be primary or secondary (1):

• primary carnitine deficiency (OMIM 212140)
  • also known as carnitine uptake defect, carnitine transporter deficiency or systemic carnitine deficiency, systemic primary carnitine deficiency (CDSP) (2)
  • an autosomal recessive disorder of the carnitine cycle that results in defective fatty acid oxidation
  • incidence is about 1:40000 with an approximate carrier rate of 1% (1)
    • although this frequency has been reported to be higher in the Faroe Islands, an isolated archipelago in the North Atlantic
  • disease is caused by heterogeneous mutations of SLC22A5 which encodes the high-affinity carnitine transporter OCTN2 in the plasma membrane
    • OCTN2 is strongly expressed in:
      • myocardium,
      • skeletal muscle,
      • renal tubules, fibroblasts,
      • intestine and placental tissue
    • over 100 mutations have been reported in the OCTN2 gene with the c.136C > T (p.P46S) mutation being the most frequent mutation identified (2)
    • Na+-coupled active transport of carnitine via OCTN2 is essential for the maintenance of high carnitine concentrations inside cell
    • defects of the OCNT2 transporter protein result in
      • urinary carnitine wasting,
      • low serum carnitine levels,
      • decreased intracellular carnitine accumulation
  • as a consequence, impaired oxidation of long chain fatty acids leads to
    • deficient energy generation as well as reduced ketogenesis, particularly during fasting or stress,
    • accumulation of long-chain fatty acids in the cytoplasm of affected tissues
  • clinical features
    • can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or cardiomyopathy, arrhythmias, or fatigability in adulthood
• secondary carnitine deficiencies
  • may be hereditary or acquired
  • secondary carnitine deficiency can be caused by a number of organic acidemias, defects of fatty acid oxidation and of the carnitine cycle
  • primary carnitine deficiency is the only genetic defect in which carnitine deficiency is the cause, rather than the consequence (1)
  • carnitine deficiency can also be acquired as a result of
    • liver disease,
    • renal disease (Fanconi syndrome, renal tubular acidosis),
    • premature birth,
    • dietary insufficiency (chronic TPN, malabsorption, soybean based infant formula),
    • drug therapy
      • valproate acid
      • pivmecillinam, pivampicillin

Reference:

• Fu L, Huang M, Chen S. Primary carnitine deficiency and cardiomyopathy. Korean Circ J. 2013 Dec;43(12):785-92. doi: 10.4070/kcj.2013.43.12.785.
• Magoulas PL, El-Hattab AW. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012 Sep 18;7:68.