RARE DISEASE
Thomsen and Becker disease
Thomsen and Becker disease
Thomsen and Becker disease
Synonyms: Myotonia congenita
Synonyms: Myotonia congenita
Synonyms: Myotonia congenita
Drug discovery
0
drugs
With orphan designations
Overview
Thomsen and Becker disease are autosomal dominant and recessive forms of myotonia congenita, respectively, caused by CLCN1 mutations impairing skeletal muscle chloride channels. Both present with myotonia (delayed muscle relaxation), typically provoked by sudden movements after rest, improving with repeated activity (warm-up phenomenon). Becker disease, more common and severe, may involve transient weakness and later onset (4–12 years), while Thomsen disease manifests earlier (infancy–childhood) without weakness. Diagnosis relies on clinical features, EMG, and genetic testing. [1][2][5][9]
Therapies
Categories: rare genetic diseases, rare neurological diseases
Research Papers
200 drug discovery papers about Thomsen and Becker disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
200 drug discovery papers about Thomsen and Becker disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Case Report: Three pathogenic molecular findings in a patient with myotonia congenita, pseudohypoparathyroidism, and a glaucoma-suspect phenotype
Background The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS -related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. Case presentation A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. Genetic and ophthalmologic findings Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. Conclusion This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.
2026-06-07 | Integrated electrophysiological, cellular, and pharmacological profiling reveals variant-specific mechanisms in SCN4A-related myotonia.
Non-dystrophic myotonias are rare skeletal muscle channelopathies characterized by delayed muscle relaxation and clinical stiffness. This study investigates the molecular mechanisms underlying three missense variants in SCN4A encoding for the voltage gated skeletal muscle sodium channel NaV1.4-p.K1308R, p.R1451H, and p.M1701V-identified in patients with non-dystrophic myotonia. All probands carried these variants in combination with the ClC-1 p.G190S mutation, a digenic configuration likely contributing to the heterogeneous clinical manifestations. An integrated approach combining electrophysiology, protein trafficking assessment, and evaluation of endoplasmic reticulum stress, revealed distinct pathogenic signatures for each variant. p.K1308R and p.M1701V primarily altered channel gating, whereas p.R1451H exhibited profound cellular impairment, including intracellular retention, reduced membrane expression, and robust activation of endoplasmic reticulum-stress pathways. Functionally, p.K1308R and p.R1451H caused marked reductions in current density and slowed activation kinetics, while p.M1701V produced milder perturbations consistent with its generally less severe phenotype. Because cold exposure exacerbated symptoms in carriers of p.R1451H and p.M1701V, the functional behaviour of these variants was examined at 37 °C. Both showed recovery of current amplitude to wild-type values and normalization of activation voltage dependence, although inactivation defects persisted. These temperature-dependent improvements were accompanied by increased window current probability, indicating partial temperature-dependent stabilization of channel gating. Pharmacological testing revealed that mexiletine modulates gating abnormalities in a variant-specific manner, reinforcing the clinical relevance of mechanistic stratification. Overall, the findings showed that clinically similar myotonic phenotypes may arise from divergent molecular defects and emphasize the relevance of precision medicine approaches tailored to variant-specific pathogenic mechanisms.
2025-11-07 | Long term safety and efficacy of lamotrigine in patients with non-dystrophic myotonia, a single-centre prospective study.
The non-dystrophic myotonias are rare genetic conditions characterised by delayed muscle relaxation, muscle stiffness, pain and fatigue. This study examines the experience of the UK National Referral Centre in using lamotrigine to treat non-dystrophic myotonias. A prospective cohort of 37 patients with genetically confirmed non-dystrophic myotonias (23 with CLCN1 variants and 14 with SCN4A variants) who were prescribed lamotrigine as part of routine clinical care were followed for a mean of 26 months. Treatment efficacy was assessed using the Myotonia Behaviour Score. 26 participants were included in the efficacy analysis where lamotrigine was found to reduce the mean Myotonia Behaviour Score from 3.3 to 1.8 (p < .001, Cohen's d = 1.2), demonstrating significant symptom improvement. Side effects, mainly rash and headache, led to discontinuation in nine out of 37 patients, but no severe adverse events occurred. In most cases, lamotrigine was chosen due to prior side effects with mexiletine or cardiac contraindications to mexiletine and proved to be an effective alternative. This study provides real-world evidence supporting the long-term use of lamotrigine and the integration of lamotrigine into personalised treatment strategies for non-dystrophic myotonias.
