Becker's Myotonia Research Articles

Distribution and cardiac outcomes of neuromuscular disorders referred to an inherited cardiac disease unit

Abstract Backgroud Neuromuscular disorders may present with varied cardiac involvement, including myocardial and conduction tissue disease. Sudden death is a common adverse event of cardiomyopathy Purpose The objective was to present clinical characteristics of neuromuscular disorders referred to a dedicated inherited cardiac disease unit with special interest in the mode of presentation, clinical course and cardiac complications. Methods Cardiological anamnesis, 12-lead electrocardiogram and bidimensional echocardiogram were performed to every individual. Gadolinium cardiac MRI/24 hour-Holter/coronariography were performed in particular cases where results of previous tests made it mandatory. Results 199 patients (aged 43.1±18.1 years, 45.2% females, 54.8% males) with neurological disorders evaluated in an inherited cardiac disease clinic from 2003–2021 were included. There were 20 (10.1%) dystrophynopathies, 20 (10.1%) limb girdle muscular dystrophy, 14 (7.0%) other muscular dystrophies (Emery-Dreifuss, facio-scapulo-humeral, oculopharyngeal), 70 (35.2%) myotonic myopathies (Steinert myotonic dystrophy, Becker myotonia congenita, Thomsen myotonia congenita), 7 (3.5%) myofibrillar myopathies, 14 (7.0%) congenital myopathies, 18 (9.0%) metabolic myopathies, 12 (6.0%) unknown origin inherited myopathies, 24 (12.1%) non-myopathic neurological diseases. There were 44 (22.11%) patients affected with a cardiomyopathy. 51/199 (25.6%) had conduction disturbances. 33/51 had pathological cardiac findings without clinical cardiomyopathy. Age of diagnosis of neurological and cardiomyopathy conditions were 28.4±20.4 and 40.6±18.4 years old respectively. Reasons for diagnosis were symptoms (164, 82.4%), family screening (27, 13.6%), incidental finding (7, 3.5%), sudden death (1, 0.5%). 31 (15.6%) had atrial fibrillation, 17 (8.5%) required pacemaker and 15 (7.5%) ICD implantation. 32 (16.1%) patients died or had severe cardiac outcome. 7 (3.5%) had sudden death or equivalent, 3 (1.5%) heart-failure-death, 1 (0.5%) received cardiac transplantation, 18 (9.1%) had other-disease-related-death and 3 (1.5%) other disease non-cadiac-related-death). Conclusion Neuromuscular diseases require periodic cardiac evaluation. Despite onset of neurological symptoms usually precede cardiac involvement, the burden of cardiac involvement and complications is highly significant. Cause of death in neurological conditions with cardiac involvement is mostly driven by the severity of the cardiomyopathy. Funding Acknowledgement Type of funding sources: None.

Pathomechanisms of a CLCN1 Mutation Found in a Russian Family Suffering From Becker's Myotonia.

Objective: Myotonia congenita (MC) is a rare muscle disease characterized by sarcolemma over-excitability inducing skeletal muscle stiffness. It can be inherited either as an autosomal dominant (Thomsen's disease) or an autosomal recessive (Becker's disease) trait. Both types are caused by loss-of-function mutations in the CLCN1 gene, encoding for ClC-1 chloride channel. We found a ClC-1 mutation, p.G411C, identified in Russian patients who suffered from a severe form of Becker's disease. The purpose of this study was to provide a solid correlation between G411C dysfunction and clinical symptoms in the affected patient.Methods: We provide clinical and genetic information of the proband kindred. Functional studies include patch-clamp electrophysiology, biotinylation assay, western blot analysis, and confocal imaging of G411C and wild-type ClC-1 channels expressed in HEK293T cells.Results: The G411C mutation dramatically abolished chloride currents in transfected HEK cells. Biochemical experiments revealed that the majority of G411C mutant channels did not reach the plasma membrane but remained trapped in the cytoplasm. Treatment with the proteasome inhibitor MG132 reduced the degradation rate of G411C mutant channels, leading to their expression at the plasma membrane. However, despite an increase in cell surface expression, no significant chloride current was recorded in the G411C-transfected cell treated with MG132, suggesting that this mutation produces non-functional ClC-1 chloride channels.Conclusion: These results suggest that the molecular pathophysiology of G411C is linked to a reduced plasma membrane expression and biophysical dysfunction of mutant channels, likely due to a misfolding defect. Chloride current abolition confirms that the mutation is responsible for the clinical phenotype.

