Novel mutations associated with carnitine palmitoyltransferase II deficiency.

The most common form of carnitine palmitoyltransferase II (CPT II) deficiency occurs in adults and is characterized by muscle pain, stiffness, and myoglobinuria, triggered by exercise, fasting, or other metabolic stress. This study reports the molecular heterogeneity of CPT2 mutations and their biochemical consequences among a series of 59 individuals who were suspected of having CPT II deficiency based on the decreased CPT activity observed in muscle or leukocytes samples, clinical findings, or referral for mutation analysis from other laboratories. Only 19 subjects were considered to be at particularly high risk of CPT II deficiency based on review of their clinical symptoms and residual CPT activity. The samples were initially screened for 11 mutations with allele-specific oligonucleotides (ASO). Extensive sequence analysis was subsequently performed on 14 samples which either had a CPT2 mutation detected by ASO screening or the residual CPT activity was below that observed in ASO positive samples. Three known (P50H, S113L, and F448L) 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. Two 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 upstream of a previously identified missense mutation, F448L. The 413 delAG mutation was the second most common mutation identified in our study (20% of mutant alleles) and all individuals with the mutation were of Ashkenazi Jewish ancestry suggesting a defined ethnic origin for the mutation. Despite rigorous mutation analysis, six of 13 individuals identified with CPT2 mutations remained as heterozygotes. We propose that heterozygosity for certain CPT2 mutations, S113L and R503C, is sufficient to render individuals at risk of clinical symptoms.