2025-07-01 | Clinical Profile, Genotype Spectrum, and Outcomes in an Indian Cohort of Patients with Myotonia Congenita
A bstract Background: Myotonia congenita (MC) is a genetic neuromuscular channelopathy characterized by impaired muscle relaxation after voluntary contraction. It is caused by a mutation in the CLCN1 gene. Dominant variants cause Thomson’s disease, while recessive inheritance is termed Becker disease. Objective: To study clinical features, molecular profile, and outcomes in MC. Results: Among 10 cases of MC, seven were males; the mean age noted was seven years. Eight were classified as Becker’s type, while two were classified as Thomson’s type. All cases presented with proximal muscle weakness, a family history of consanguinity, transient muscle stiffness, and weakness after rest which improved with repeated contractions and body builders' appearance. Gower’s signs were noted in nine cases. The symptoms were aggravated by cold weather and stress. Investigations performed showed a mean creatine phosphokinase (CPK) of 243.8 U/L with normal nerve conduction studies. Electromyography (EMG) performed in two children revealed myotonic changes in one, while the other was inconclusive. Exome sequencing identified CLCN1 variants in all, heterozygous mutations in two, and homozygous in eight. Treatment with carbamazepine, phenytoin, and acetazolamide in various combinations improved symptoms to varying degrees. Conclusion: This study reports the phenotypic and mutational spectrum of MC in Indian patients. It also evaluates the effectiveness of various therapeutic modalities and their response in reducing myotonia symptoms. Furthermore, we highlight recurrent genetic variants found in unrelated families, which may suggest a possible founder effect. Additionally, we observe the p.(Arg338Ter) variant as a cause of both dominant and recessive forms of the disease.
2025-05-14 | High-dose flecainide for symptomatic relief in paramyotonia congenita/severe neonatal episodic laryngospasm due to SCN4A G1306E: a case report.
Severe neonatal episodic laryngospasm has been previously reported in multiple patients with the heterozygous pathogenic variant G1306E in SCN4A. Treatment can be difficult due to side effects from therapies utilized conventionally for the management of myotonia and paramyotonia congenita. We report on two female siblings of Irish, Scandinavian, and German ethnicity aged 7 and 3 years with severe neonatal episodic laryngospasm and paramyotonia congenita due to a paternally inherited heterozygous pathogenic variant of the SCN4A gene and the use of high-dose flecainide therapy for symptomatic management. Interestingly, one of the two siblings has a coexisting separate maternally inherited and pathogenic CLCN1 variant that may further impact phenotype. High-dose flecainide 220-250 mg/m2/day was not associated with any cardiac side effects. This report supports the use of high-dose flecainide in combination with standard therapies in pediatric patients with SCN4A mutations to modulate acute symptoms and provides suggested dosing with an acute and long-term monitoring protocol.
gene therapies
2026-05-11 | Myotonia: Recognition, Evaluation, and Differential Diagnosis.
Myotonia is a non-neurotypical muscle physiology of sarcolemmal hyperexcitability due to alterations in the structure and/or function of ion channels in the muscle cell membrane. This hyperexcitability can be observed electrically as spontaneous myotonic discharges during needle electromyography. Myotonic discharges consist of continuous sequential fibrillation or positive sharp wave morphology potentials which exhibit unstable, gradually changing, firing frequencies and amplitudes. In myotonic disorders, a clinical correlate of muscle stiffness is often present. Myotonic disorders are broadly divided into myotonic dystrophies (Types 1 and 2) and non-dystrophic myotonias (myotonia congenita, paramyotonia congenita, and sodium channel myotonias). The myotonic dystrophies are systemic disorders of dysregulated RNA splicing clinically exhibiting fixed weakness, cataracts, diabetes and cardiac disease. Non-dystrophic myotonic disorders are due to specific sarcolemmal ion channel genetic variants and generally clinically limited to muscle stiffness (myotonia) sometimes with muscle weakness which can be fixed or periodic. Although electrical myotonia is a distinctive feature of myotonic disorders, it is nonspecific and may occur in other neuromuscular conditions. Widespread myotonic discharges strongly suggest a myotonic disorder or a handful of other conditions including necrotizing autoimmune myopathy, some toxic myopathies, Pompe disease and several congenital myopathies. This monograph reviews clinical myotonia and mimics, electrical myotonic discharges, electrodiagnostic testing in myotonic disorders and clinical features of myotonic disorders and other myopathies with myotonia.
