Dataset Information

Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people.

ABSTRACT:

Background

This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze the relationship between genotype and clinical phenotype.

Methods

CLCN1 and SCN4A genes in patients with clinical features and muscle pathology indicative of NDM were sequenced. Furthermore, KCNE3 and CACNA1S genes were assessed in patients with wild-type CLCN1 and SCN4A.

Results

Patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia, and joint contracture as determined by needle electromyography. All the study participants were administered mexiletine in combination with carbamazepine and showed significant improvements in myotonia symptoms in response to this therapy. CLCN1 gene mutation was detected in 8 cases diagnosed with myotonia congenital using gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion, and 2 insertions. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita.

Conclusions

Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in associated with clinical features.

SUBMITTER: Meng YX

PROVIDER: S-EPMC9302320 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people.

Meng Yan-Xin YX Yu Mei M Liu Chunmiao C Zhang Haijuan H Yang Yuxiu Y Zhang Jing J

Medicine 20220722 29

<h4>Background</h4>This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze the relationship between genotype and clinical phenotype.<h4>Methods</h4>CLCN1 and SCN4A genes in patients with clinical features and muscle pathology indicative of NDM were sequenced. Furthermore, KCNE3 and CACNA1S genes were assessed in patients with wild-type CLCN1 and SCN4A.<h4>Results</h4>Patients may have ...[more]

PMID: 35866763

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Project description: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.

Project description:ContextNondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible.ObjectiveTo determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs.Design, setting, and participantsA randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network.InterventionOral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between.Main outcome measuresPatient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact).ResultsMexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related.ConclusionIn this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding.Trial registrationclinicaltrials.gov Identifier: NCT00832000.

Project description:ImportanceIn rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed.ObjectiveTo investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT.Design, setting, and participantsA series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016.InterventionsMexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks.Main outcomes and measuresReduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference.ResultsAmong 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26).Conclusions and relevanceIn a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.Trial registrationClinicalTrials.gov Identifier: NCT02045667.

Dataset Information

Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people.

Background

Methods

Results

Conclusions

Publications

Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people.

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