Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency
- 198 Downloads
Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation, a wider range of CPT II activity (10–60%) but little evidence of genotype-phenotype correlation. Residual CPT II mutant protein from myopathic patients shows thermal instability at 41°C. The common 'polymorphisms' V3681 and M647V are strikingly overrepresented in the myopathic patients, the implication being that they may significantly influence the manifestation of clinical disease and could therefore potentially be considered as a susceptibility variants. Among myopathic individuals, males comprised 88! of patients, suggesting increased susceptibility to clinical disease. A small number of symptomatic patients appear to have significant residual CPT II activity (42–60%) The synergistic interaction of partial deficiencies of CPT II, muscle adenosine monophosphate deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration.
Unable to display preview. Download preview PDF.
- Demaugre F, Bonnefont J-P, Colonna M, Cepanec C, Leroux JP, Saudubray JM (1991) Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symp-toms and sudden death. Physiopathalogical approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest 87: 859–864.PubMedCrossRefGoogle Scholar
- Demaugre F, Bonnefont J-P, Brivet M, et al (1992) Pathophysiological approach to carnitine palmitoyltransferase II deficiencies. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation. New York: Wiley-Liss, 301–308.Google Scholar
- Dimauro S, Papadimitriou A (1986) Carnitine palmitoyltransferase deficiency. In Engel AG, Banker BQ, eds; Myology. New York: McGraw-Hill, 1697–1708.Google Scholar
- Gregersen N, Winter VS, Corydon MJ, et al (1998) Identification of four new mutations in the short chain acyl-CoA dehydrogenase (SCAD) gene in two patients: One of the variant alleles, 511—+T, is present in an unexpectedly high frequency in the general population, as was the case for the 625—A, together conferring susceptibility to ethylmalonic aciduria. Hum Mol Genet 7: 619–627.PubMedCrossRefGoogle Scholar
- Ijlst L, Hendriksen AGJ, Ruiter JPN, Wanders RJA (1999) Molecular basis of CPT II deficiency: identification of 9 novel mutations. J Inherit Metab Dis 22(supplement 1): 113.Google Scholar
- Roe CR, Coates PM (1995) Mitochondrial fatty acid oxidation disorders. In Scriver C, Sly WS, Valle D, eds; The Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York: McGraw-Hill, 1501–1533.Google Scholar
- Taroni F, Verderio E, Garavaglia B, et al (1992a) Biochemical and molecular studies of carnitine palmitoyltransferase II deficiency with hepatocardiomyopathic presentation. In: Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation. New York: Wiley-Liss, 521–531.Google Scholar
- Vladutiu GD, Smail D (1999) Variant alleles in CPT2 gene are associated with increased susceptibility to carnitine palmitoyltransferase II deficiency: Am J Hum Genet 65: A496.Google Scholar
- Weiser T, Deschauer M, Zierz S (1997) Carnitine palmitoyltransferase II deficiency: three novel mutations. Ann Neurol 42: 414.Google Scholar