Congenital myotonia: a review of twenty cases and a new splice-site mutation in the CLCN1 gene.

Congenital Myotonia (CM) is a disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1). Mutations can be transmitted as autosomal dominant (Thomsen's disease) or recessive (Becker's disease). CM is more common in men and Becker myotonia may be 10 times more common than Thomsen myotonia. Genotypic and phenotypic characteristics of CM may vary according to geographical region and ethnicity. In this study, we present the genotypic and phenotypic characteristics of 20 Turkish CM patients all diagnosed by molecular genetic testing. The clinical and laboratory features of the patients with mutation in CLCN1 gene were retrospectively analyzed. Eleven of the patients were female. c.1064+1G > A splice-site change, p.Arg338X (c.1012 C > T) stop codon, p.Gly190Ser (c.568_569delinsTC) missense mutations were detected. Eight of the 20 patients were found to be compatible with Becker type and 12 with Thomsen type, based on mode of inheritance, neurological examination findings and genetic test results. The c.1064+1G > A splice-site change mutation, defined for the first time in this study, expands the spectrum of mutations in the CLCN1 gene. Thomsen type and female gender were observed to be more frequent in this series of patients from Turkey.

A case of Becker myotonia with pseudodominant inheritance: сurrent approaches to the differential diagnosis of Thomsen’s and Becker's myotonia congenita

Myotonia congenital (MC) is the most common form of the hereditary nondystrophic myotonias caused by mutations in the skeletal muscle chloride channel gene (CLCN1) which change the functional features of muscle fibers membrane. MC is represented by two allelic forms with different types of inheritance: Thomsen’s myotonia congenita (TMC) with an autosomal dominant and Becker’s myotonia congenita (BMC) with an autosomal recessive inheritance. Both forms, TMC and BMC have the same clinical manifestation: skeletal muscle hypertrophy, transient weakness, generalized myotonia, debut in early childhood and a stationary development. Diseases are characterized by equal neurophysiological changes. In the family usually only one patient is detected. In some cases with the horizontal segregation diseases, more than one mutation in CLCN1 gene is found. These factors complicate the diagnosis of TMC and BMC, further medical and genetic counseling of the family members even after the patient’s genotype is detected. The confirmed BMC case with pseudo dominant type of inheritance and limited clinical manifestation is discussed in the light of differential diagnosis of the two discussed diseases.

Juvenile-onset Becker type myotonia congenita

Introduction: Becker type myotonia congenita is a very rare (1:100,000) autosomal recessive disease which usually begins between the ages of 4 and 12years old and its characteristics are defined by small patients series. CLCN1 genetic alterations that occur are multiple and usually heterozygous. We present a juvenile-onset Becker myotonia series.

Peter Becker and His Nazi Past

Peter Becker was a German neurologist who helped classify the muscular dystrophies, and described Becker muscular dystrophy and Becker myotonia. His involvement in National Socialism began in 1933, when he was compelled by his peers to join the SA (brown shirts). He later joined the Nazi party, the Nazi Doctors Association, and the Nazi Lecturers' Association. He renewed his SA membership to maintain his position at a genetics institute. Colleagues stated postwar that he was not an active Nazi, and he was de-Nazified in 1947, able to continue his career. Later, Becker admitted to most, but not all, of his Nazi memberships in his autobiography, and wrote 2 books exploring the origins of Nazism and racial hygiene. The "neurologic court of opinion" must weigh in on how we should best remember Becker, and at the very least, we as neurologists must learn the dangers of career opportunism at any cost.

