Disorders of carnitine transport and the carnitine cycle

Division of Medical Genetics, Department of Pediatrics, University of Utah, 2C412 SOM, 50 North Medical Drive, Salt Lake City, UT, USA.
American Journal of Medical Genetics Part C Seminars in Medical Genetics (Impact Factor: 3.54). 05/2006; 142C(2):77-85. DOI: 10.1002/ajmg.c.30087
Source: PubMed

ABSTRACT Carnitine plays an essential role in the transfer of long-chain fatty acids across the inner mitochondrial membrane. This transfer requires enzymes and transporters that accumulate carnitine within the cell (OCTN2 carnitine transporter), conjugate it with long chain fatty acids (carnitine palmitoyl transferase 1, CPT1), transfer the acylcarnitine across the inner plasma membrane (carnitine-acylcarnitine translocase, CACT), and conjugate the fatty acid back to Coenzyme A for subsequent beta oxidation (carnitine palmitoyl transferase 2, CPT2). Deficiency of the OCTN2 carnitine transporter causes primary carnitine deficiency, characterized by increased losses of carnitine in the urine and decreased carnitine accumulation in tissues. Patients can present with hypoketotic hypoglycemia and hepatic encephalopathy, or with skeletal and cardiac myopathy. This disease responds to carnitine supplementation. Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia. The heart and the muscle, which express a genetically distinct form of CPT1, are usually unaffected. These patients can have elevated levels of plasma carnitine. CACT deficiency presents in most cases in the neonatal period with hypoglycemia, hyperammonemia, and cardiomyopathy with arrhythmia leading to cardiac arrest. Plasma carnitine levels are extremely low. Deficiency of CPT2 present more frequently in adults with rhabdomyolysis triggered by prolonged exercise. More severe variants of CPT2 deficiency present in the neonatal period similarly to CACT deficiency associated or not with multiple congenital anomalies. Treatment for deficiency of CPT1, CPT2, and CACT consists in a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from carnitine, carnitine supplements, and avoidance of fasting and sustained exercise.

  • Source
    • "The dysfunction leads to high renal loss of carnitine and lower concentrations of carnitine in blood and tissues. Thus, lower concentrations of carnitine will be available for the transfer of long chain fatty acids [2] [3]. SPCD has many variations in its presentation, from asymptomatic over metabolic crises at young age (sudden infant death syndrome, episodes of hypoglycemia, and Reye-like syndrome) to progressive cardiomyopathy [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations.
    01/2015; 2015:1-4. DOI:10.1155/2015/101468
  • Source
    • "Analysis of data from the screening programme revealed that the prevalence of PCD in the Faroe Islands, a small island community in the North Atlantic Ocean with a population of approximately 50,000 inhabitants, was by far the highest reported in the world (1:300) [2] [3] [4]. PCD is an autosomal recessive disorder of fatty acid β-oxidation caused by a lack of functional organic cation transporter 2 (OCTN2) transporters, which transport carnitine from the extracellular to the intracellular space and also prevent excretion of carnitine in urine [3] [5]. Carnitine is involved in the transfer of long chain fatty acids across the inner mitochondrial membrane for β-oxidation and also participates in several other important cellular processes [6] [7] [8]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The prevalence of primary carnitine deficiency (PCD) in the Faroe Islands is the highest reported in the world (1:300). Serious symptoms related to PCD, e.g. sudden death, have previously only been associated to the c.95A > G/c.95A > G genotype in the Faroe Islands. We report and characterize novel mutations associated with PCD in the Faroese population and report and compare free carnitine levels and OCTN2 transport activities measured in fibroblasts from PCD patients with different genotypes. Methods Genetic analyses were used to identify novel mutations, and carnitine uptake analyses in cultured skin fibroblasts from selected patients were used to examine residual OCTN2 transporter activities of the various genotypes. Results Four different mutations, including the unpublished c.131C > T (p.A44V), the novel splice mutation c.825-52G > A and a novel risk-haplotype (RH) were identified in the Faroese population. The two most prevalent genotypes were c.95A > G/RH (1:600) and c.95A > G/c.95A > G (1:1300). Patients homozygous for the c.95A > G mutation had both the significantly (p < 0.01) lowest mean free carnitine level at 2.03 (SD 0.66) μmol/L and lowest residual OCTN2 transporter activity (4% of normal). There was a significant positive correlation between free carnitine levels and residual OCTN2 transporter activities in PCD patients (R2 = 0.430, p < 0.01). Conclusion There was a significant positive correlation between carnitine levels and OCTN2 transporter activities. The c.95A > G/c.95A > G genotype had the significantly lowest mean free carnitine level and residual OCTN2 transporter activity.
    12/2014; 1:241–248. DOI:10.1016/j.ymgmr.2014.04.008
  • Source
    • "Besides, L-carnitine is essential for energy generation provided by the transportation of long-chain fatty acids into the mitochondria for beta-oxidation (Bieber, 1988). This mechanism is essential in binding/removing abnormal organic acids in several organic acidemias and explains the secondary carnitine deficiency that can result from them (Longo et al., 2006). The mitochondrial oxidation of fatty acids is also the main primary fuel source in some tissues, what indicates the relative importance of this nutrient for the proper functioning of them (Kelly, 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Doxorubicin, an anticancer drug, is widely included in chemotherapy protocols to combat childhood cancer. Carnitine, an important quaternary amine, is present in testis and epididymis and is involved in sperm maturation; it has been used in infertility treatment. In a previous study, our group observed that l-carnitine given before etoposide, another chemotherapeutic drug, reduces the spermatogenic damage and protects germ cells against apoptosis. This study aimed to evaluate the antiapoptotic and cytoprotective actions of l-carnitine in long- and mid-term basis, on the seminiferous epithelium of doxorubicin-treated pre-pubertal rats. Forty-eight 30-day-old male Wistar rats were distributed into four groups: sham-control; doxorubicin; carnitine; carnitine/doxorubicin (l-carnitine injected 1 h before doxorubicin). The rats were submitted to euthanasia at 64 and 100 days of age and their testes were collected for biometric, morphometric, and histopathological analyses. The numerical density of apoptotic germ cells was obtained (TUNEL method). In adult phase (100 days), the following spermatic parameters were analyzed: mature spermatid (19 step) count and sperm daily production per testis; sperm number and transit time through the epididymal caput/corpus and cauda; frequency of morphologically abnormal spermatozoa (from epididymal fluid), as well as sperm DNA integrity (Comet assay). The testicular and spermatic parameters at both ages were improved in rats treated with carnitine before doxorubicin. At 64 days, the TUNEL-positive germ cell frequency was lower in the carnitine/doxorubicin-treated rats comparatively to the doxorubicin-treated rats. At 100 days of age, the sperm DNA fragmentation was also lower in the previously carnitine-treated rats, as evidenced by the analysis of three parameters. Carnitine reduced the late testicular and spermatic damages caused by doxorubicin, probably providing a partial cytoprotection against the deleterious action of doxorubicin administration to pre-pubertal rats. However, further studies shall be undertaken to investigate the protective mechanisms involved in such germ cell preservation.
    Andrology 09/2014; 2(6). DOI:10.1111/andr.279 · 3.37 Impact Factor
Show more


Available from