Malignant Hyperthermia in Japan

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.

Functional analysis of ryanodine receptor type 1 p.R2508C mutation in exon 47

“…The p.R2508C mutation identifi ed in these cases was located outside the C-terminal near the central region. Of note, a CCD mutation in the non-C-terminal region is reported to predispose a patient to MH [4,5]. Our case 1 had had an episode of MH and case 2 was a member of an MH family, and both cases showed acceleration in the CICR rate test.…”

“…Most of the previously documented mutations in exon 47 have been identifi ed in Japanese and Korean people [3,[4][5][6]; however, no functional analysis of p. R2508C was performed in these reports. This is the fi rst report of the pathogenic analysis of the RYR1 p.R2508C mutation in exon 47.…”

“…It was suggested that p.R2508C is not a common variant. We investigated this mutation from two independent pedigrees, and accelerations of the CICR rate in three independent pedigrees have been reported [4,5]. These results meet EMHG criteria for gene mutations to be used in the genetic testing of susceptibility to malignant hyperthermia [7].…”

“…The CICR rate test was performed In fi ve patients with the p.R2508C mutation, four Japanese patients and one Korean patient, and all showed acceleration of the CICR rate [5]. In a previous genetic study in the Japanese individuals with CICR rate acceleration, the RYR1 mutation detection rate was 56.9% [4].…”

“…A Japanese mutation index was then reported, showing the fi rst documentation of a mutation in exon 47 [4], which is located outside the "hot spot" central region (exons 39-46). Including two cases in the present study, most of the mutations in exon 47 previously reported were found in Asian patients (Table 1) [3,[4][5][6]. However, no functional analysis of p.R2508C in exon 47 has been performed.…”