Mutation spectrum and health status in skeletal muscle channelopathies in Japan

Sasaki, Ryo; Nakaza, Maki; Furuta, Mitsuru; Fujino, Haruo; Kubota, Tomoya; Takahashi, Masanori

doi:10.1016/j.nmd.2020.06.001

Cited by 15 publications

(13 citation statements)

References 38 publications

(42 reference statements)

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“…In our cohort, the most common variants were c.892G>A (p.A298T), which contributed 20%, followed by c.1679T>C (p.M560T), c.139C>T (p.R47W), c.1205C>T (p.A402V), and c.1657A>T (p.I553F). This was, to some degree, consistent with one report in 2020, which pointed that A298T, P480T, T539A, and M560T mutations in CLCN1 gene was common in Japan ( 27 ).…”

Section: Discussionsupporting

confidence: 92%

“…Based on the review of all previously reported CLCN1related MC patients in China, autosomal dominant Thomsen's disease compromised 48.3% of the patients, which was much higher than the percentage of 19-20% in one study (32), but lower than another report from Japan, which enrolled 30 families with myotonia congenita and showed that the dominant form consisted of 67% (27). Thus, it is possible that the dominant form of MC is more prevalent in Asia than in western countries.…”

Section: Discussionmentioning

confidence: 75%

“…This variant has been observed in affected individuals in the heterozygous state with dominant transmission ( 26 ), with high clinical heterogeneity, ranging from occasional stiffness with EMG myotonic discharges finding to mild phenotype ( 24 ). It was possibly related with either reduced penetrance or incomplete dominance, which has also been observed in other variants including c.1444G>A (p.G482R) ( 23 ) or potential myotonia ( 27 ), but it also cannot be excluded that a second deep-intronic variant or small deletion may be missed in patients with a heterozygous state due to technical limitation. What is more, the c.1649C>T (p.T550M) variant has also been observed in combination with another CLCN1 variant in several individuals affected with autosomal recessive myotonia congenita ( 28 , 29 ).…”

Section: Discussionmentioning

confidence: 92%

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Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients

Shi

Zhao

et al. 2021

Front. Pediatr.

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Background:CLCN1-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China.Patients and Methods: Five patients with myotonia congenita due to mutations in CLCN1 gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed.Results: The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in CLCN1 gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in CLCN1 gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) (n = 9), c.139C>T (p.R47W) (n = 3), c.1205C>T(p.A402V) (n = 3), c.1657A>T (p.I553F) (n = 3), c.1679T>C (p.M560T) (n = 3), c.350A>G (p.D117G) (n = 2), c.762C>G (p.C254W) (n = 2), c.782A>G (P.Y261C) (n = 2), and c.1277C>A (p.T426N) (n = 2).Conclusion: Our results reported five CLCN1-related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 92%

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Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients

Shi

Zhao

et al. 2021

Front. Pediatr.

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“…MC is classified into the AD-Thomsen type (DMC) and the AR-Becker type (RMC). The incidence of RMC is higher than that of DMC in Western nations (21,22), while the incidence of DMC (10/17, 59%) was higher than that of RMC (7/17, 41%) in our study, in agreement with several studies in Asia (20,23), which might be due to racial differences. The age at onset of NDM is usually <20 years.…”

Section: Clinical Phenotypessupporting

confidence: 92%

The Clinical, Myopathological, and Genetic Analysis of 20 Patients With Non-dystrophic Myotonia

et al. 2022

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IntroductionNon-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by CLCN1 or SCN4A mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.MethodsWe reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.ResultsCases included myotonia congenita (MC, 17/20) and paramyotonia congenita (PMC, 3/20). Muscle stiffness and hypertrophy, grip and percussion myotonia, and the warm-up phenomenon were frequently observed in MC and PMC patients. Facial stiffness, eye closure myotonia, and cold sensitivity were more common in PMC patients and could be accompanied by permanent weakness. Nine MC patients and two PMC patients had cardiac abnormalities, mainly manifested as cardiac arrhythmia, and the father of one patient died of sudden cardiac arrest. Myotonic runs in electromyography were found in all patients, and seven MC patients had mild myopathic changes. There was no difference in muscle pathology between MC and PMC patients, most of whom had abnormal muscle fiber type distribution or selective muscle fiber atrophy. Nineteen CLCN1 variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two SCN4A variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.ConclusionsMC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.

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“…This variant has been observed in affected individuals in the heterozygous state with dominant transmission (26), with high clinical heterogeneity, ranging from occasional stiffness with EMG myotonic discharges finding to mild phenotype (24). It was possibly related with either reduced penetrance or incomplete dominance, which has also been observed in other variants including c.1444G>A (p.G482R) (23) or potential myotonia (27), but it also cannot be excluded that a second deepintronic variant or small deletion may be missed in patients with a heterozygous state due to technical limitation. What is more, the c.1649C>T (p.T550M) variant has also been observed in combination with another CLCN1 variant in several individuals affected with autosomal recessive myotonia congenita (28,29).…”

Section: Discussionmentioning

confidence: 87%

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Mutation spectrum and health status in skeletal muscle channelopathies in Japan

Cited by 15 publications

References 38 publications

Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients

Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients

The Clinical, Myopathological, and Genetic Analysis of 20 Patients With Non-dystrophic Myotonia

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