Carnitine palmitoyltransferase II deficiency

Carnitine palmitoyltransferase II deficiency

Classification and external resources
Specialty endocrinology
ICD-10 E71.3
ICD-9-CM 277.85
OMIM 255110
DiseasesDB 32534
eMedicine ped/321

Carnitine palmitoyltransferase II deficiency (CPT-II) is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source.

The adult myopathic form of this disease was first characterized in 1973 by DiMauro and DiMauro.[1] It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults.[2] CPT II deficiency is also the most frequent cause of hereditary myoglobinuria.[3] Symptoms of this disease are commonly provoked by prolonged exercise or periods without food.

Signs and symptoms

There are three main types of carnitine palmitoyltransferase II deficiency classified on the basis of tissue-specific symptomotology and age of onset:[4]

It should be noted that among the few people diagnosed with CPT2, some have unknown and/or novel mutations that place them outside these three categories while remaining positive for CPT2.

Adult form

This exclusively myopathic form is the most prevalent and least severe phenotypic presentation of this disorder.[4] Characteristic signs and symptoms include rhabdomyolysis (breakdown of muscle fibers and subsequent release of myoglobin),[5] myoglobinuria, recurrent muscle pain, and weakness. It is important to note that muscle weakness and pain typically resolves within hours to days, and patients appear clinically normal in the intervening periods between attacks.[4] Symptoms are most often exercise-induced, but fasting, a high-fat diet, exposure to cold temperature, or infection (especially febrile illness) can also provoke this metabolic myopathy.[4][5] In a minority of cases, disease severity can be exacerbated by three life-threatening complications resulting from persistent rhabdomyolysis: acute kidney failure, respiratory insufficiency, and episodic abnormal heart rhythms. Severe forms may have continual pain from general life activity.[4] The adult form has a variable age of onset. The first appearance of symptoms usually occurs between 6 and 20 years of age but has been documented in patients as young as 8 months as well as in adults over the age of 50. roughly 80% cases reported to date have been male.[4]

Infantile form

Symptomatic presentation usually occurs between 6 and 24 months of age, but the majority of cases have been documented in children less than 1 year of age.[4] The infantile form involves multiple organ systems and is primarily characterized by hypoketotic hypoglycemia (recurring attacks of abnormally low levels of fat breakdown products and blood sugar) that often results in loss of consciousness and seizure activity.[4] Acute liver failure, liver enlargement, and cardiomyopathy are also associated with the infantile presentation of this disorder. Episodes are triggered by febrile illness, infection, or fasting.[5] Some cases of sudden infant death syndrome are attributed to infantile CPT II deficiency at autopsy.[4]

Neonatal form

The neonatal form is the least common clinical presentation of this disorder and is almost invariably fatal in rapid fashion regardless of intervention.[5][6] Symptomatic onset has been documented just hours after birth to within 4 days of life.[4] Affected newborns typically experience respiratory failure, low blood sugar, seizures, liver enlargement, liver failure, and heart enlargement with abnormal heart rhythms leading to cardiac arrest.[6] In most cases, elements of abnormal brain and kidney development are apparent, sometimes even at prenatal ultrasound.[7] Neuronal migration defects have also been documented, to which the CNS pathology of the disorder is often attributed.[6]

Biochemistry

Enzyme structure

CPT II shares structural elements with other members of the carnitine acyltransferase protein family.[8] The crystal structure of rat CPT II was recently elucidated by Hsiao et al.[9] The human homolog of the CPT II enzyme shows 82.2% amino acid sequence homology with the rat protein.[10] Significant structural and functional information about CPT II has thus been derived from the crystallographic studies with the rat protein.

In addition to similarities shared by the acyltransferases, CPT II also contains a distinct insertion of 30 residues in the amino domain that forms a relatively hydrophobic protrusion composed of two alpha helices and a small anti-parallel beta sheet.[9] It has been proposed that this segment mediates the association of CPT II with the inner mitochondrial membrane.[9] Moreover, the insert might also facilitate the shuttling of palmitoylcarnitines directly into the active site of CPT II after translocation across the inner membrane by virtue of its juxtaposition to the active site tunnel of the enzyme.[9]

Catalytic mechanism

CPT II catalyzes the formation of palmitoyl-CoA from palmitoylcarnitine imported into the matrix via the acylcarnitine translocase. The catalytic core of the CPT II enzyme contains three important binding sites that recognize structural aspects of CoA, palmitoyl, and carnitine.[11]

Although kinetic studies are hindered by high substrate inhibition, strong product inhibition, very low Km values for the acyl-CoA substrates, and complex detergent effects with respect to micelle formation,[11] studies have shown that CPT II demonstrates a compulsory-order mechanism in which the enzyme must bind CoA before palmitoylcarnitine, and then the resulting product palmitoyl-CoA is the last substrate to be released from the enzyme. The carnitine binding site is made accessible by the conformational change induced in the enzyme by the binding of CoA.[11] This ordered mechanism is believed to be important so that the enzyme responds appropriately to the acylation state of the mitochondrial pool of CoA despite the fact that the concentrations of both CoA and acyl-CoA found in the matrix well exceed the measured km value of the enzyme (most CPT II will already have bound the CoA).[12]