2026-05-01 | B80-1-04 Myotonia Congenita: A Rare Chloride Channelopathy Leading to Neuromuscular Ventilatory Dysfunction
Abstract Introduction Skeletal muscle channelopathies are a group of rare genetic neuromuscular diseases that have underrecognized respiratory implications. Mutation of the gene that encodes the chloride channel found in skeletal muscle leads to a condition known as myotonia congenita: a type of non-dystrophic myotonia in which there is excessive muscle stiffness and delayed relaxation after muscle contraction. This report presents a rare case of this chloride channel neuromuscular disease manifesting as dyspnea. Case Presentation A 58-year-old male of Scandinavian descent presents with muscular hypertrophy and chronic muscle fatigue with no increase in physical activity. He experiences frequent neck spasms, ocular muscle tension, and excessive teeth grinding. Laughter triggers a sensation of a valve closing in his airway leading to a feeling of breathlessness and near syncope. His symptoms are mildly alleviated by movement. He has frequent flares that are inadequately controlled with corticosteroids. Pulmonary function testing (PFT) shows low forced vital capacity (FVC) out of proportion to total lung capacity (TLC), low maximum voluntary ventilation (MVV), low expiratory reserve volume (ERV), and elevated residual volume (RV). This respiratory physiology pattern was suspicious for underlying neuromuscular weakness as a cause for his chronic shortness of breath. PFT also revealed flattening of the inspiratory limb of the flow volume loop, which raised concern for airway obstruction due to vocal cord dysfunction. Otolaryngologic evaluation revealed normal anatomical vocal cords with paradoxical movement during respiration. Additional investigation of possible underlying neuromuscular disease was completed, and muscle biopsy and genetic testing revealed mutation of the chloride channel protein 1 (CLCN1) seen in myotonia congenita. Discussion/Conclusion Genetic channelopathies are a rare subset of neuromuscular disease that result in motor dysfunction and impaired ventilation. The extrapulmonary symptoms of muscle fatigue and spasms relieved with movement (“warm up phenomenon”) are a known characteristic of myotonia congenita. However, the pulmonary symptoms of this rare condition were relatively unknown and prior to this case presentation were not well-characterized. This novel report highlights the respiratory symptoms of chronic dyspnea demonstrated by neuromuscular disease pattern on pulmonary function testing in addition to upper airway obstruction confirmed by visualization of paradoxical vocal cord movement. Knowledge of the respiratory mechanics seen in myotonia congenita can lead to expedited pulmonary evaluation and management. Current pharmacological management of channelopathies involves the use of ion channel blockers and anti-epileptic medications for symptom control; further research is needed for targeted gene therapies. This abstract is funded by: None
2025-08-09 | Uncovering the CLCN1 Y150* nonsense variant in myotonia congenita: genetic evidence from segregation analysis.
Myotonia congenita is a rare genetic disorder characterized by skeletal muscle membrane hyperexcitability due to CLCN1 mutations. It can be inherited in either an autosomal dominant (Thomsen disease) or autosomal recessive (Becker disease) manner. This study describes a homozygous null alteration and its segregation analysis, confirming its pathogenicity. A 30-year-old male, presenting with myotonia since the age of five, was referred to the Medical Genetics clinic. His parents were from the same village, and two of his siblings exhibited similar symptoms. Clinical evaluation was consistent with Becker's myotonia. Next-generation sequencing revealed a homozygous nonsense variant in CLCN1 (NM_000083.2:c.450 C > A, p.Tyr150Ter [Y150*]), which was confirmed by Sanger sequencing in both the proband and his affected brother. This variant has been reported in only five patients. Given that all cases were of Turkish origin and exhibited Becker-type myotonia, our findings support a potential genotype-phenotype association and raise the possibility that this variant may be relatively more prevalent in patients from Türkiye.
