Malignant Hyperthermia in Japan

Author:

Ibarra M Carlos A.1,Wu Shiwen1,Murayama Kumiko2,Minami Narihiro3,Ichihara Yasuko4,Kikuchi Hirosato5,Noguchi Satoru6,Hayashi Yukiko K.6,Ochiai Ryoichi7,Nishino Ichizo8

Affiliation:

1. Research Fellow.

2. Research Assistant.

3. Chief of Molecular and Genetic Diagnosis Section, Department of Laboratory Medicine; National Center of Neurology and Psychiatry, Tokyo, Japan.

4. Coordinator of the Japanese Malignant Hyperthermia Association, Department of Anesthesiology, Tokyo Rinkai Hospital, Tokyo, Japan.

5. Professor and Chairman, Department of Anesthesiology, Saitama Medical School, Saitama, Japan.

6. Section Chief.

7. Professor and Chairman, First Department of Anesthesiology, Toho University Graduate School of Medicine, Tokyo, Japan.

8. Director, Department of Neuromuscular Research, National Institute of Neuroscience.

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine

Reference45 articles.

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