The histidine residue (at position 372 in CPT II) is fully conserved in all members of the carnitine acyltransferase family and has been localized to the enzyme active site, likely playing a direct role in the catalytic mechanism of the enzyme.[8] A general mechanism for this reaction is believed to involve this histidine acting as a general base. More specifically, this reaction proceeds as a general base-catalyzed nucleophilic attack of the thioester of acetyl-CoA by the hydroxyl group of carnitine.[13]

Biochemical significance of disease-causing mutations

The majority of the genetic abnormalities in CPT II deficient patients affect amino acid residues somewhat removed from the active site of the enzyme. Thus, these mutations are thought to compromise the stability of the protein rather than the catalytic activity of the enzyme.[9] Theories regarding the biochemical significance of the two most common mutations are noted below:

Enzyme activity and disease severity

The clinical significance of the biochemical consequences that result from the genetic abnormalities in patients with CPT II Deficiency is a contested issue. Rufer et al. support the theory that there is an association between level of enzyme activity and clinical presentation.[14] Multiple research groups have transfected COS-1 cells with different CPT II mutations and found varying levels of reduction in enzyme activity compared with controls: Phe352Cys reduced enzyme activity to 70% of wild-type, Ser113Leu reduced enzyme activity to 34% of wild-type, and several severe mutations reduced activity to 5-10% of wild-type.[8]

However, most researchers are reluctant to accept the existence of a causal relationship between enzyme functionality and clinical phenotype.[8] Two groups[2][15] have recently reported a limited correlation (lacking in statistical significance) between the genotypic array and the clinical severity of the phenotype in their patient cohorts. There is a need for further explorations of this topic in order to fully assess the biochemical ramifications of this enzymatic deficiency.

The rate of long-chain fatty acid oxidation in CPT II-deficient patients has been proposed to be a stronger predictor of clinical severity than residual CPT II enzyme activity. For example, one study found that although the level of residual CPT II activity in adult versus infantile onset groups overlapped, a significant decrease in palmitate oxidation was noted in the infantile group when compared to the adult group.[16] This group concluded that both the type and location of CPT2 mutation in combination with at least one secondary genetic factor modulate the long-chain fatty acid flux and, therefore, the severity of the disease.[16]

Pathophysiology

Carnitine is a hydrophilic natural substance acquired mostly through dietary meats and dairy products and is used by cells to transport hydrophobic fatty acids.[6] The "carnitine shuttle"[17] is composed of three enzymes that utilize carnitine to facilitate the import of hydrophobic long-chain fatty acids from the cytosol into the mitochondrial matrix for the production of energy via β-oxidation.[18]

Molecular genetics

Carnitine palmitoyltransferase II deficiency has an autosomal recessive pattern of inheritance.

CPT II deficiency has an autosomal recessive pattern of inheritance.[2] CPT2 is the gene that encodes the CPT II enzyme, and it has been mapped to chromosomal locus 1p32.[3] This gene is composed of 5 exons that encode a protein 658 amino acids in length.[2] To date, sixty disease-causing mutations within the coding sequence of CPT2 have been reported in the literature, of which 41 are thought to result in amino acid substitutions or deletions at critical residues.[8]

Amino acid consequences of some reported mutations

Recent research[16] found that mutations associated with a specific disease phenotype segregated to specific exons. In this study, infantile-onset cases had mutations in exon 4 or 5 of the CPT2 gene, while adult-onset cases had at least one mutation in exon 1 and/or exon 3. This group suggested that Ser113Leu (exon 3) and Pro50His (exon 1) might confer some sort of protective advantage against the development of the severe infantile phenotype in patients predisposed to develop the adult form of the disorder, since these two mutations have never been identified in cases of compound heterozygous infantile cases.[16] In support of this theory, an independent group reported two cases where mutations that have been shown to cause the infantile (Arg151Gln) or neonatal (Arg631Cys) forms when homozygous instead were associated with the milder, adult-onset phenotype when present as compound heterozygous mutations with Ser113Leu as the second mutation.[2]

Diagnosis

Treatment

Standard of care for treatment of CPT II deficiency commonly involves limitations on prolonged strenuous activity and the following dietary stipulations:

See also

External links

This article incorporates public domain text from The U.S. National Library of Medicine