2025-06-10 | Clinical and genetic analysis and literature review of children with myotonia congenita due to CLCN1 mutations.
Myotonia congenita (MC) is mainly caused by variants in the CLCN1 Gene, which is characterized by having difficulty in relaxing the muscle after active contraction, known as myotonia. This study aims to investigate the clinical characteristics and gene mutations of myotonia congenita caused by CLCN1 mutation. Five children with myotonia congenita due to CLCN1 mutations admitted to Nanjing Children's Hospital were included. All five children had a juvenile onset of the disease (1 to 11 years of age). Two had onset before 2 years of age, and three had onset after 10 years of age. All patients experienced muscle stiffness (5/5, 100.0%), two reported delayed relaxation of the hand after forceful grasping (2/5, 40.0%), and three reported that the muscle stiffness worsened with changes in motor status (3/5, 60.0%). These symptoms improved with exercise (warm-up phenomenon) (5/5, 100.0%).Two children had elevated CK (2/5, 40.0%), and EMG showed muscle tonic potentials in all five children (5/5, 100.0%). Eight CLCN1 gene mutation sites were identified in five patients, including four unreported variants: c.688G > A (p.G230R), c.2653_c.2654insC (p.A885Afs*27), c.1938G > T (p.M646I) and c.1825 A > G (p.M609V). In this paper, we also summarized the Chinese CLCN1 mutation sites reported in the last 10 years, revealing that exons 8 and 15 may be the hotspot regions of mutation in Chinese children. This study expands the clinical and genetic spectrum of Chinese children with myotonia congenita. The clinical manifestations observed in these children were similar with those previously reported in the literature. Additionally, exons 8 and 15 may be the hotspot regions for gene mutations in Chinese children with myotonia congentia.
2024-08-22 | Inherited myotonias.
The inherited myotonias are a complex group of diseases caused by variations in genes that encode or modulate the expression of ion channels that regulate muscle excitability. These variations alter muscle membrane excitability allowing mild depolarization, causing myotonic discharges. There are two groups of inherited myotonia, the dystrophic and the nondystrophic myotonias (NDM). Patients with NDM have a pure muscle phenotype with variations in channel genes expressed in muscle. The dystrophic myotonias are caused by genes that alter splicing leading to more systemic effects with myotonia being one of a number of systemic symptoms. This chapter therefore focuses on the key aspects of the NDMs. The NDMs manifest with varying clinical phenotypes, which change from infancy to adulthood. The pathogenicity of different variants can be determined using heterologous expression systems to understand the alteration in channel properties and predict the likelihood of causing disease. Myotonia itself can be managed by lifestyle modifications. A number of randomized controlled trials demonstrate efficacy of mexiletine and lamotrigine in treating myotonia, but there is an evidence that specific variants may be more or less well-treated by the different agents because of how they alter the channel kinetics. More work is needed to develop more targeted genetic treatments.
cell therapies
2026-01-05 | [Functional analysis of the mutant channels associated with skeletal muscle channelopathies].
Skeletal muscle channelopathies are rare genetic disorders caused by mutations in voltage-gated ion channel genes that regulate sarcomere excitability, including the CLCN1 gene encoding ClC-1, the KCNJ2 gene encoding Kir2.1, the SCN4A gene encoding Nav1.4, and the CACNA1S gene encoding Cav1.1. More than one hundred heterozygous missense mutations have been identified in SCN4A, representing a broad spectrum of clinical phenotypes, including sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). In addition, recent case reports have shown that compound heterozygous mutations or homozygous mutations in SCN4A are associated with congenital myopathy or congenital myasthenic syndrome. Regarding the pathological mechanisms of SCM/PMC and HyperPP, a large number of electrophysiological analyses have shown an association between the functional alteration of the mutant Nav1.4 and the clinical phenotype. On the other hand, HypoPP has long been a mysterious disorder. In 2007, the recent discovery of aberrant leak currents, called "gating pore currents", brought a breakthrough in the field of HypoPP research and contributed to the elucidation of the structure-function relationship of the voltage sensing domain of voltage-gated ion channels. However, there has been little progress in the discovery of the therapeutics. Recently, we have generated HEK293T-based HypoPP model cell lines aiming to establish the in vitro platform for the high-throughput drug screening. Our HypoPP model cells would provide new insight into the development of novel therapeutics for channelopathies.
