Novel mutations associated with carnitine palmitoyltransferase II deficiency

The most common form of carnitine palmitoyltransferase II (CPT II) deficien cy occurs in adults and is characterized by muscle pain, stiffness, and myo globinuria, triggered by exercise, fasting, or other metabolic stress. This study reports the molecular heterogeneity of CPT2 mutations and their bioc hemical consequences among a series of 59 individuals who were suspected of having CPT II deficiency based on the decreased CPT activity observed in m uscle or leukocytes samples, clinical findings, or referral for mutation an alysis from other laboratories, Only 19 subjects were considered to he at p articularly high risk of CPT II deficiency based on review of their clinica l symptoms and residual CPT activity. The samples were initially screened f or 11 mutations with allele-specific oligonucleotides (ASO). Extensive sequ ence analysis was subsequently performed on 14 samples which either had a C PT2 mutation detected by ASO screening or the residual CPT activity was bel ow that observed in ASO positive samples. Three known (P50H, S113L, and F44 8L) and three novel mutations were identified among 13 individuals in this study, A single nucleotide polymorphism was also identified 11 bp distal to the CPT2 polyadenylation site that will be useful for linkage analysis. Tw o of the new mutations were single nucleotide missense mutations, R503C and G549D, that occurred in highly conserved regions of the CPT isoforms, and the third was a frameshift mutation, 413 delAG, caused by a 2-bp deletion u pstream of a previously identified missense mutation, F448L. The 413 delAG mutation was the second most common mutation identified in our study (20% o f mutant alleles) and all individuals with the mutation were of Ashkenazi J ewish ancestry suggesting a defined ethnic origin for the mutation. Despite rigorous mutation analysis, six of 13 individuals identified with CPT2 mut ations remained as heterozygotes, We propose that heterozygosity for certai n CPT2 mutations, S113L and R503C, is sufficient to render individuals at r isk of clinical symptoms. Hum Mutat 13:210-220, 1999. (C) 1999 Wiley-Liss, Inc.