Mutation spectrum and health status in skeletal muscle channelopathies in Japan
Introduction
Skeletal muscle channelopathies are rare inherited neuromuscular disorders that are associated with mutations in the genes encoding voltage-gated ion channels expressed in skeletal muscle [1]. They are divided into two main categories according to their major clinical symptoms: non-dystrophic myotonia (NDM) and periodic paralysis (PP) [2,3]. NDM includes three types of clinical disorders: myotonia congenita (MC), paramyotonia congenita (PMC), and sodium channel myotonia (SCM). MC is caused by mutations in the skeletal muscle chloride channel (CLCN1) gene, whereas PMC and SCM are caused by mutations in the skeletal muscle sodium channel (SCN4A) gene. PP comprises two types of clinical disorders that are characterized by the serum potassium concentrations during paralytic attacks: hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). HyperPP is caused by the SCN4A mutations, whereas HypoPP is caused by mutations in two different genes; i.e., the SCN4A (HypoPP2) or the skeletal muscle calcium channel (CACNA1S) gene (HypoPP1). In other words, PMC, SCM, HyperPP, and hypoPP2 are allelic disorders caused by mutations in the identical gene, SCN4A.
Many mutations in the SCN4A, CLCN1, and CACNA1S genes have been identified in patients with skeletal muscle channelopathies worldwide, but genetic etiology studies have not been often performed in Asian countries [4,5]. Additionally, several nationwide studies of skeletal muscle channelopathies in Western countries have assessed the quality of life (QOL) using patient-reported outcome (PRO) measures including the Short Form 36 Item Health Survey (SF-36) and Individualized Neuromuscular Quality of Life (INQoL) [6], [7], [8]. These PRO instruments were utilized in a double-blind clinical trial for skeletal muscle channelopathies as secondary endpoints and provided evidence for intervention, the beneficial effects of mexiletine [9].
To date, no systematic study has been carried out in Japan. Several case reports from Japan have suggested that the number of skeletal muscle channelopathies observed in Japan seems to be fewer than observed in Western countries, and the mutations found in Japanese patients are unique. In addition, the QOL of the patients has never been investigated. In our study, we aimed to clarify the frequency and distribution of the associated mutations in the Japanese population. We reviewed the clinical and genetic data that were collected from 1996 to 2016 by two Japanese laboratories. These laboratories have been conducting genetic analysis on skeletal muscle channelopathies at the request of medical institutions from all over Japan. Additionally, to explore the influence of the symptoms on the patient's QOL, we conducted questionnaire surveys using two types of PRO instruments that were validated in the Japanese language; i.e., the SF-36 and INQoL.
Section snippets
Family materials and genetic analysis
We analyzed consecutive pedigrees with a diagnosis of skeletal muscle channelopathies that was genetically confirmed between April 1996 and December 2016. We performed genetic analyses of the Japanese patients who were clinically diagnosed with NDM or PP and who were referred to our laboratories by medical institutions in Japan. In brief, we conducted Sanger DNA sequencing of all exons of the CLCN1 (NM_000083.3) and/or SCN4A (NM_000334.4) genes for patients with NDM and hyperPP, and of “hot
Results
We identified 105 probands with CLCN1, SCN4A, and CACNA1S mutations in unrelated pedigrees, of which 82 (78%) had a positive family history. Sixty-six probands (63%) were diagnosed with NDM (MC and PMC/SCM), whereas 39 probands (37%) were diagnosed with PP (hyperPP, hypoPP1 and hypoPP2; Fig. 1). Within NDM, 30 probands (45%) were diagnosed with MC and 36 probands (55%) were diagnosed with PMC/SCM. One proband with NDM had both CLCN1 and SCN4A mutations. Within PP, 28 PP probands (72%) were
Discussion
Our study included one of the largest cohorts of patients with genetically defined muscle channelopathies in Japan. The frequency and spectrum of genetic alterations observed in patients with NDM and PP in Japan were different from those previously reported in the literature. Of 105 cases in our study, 23 (22%) were sporadic. This showed that sporadic cases of muscle channelopathies are not rare.
MC is the most common skeletal muscle channelopathy [2]. There are both an autosomal dominant
Conclusions
In our cohort, the mutation spectrum in skeletal muscle channelopathies in Japan was different from that in Western countries. In NDM dominant pedigrees, MC was more frequent than recessive MC and unique mutations were found in Japan. In PP, hypoPP2 was more frequent than hypoPP1.
Acknowledgments
All authors thank Makoto Ikejiri, Maki Nakamura, Kimie Hayashi, and Terumi Kikuchi for their technical supports and Dr. Kaname Nakatani for his invaluable suggestions and help.
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