small molecules
2026-08-14 | Case Report: Three pathogenic molecular findings in a patient with myotonia congenita, pseudohypoparathyroidism, and a glaucoma-suspect phenotype
Background The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS -related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. Case presentation A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. Genetic and ophthalmologic findings Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. Conclusion This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.
2026-06-07 | Integrated electrophysiological, cellular, and pharmacological profiling reveals variant-specific mechanisms in SCN4A-related myotonia.
Non-dystrophic myotonias are rare skeletal muscle channelopathies characterized by delayed muscle relaxation and clinical stiffness. This study investigates the molecular mechanisms underlying three missense variants in SCN4A encoding for the voltage gated skeletal muscle sodium channel NaV1.4-p.K1308R, p.R1451H, and p.M1701V-identified in patients with non-dystrophic myotonia. All probands carried these variants in combination with the ClC-1 p.G190S mutation, a digenic configuration likely contributing to the heterogeneous clinical manifestations. An integrated approach combining electrophysiology, protein trafficking assessment, and evaluation of endoplasmic reticulum stress, revealed distinct pathogenic signatures for each variant. p.K1308R and p.M1701V primarily altered channel gating, whereas p.R1451H exhibited profound cellular impairment, including intracellular retention, reduced membrane expression, and robust activation of endoplasmic reticulum-stress pathways. Functionally, p.K1308R and p.R1451H caused marked reductions in current density and slowed activation kinetics, while p.M1701V produced milder perturbations consistent with its generally less severe phenotype. Because cold exposure exacerbated symptoms in carriers of p.R1451H and p.M1701V, the functional behaviour of these variants was examined at 37 °C. Both showed recovery of current amplitude to wild-type values and normalization of activation voltage dependence, although inactivation defects persisted. These temperature-dependent improvements were accompanied by increased window current probability, indicating partial temperature-dependent stabilization of channel gating. Pharmacological testing revealed that mexiletine modulates gating abnormalities in a variant-specific manner, reinforcing the clinical relevance of mechanistic stratification. Overall, the findings showed that clinically similar myotonic phenotypes may arise from divergent molecular defects and emphasize the relevance of precision medicine approaches tailored to variant-specific pathogenic mechanisms.
2025-11-07 | Long term safety and efficacy of lamotrigine in patients with non-dystrophic myotonia, a single-centre prospective study.
The non-dystrophic myotonias are rare genetic conditions characterised by delayed muscle relaxation, muscle stiffness, pain and fatigue. This study examines the experience of the UK National Referral Centre in using lamotrigine to treat non-dystrophic myotonias. A prospective cohort of 37 patients with genetically confirmed non-dystrophic myotonias (23 with CLCN1 variants and 14 with SCN4A variants) who were prescribed lamotrigine as part of routine clinical care were followed for a mean of 26 months. Treatment efficacy was assessed using the Myotonia Behaviour Score. 26 participants were included in the efficacy analysis where lamotrigine was found to reduce the mean Myotonia Behaviour Score from 3.3 to 1.8 (p < .001, Cohen's d = 1.2), demonstrating significant symptom improvement. Side effects, mainly rash and headache, led to discontinuation in nine out of 37 patients, but no severe adverse events occurred. In most cases, lamotrigine was chosen due to prior side effects with mexiletine or cardiac contraindications to mexiletine and proved to be an effective alternative. This study provides real-world evidence supporting the long-term use of lamotrigine and the integration of lamotrigine into personalised treatment strategies for non-dystrophic myotonias.
