title: Allelic and phenotypic heterogeneity in 49 Italian patients with the muscle form of CPT-II deficiency.
abstract: As genotype-phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine-palmitoyl-transferase-II (CPT-II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a genetic isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life-threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.
authors.affiliation: Neuromuscular Center, Department of Neurosciences, University of Padova, Padova, Italy. marina.fanin@unipd.it
authors.forename: M
authors.initials: M
authors.lastname: Fanin
authors.forename: A
authors.initials: A
authors.lastname: Anichini
authors.forename: D
authors.initials: D
authors.lastname: Cassandrini
authors.forename: C
authors.initials: C
authors.lastname: Fiorillo
authors.forename: S
authors.initials: S
authors.lastname: Scapolan
authors.forename: C
authors.initials: C
authors.lastname: Minetti
authors.forename: M
authors.initials: M
authors.lastname: Cassanello
authors.forename: M A
authors.initials: MA
authors.lastname: Donati
authors.forename: G
authors.initials: G
authors.lastname: Siciliano
authors.forename: A
authors.initials: A
authors.lastname: D'Amico
authors.forename: F
authors.initials: F
authors.lastname: Lilliu
authors.forename: C
authors.initials: C
authors.lastname: Bruno
authors.forename: C
authors.initials: C
authors.lastname: Angelini
mesh_terms: D000328:Adult; D000483:Alleles; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics; D002675:Child, Preschool; D056726:Genetic Association Studies; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D002334:Carnitine O-Palmitoyltransferase