References

  1. ↑ DiMauro S, DiMauro PMM (1973). "Muscle carnitine palmitoyltransferase deficiency and myoglobinuria". Science 182 (4115): 929–931. doi:10.1126/science.182.4115.929. PMID 4745596.
  2. 1 2 3 4 5 6 Corti S, Bordoni A, Ronchi D; et al. (March 2008). "Clinical features and new molecular findings in Carnitine Palmitoyltransferase II (CPT II) deficiency". Journal of the Neurological Sciences 266 (1-2): 97–103. doi:10.1016/j.jns.2007.09.015. PMID 17936304.
  3. 1 2 Gellera C; et al. (1994). "Assignment of the human carnitine palmitoyltransferase II gene (CPT1) to chromosome 1p32". Genomics 24 (1): 195–7. doi:10.1006/geno.1994.1605. PMID 7896283.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Bonnefont JP et al. (2004). Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Molec Aspects Med, 25(5-6): 495-520. doi:10.1016/j.mam.2004.06.004 PMID 15363638
  5. 1 2 3 4 5 6 Sigauke E et al. (2003). Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review. Laboratory Invest, 83(11): 1543-54. doi:10.1097/01.LAB.0000098428.51765.83 PMID 14615409
  6. 1 2 3 4 5 Longo N, Amat , San Filippo C, Pasquali M (2006). "Disorders of Carnitine Transport and the Carnitine Cycle". Am J Med Genet C Semin Med Genet 142 (2): 77–85. doi:10.1002/ajmg.c.30087. PMC 2557099. PMID 16602102.
  7. ↑ Sharma R, Perszyk AA, Marangi D, Monteiro C, Raja S (January 2003). "Lethal neonatal carnitine palmitoyltransferase II deficiency: an unusual presentation of a rare disorder". American Journal of Perinatology 20 (1): 25–32. doi:10.1055/s-2003-37952. PMID 12638078.
  8. 1 2 3 4 5 6 7 8 9 10 Isackson PJ, Bennett MJ, Vladutiu GD (December 2006). "Identification of 16 new disease-causing mutations in the CPT2 gene resulting in carnitine palmitoyltransferase II deficiency". Molecular Genetics and Metabolism 89 (4): 323–31. doi:10.1016/j.ymgme.2006.08.004. PMID 16996287.
  9. 1 2 3 4 5 6 7 8 Hsiao Y, Jogl G, Esser V, Tong L (2006). "Crystal structure of rat carnitine palmitoyltransferase II (CPT-II)". Biochem Biophys Res Commun 346 (3): 974–80. doi:10.1016/j.bbrc.2006.06.006.
  10. ↑ Finocchiaro G; et al. (1991). "cDNA cloning, sequence analysis, and chromosomal localization of the gene for human carnitine palmitoyltransferase". Proc. Natl. Acad. Sci. USA 88 (2): 661–5. doi:10.1073/pnas.88.2.661. PMC 50872. PMID 1988962.
  11. 1 2 3 Nic , Bhaird N; et al. (1993). "Comparison of the active sites of the purified carnitine acyltransferases from peroxisomes and mitochondria by using a reaction-intermediate analogue". Biochem J 294: 645–51. doi:10.1042/bj2940645.
  12. ↑ Ramsay R; et al. (2001). "Molecular enzymology of carnitine transfer and transport". Biochima et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1546: 21–43. doi:10.1016/s0167-4838(01)00147-9.
  13. ↑ Wu D; et al. (2003). "Structure of Human Carnitine Acetyltransferase: Molecular Basis For Fatty Acyl Transfer". J Biol Chem 278 (15): 13159–65. doi:10.1074/jbc.m212356200.
  14. 1 2 Rufer A; et al. (2006). "The Crystal Structure of Carnitine Palmitoyltransferase 2 and Implications for Diabetes Treatment". Structure 14: 713–23. doi:10.1016/j.str.2006.01.008.
  15. ↑ Wieser T; et al. (2003). "Carnitine palmitoyltransferase II deficiency: molecular and biochemical analysis of 32 patients". Neurology 60 (8): 1351–3. doi:10.1212/01.wnl.0000055901.58642.48.
  16. 1 2 3 4 Thuillier L et al. (2003). Correlation between genotype, metabolic data, and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency. Hum Metab, 21: 493-501.
  17. ↑ Nelson DL and Cox MM (2005). "Fatty Acid Catabolism" in Lehninger Principles of Biochemistry, 4th Ed. New York: W.H. Freeman and Company, 631-55.
  18. ↑ Kerner J, Hoppel C (June 2000). "Fatty acid import into mitochondria". Biochim. Biophys. Acta 1486 (1): 1–17. doi:10.1016/s1388-1981(00)00044-5. PMID 10856709.
  19. ↑ Brivet M et al. (1999). Defects in activation and transport of fatty acids. J Inher Metab Dis, 22: 428-441.
  20. ↑ Rettinger A et al. (2002). Tandem Mass Spectrometric Assay for the Determination of Carnitine Palmitoyltransferase II Activity in Muscle Tissue. Analyt Biochem, 302: 246-251.
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