2025-07-01 | Clinical Profile, Genotype Spectrum, and Outcomes in an Indian Cohort of Patients with Myotonia Congenita
A bstract Background: Myotonia congenita (MC) is a genetic neuromuscular channelopathy characterized by impaired muscle relaxation after voluntary contraction. It is caused by a mutation in the CLCN1 gene. Dominant variants cause Thomson’s disease, while recessive inheritance is termed Becker disease. Objective: To study clinical features, molecular profile, and outcomes in MC. Results: Among 10 cases of MC, seven were males; the mean age noted was seven years. Eight were classified as Becker’s type, while two were classified as Thomson’s type. All cases presented with proximal muscle weakness, a family history of consanguinity, transient muscle stiffness, and weakness after rest which improved with repeated contractions and body builders' appearance. Gower’s signs were noted in nine cases. The symptoms were aggravated by cold weather and stress. Investigations performed showed a mean creatine phosphokinase (CPK) of 243.8 U/L with normal nerve conduction studies. Electromyography (EMG) performed in two children revealed myotonic changes in one, while the other was inconclusive. Exome sequencing identified CLCN1 variants in all, heterozygous mutations in two, and homozygous in eight. Treatment with carbamazepine, phenytoin, and acetazolamide in various combinations improved symptoms to varying degrees. Conclusion: This study reports the phenotypic and mutational spectrum of MC in Indian patients. It also evaluates the effectiveness of various therapeutic modalities and their response in reducing myotonia symptoms. Furthermore, we highlight recurrent genetic variants found in unrelated families, which may suggest a possible founder effect. Additionally, we observe the p.(Arg338Ter) variant as a cause of both dominant and recessive forms of the disease.
2025-05-14 | High-dose flecainide for symptomatic relief in paramyotonia congenita/severe neonatal episodic laryngospasm due to SCN4A G1306E: a case report.
Severe neonatal episodic laryngospasm has been previously reported in multiple patients with the heterozygous pathogenic variant G1306E in SCN4A. Treatment can be difficult due to side effects from therapies utilized conventionally for the management of myotonia and paramyotonia congenita. We report on two female siblings of Irish, Scandinavian, and German ethnicity aged 7 and 3 years with severe neonatal episodic laryngospasm and paramyotonia congenita due to a paternally inherited heterozygous pathogenic variant of the SCN4A gene and the use of high-dose flecainide therapy for symptomatic management. Interestingly, one of the two siblings has a coexisting separate maternally inherited and pathogenic CLCN1 variant that may further impact phenotype. High-dose flecainide 220-250 mg/m2/day was not associated with any cardiac side effects. This report supports the use of high-dose flecainide in combination with standard therapies in pediatric patients with SCN4A mutations to modulate acute symptoms and provides suggested dosing with an acute and long-term monitoring protocol.
gene therapies
2026-05-11 | Myotonia: Recognition, Evaluation, and Differential Diagnosis.
Myotonia is a non-neurotypical muscle physiology of sarcolemmal hyperexcitability due to alterations in the structure and/or function of ion channels in the muscle cell membrane. This hyperexcitability can be observed electrically as spontaneous myotonic discharges during needle electromyography. Myotonic discharges consist of continuous sequential fibrillation or positive sharp wave morphology potentials which exhibit unstable, gradually changing, firing frequencies and amplitudes. In myotonic disorders, a clinical correlate of muscle stiffness is often present. Myotonic disorders are broadly divided into myotonic dystrophies (Types 1 and 2) and non-dystrophic myotonias (myotonia congenita, paramyotonia congenita, and sodium channel myotonias). The myotonic dystrophies are systemic disorders of dysregulated RNA splicing clinically exhibiting fixed weakness, cataracts, diabetes and cardiac disease. Non-dystrophic myotonic disorders are due to specific sarcolemmal ion channel genetic variants and generally clinically limited to muscle stiffness (myotonia) sometimes with muscle weakness which can be fixed or periodic. Although electrical myotonia is a distinctive feature of myotonic disorders, it is nonspecific and may occur in other neuromuscular conditions. Widespread myotonic discharges strongly suggest a myotonic disorder or a handful of other conditions including necrotizing autoimmune myopathy, some toxic myopathies, Pompe disease and several congenital myopathies. This monograph reviews clinical myotonia and mimics, electrical myotonic discharges, electrodiagnostic testing in myotonic disorders and clinical features of myotonic disorders and other myopathies with myotonia.
