Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing

Abstract

Background: Malignant hyperthermia (MH) is a disorder of calcium homeostasis in skeletal muscle triggered by volatile anesthetics or succinylcholine in susceptible persons. More than 100 mutations in the ryanodine receptor type 1 gene (RYR1) have been associated with MH susceptibility, central core disease, or both. RYR1 mutations may account for up to 70% of MH-susceptible cases. The authors aimed to determine the frequency and distribution of RYR1 mutations in the Japanese MH-susceptible population.

Methods: The authors selected 58 unrelated Japanese diagnosed as MH-susceptible for having an enhanced Ca-induced Ca release rate from the sarcoplasmic reticulum on chemically skinned muscle fibers. They sequenced the entire RYR1 coding region from genomic DNA. Muscle pathology was also characterized.

Results: Seven previously reported and 26 unknown RYR1 potentially pathogenic sequence variations were identified in 33 patients (56.9%). Of these patients, 48% had cores on muscle biopsy. The mutation detection rate was higher in patients with clear enhancement of Ca-induced Ca release rate (72.4%), whereas all patients with central core disease had RYR1 mutations. Six patients harbored potentially causative compound heterozygous sequence variations.

Conclusions: Distribution and frequency of RYR1 mutations differed markedly from those of the North American and European MH-susceptible population. Comprehensive screening of the RYR1 gene is recommended for molecular investigations in MH-susceptible individuals, because many mutations are located outside the "hot spots." Based on the observed occurrence of compound heterozygous state, the prevalence of a possibly predisposing phenotype in the Japanese population might be as high as 1 in 2,000 people.