2026-05-01 | B80-1-04 Myotonia Congenita: A Rare Chloride Channelopathy Leading to Neuromuscular Ventilatory Dysfunction
Abstract Introduction Skeletal muscle channelopathies are a group of rare genetic neuromuscular diseases that have underrecognized respiratory implications. Mutation of the gene that encodes the chloride channel found in skeletal muscle leads to a condition known as myotonia congenita: a type of non-dystrophic myotonia in which there is excessive muscle stiffness and delayed relaxation after muscle contraction. This report presents a rare case of this chloride channel neuromuscular disease manifesting as dyspnea. Case Presentation A 58-year-old male of Scandinavian descent presents with muscular hypertrophy and chronic muscle fatigue with no increase in physical activity. He experiences frequent neck spasms, ocular muscle tension, and excessive teeth grinding. Laughter triggers a sensation of a valve closing in his airway leading to a feeling of breathlessness and near syncope. His symptoms are mildly alleviated by movement. He has frequent flares that are inadequately controlled with corticosteroids. Pulmonary function testing (PFT) shows low forced vital capacity (FVC) out of proportion to total lung capacity (TLC), low maximum voluntary ventilation (MVV), low expiratory reserve volume (ERV), and elevated residual volume (RV). This respiratory physiology pattern was suspicious for underlying neuromuscular weakness as a cause for his chronic shortness of breath. PFT also revealed flattening of the inspiratory limb of the flow volume loop, which raised concern for airway obstruction due to vocal cord dysfunction. Otolaryngologic evaluation revealed normal anatomical vocal cords with paradoxical movement during respiration. Additional investigation of possible underlying neuromuscular disease was completed, and muscle biopsy and genetic testing revealed mutation of the chloride channel protein 1 (CLCN1) seen in myotonia congenita. Discussion/Conclusion Genetic channelopathies are a rare subset of neuromuscular disease that result in motor dysfunction and impaired ventilation. The extrapulmonary symptoms of muscle fatigue and spasms relieved with movement (“warm up phenomenon”) are a known characteristic of myotonia congenita. However, the pulmonary symptoms of this rare condition were relatively unknown and prior to this case presentation were not well-characterized. This novel report highlights the respiratory symptoms of chronic dyspnea demonstrated by neuromuscular disease pattern on pulmonary function testing in addition to upper airway obstruction confirmed by visualization of paradoxical vocal cord movement. Knowledge of the respiratory mechanics seen in myotonia congenita can lead to expedited pulmonary evaluation and management. Current pharmacological management of channelopathies involves the use of ion channel blockers and anti-epileptic medications for symptom control; further research is needed for targeted gene therapies. This abstract is funded by: None
2025-08-09 | Uncovering the CLCN1 Y150* nonsense variant in myotonia congenita: genetic evidence from segregation analysis.
Myotonia congenita is a rare genetic disorder characterized by skeletal muscle membrane hyperexcitability due to CLCN1 mutations. It can be inherited in either an autosomal dominant (Thomsen disease) or autosomal recessive (Becker disease) manner. This study describes a homozygous null alteration and its segregation analysis, confirming its pathogenicity. A 30-year-old male, presenting with myotonia since the age of five, was referred to the Medical Genetics clinic. His parents were from the same village, and two of his siblings exhibited similar symptoms. Clinical evaluation was consistent with Becker's myotonia. Next-generation sequencing revealed a homozygous nonsense variant in CLCN1 (NM_000083.2:c.450 C > A, p.Tyr150Ter [Y150*]), which was confirmed by Sanger sequencing in both the proband and his affected brother. This variant has been reported in only five patients. Given that all cases were of Turkish origin and exhibited Becker-type myotonia, our findings support a potential genotype-phenotype association and raise the possibility that this variant may be relatively more prevalent in patients from Türkiye.
2025-06-10 | Clinical and genetic analysis and literature review of children with myotonia congenita due to CLCN1 mutations.
Myotonia congenita (MC) is mainly caused by variants in the CLCN1 Gene, which is characterized by having difficulty in relaxing the muscle after active contraction, known as myotonia. This study aims to investigate the clinical characteristics and gene mutations of myotonia congenita caused by CLCN1 mutation. Five children with myotonia congenita due to CLCN1 mutations admitted to Nanjing Children's Hospital were included. All five children had a juvenile onset of the disease (1 to 11 years of age). Two had onset before 2 years of age, and three had onset after 10 years of age. All patients experienced muscle stiffness (5/5, 100.0%), two reported delayed relaxation of the hand after forceful grasping (2/5, 40.0%), and three reported that the muscle stiffness worsened with changes in motor status (3/5, 60.0%). These symptoms improved with exercise (warm-up phenomenon) (5/5, 100.0%).Two children had elevated CK (2/5, 40.0%), and EMG showed muscle tonic potentials in all five children (5/5, 100.0%). Eight CLCN1 gene mutation sites were identified in five patients, including four unreported variants: c.688G > A (p.G230R), c.2653_c.2654insC (p.A885Afs*27), c.1938G > T (p.M646I) and c.1825 A > G (p.M609V). In this paper, we also summarized the Chinese CLCN1 mutation sites reported in the last 10 years, revealing that exons 8 and 15 may be the hotspot regions of mutation in Chinese children. This study expands the clinical and genetic spectrum of Chinese children with myotonia congenita. The clinical manifestations observed in these children were similar with those previously reported in the literature. Additionally, exons 8 and 15 may be the hotspot regions for gene mutations in Chinese children with myotonia congentia.
2024-08-22 | Inherited myotonias.
The inherited myotonias are a complex group of diseases caused by variations in genes that encode or modulate the expression of ion channels that regulate muscle excitability. These variations alter muscle membrane excitability allowing mild depolarization, causing myotonic discharges. There are two groups of inherited myotonia, the dystrophic and the nondystrophic myotonias (NDM). Patients with NDM have a pure muscle phenotype with variations in channel genes expressed in muscle. The dystrophic myotonias are caused by genes that alter splicing leading to more systemic effects with myotonia being one of a number of systemic symptoms. This chapter therefore focuses on the key aspects of the NDMs. The NDMs manifest with varying clinical phenotypes, which change from infancy to adulthood. The pathogenicity of different variants can be determined using heterologous expression systems to understand the alteration in channel properties and predict the likelihood of causing disease. Myotonia itself can be managed by lifestyle modifications. A number of randomized controlled trials demonstrate efficacy of mexiletine and lamotrigine in treating myotonia, but there is an evidence that specific variants may be more or less well-treated by the different agents because of how they alter the channel kinetics. More work is needed to develop more targeted genetic treatments.
cell therapies
2026-01-05 | [Functional analysis of the mutant channels associated with skeletal muscle channelopathies].
Skeletal muscle channelopathies are rare genetic disorders caused by mutations in voltage-gated ion channel genes that regulate sarcomere excitability, including the CLCN1 gene encoding ClC-1, the KCNJ2 gene encoding Kir2.1, the SCN4A gene encoding Nav1.4, and the CACNA1S gene encoding Cav1.1. More than one hundred heterozygous missense mutations have been identified in SCN4A, representing a broad spectrum of clinical phenotypes, including sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). In addition, recent case reports have shown that compound heterozygous mutations or homozygous mutations in SCN4A are associated with congenital myopathy or congenital myasthenic syndrome. Regarding the pathological mechanisms of SCM/PMC and HyperPP, a large number of electrophysiological analyses have shown an association between the functional alteration of the mutant Nav1.4 and the clinical phenotype. On the other hand, HypoPP has long been a mysterious disorder. In 2007, the recent discovery of aberrant leak currents, called "gating pore currents", brought a breakthrough in the field of HypoPP research and contributed to the elucidation of the structure-function relationship of the voltage sensing domain of voltage-gated ion channels. However, there has been little progress in the discovery of the therapeutics. Recently, we have generated HEK293T-based HypoPP model cell lines aiming to establish the in vitro platform for the high-throughput drug screening. Our HypoPP model cells would provide new insight into the development of novel therapeutics for channelopathies.
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