Electrophysiological Properties of Novel Mutations in CLC-1 Chloride Channel of Korean Patients with Myotonia Congenita

Myotonia Congenita is a genetic disease that displays the symptom of muscle stiffness and impaired muscle relaxation caused by hyperexcitability of the plasma membrane. There are two types of Myotonia Congenita; Autosomal dominant Myotonia Congenital (Thomsen's disease) and autosomal recessive generalized Myotonia (Becker's myotonia) are caused by mutations in the skeletal muscle chloride channel, ClC-1.ClC-1, the member of a large family of anion channels, is voltage-gated chloride channel. It is abundantly expressed in human skeletal muscle. In skeletal muscle, the voltage-gated chloride channels contribute to stabilize the resting membrane potential and control electrical excitability. ClC-1 channels contain double-barreled structure which consists of two identical protopores. Each pore is voltage dependent and functions independently.When mutations in the gene for ClC-1 underlie Myotonia Congenita, it can affect normal function of the channel and damage the specialized property of independently working double pores. Since Mytonia Congenital was first diagnosed, a number of mutations widely displayed in the protein have been revealed so far. Here, nine mutants (p.M128I, p.S189C, p.M373L, p.P480S, p.G523D, p.M609K, p.T310M, p.R317X, p.R47W, A298T and p.G355R) from Korean patients who suffer from Myotonia Congenita were reported in 2009. We studied the functional changes of each mutant by using patch clamp method. We observed remarkably reduced chloride conductance from most of mutants. Mutants, p.M128I, and p.G523D showed steady-opened current pattern compared to WT. Furthermore, open probability of mutants was slightly or markedly altered and this clearly indicates the modification of pore property.

Mexiletine for Treatment of Myotonia

Mexiletine for Treatment of Myotonia

G.P.101 New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics

<h2>Abstract</h2> Most patients with myotonia have either congenital myotonia caused by mutated chloride or sodium channel, or progressive myotonic dystrophy (types 1 and 2). Currently, final diagnosis is frequently obtained by molecular genetic DNA testing. However, the increased use of genetic testing also results in many cases when the tests do not provide full clarification of the clinical disease. An immunohistochemical method using two different chloride channel protein specific antibodies for diagnostic purposes This method provided means to identify new mutations, to reclassify the W118G CLCN1 change as a moderately pathogenic mutation, and to clarify recessive Becker myotonia in cases when only one recessive mutation was identified by genetic testing. The developed immunohistochemical staining method for CLC-1 in muscle fibers proved to be a robust method for the detection of presence or loss of sarcolemmal CLC-1 protein on muscle sections. This in combination with gene sequencing is a powerful approach to achieving a final diagnosis of non-dystrophic myotonia.

The spectrum of CLCN1 gene mutations in patients with nondystrophic Thomsen’s and Becker’s myotonias

Thomsen's and Becker's diseases are the most prevalent nondystrophic myotonias. Their frequency varies, according to different sources, from 1 : 100 000 to 1 : 10 000. Thomsen's myotonia is autosomal dominant, and Becker's myotonia is autosomal recessive. Both diseases result from mutations of the CLCN1 gene encoding chloride ion channels of skeletal muscles. Molecular genetic analysis of the CLCN1 gene has been performed in patients with diagnoses of nondystrophic Thomsen's and Becker's myotonias living in the Russian Federation. A sample of 79 unrelated probands with nondystrophic Thomsen's and Becker's myotonias and 44 their relatives has been formed in the Laboratory of DNA Diagnosis of the Medical Genetic Research Center of the Russian Academy of Medical Sciences. Forty CLCN1 gene mutations have been found in a total of 118 chromosomes of 66 probands, including 21 familial and 45 sporadic cases. About half the mutations detected (45%) have been found for the first time; they are not described in the SNP database (ncbi.nlm.nih.gov). The following mutations (substitutions) have been detected in more than one chromosome, accounting for a total of 59.3% of chromosomes with mutations: Glyl90Ser (5.9%), c.1437-1450del14 (9.3%), Ala493Glu (5.1%), Thr550Met (3.4%), Tyr686Stop (5.1%), and Arg894Stop (30.5%).

Novel CLCN1 mutation in a young male with Becker Myotonia and unique clinical phenotype

Aims: In the late 50s, Becker (1957) discovered an autosomal recessive mode of inheritance in his myotonia congenita patients with a more severe phenotype than in autosomal dominant Thomson Myotonia and henceforth called it Myotonia congenita Becker. To date, approximately 130 different CLCN1 gene mutations have been identified and genotype-phenotype relationships have been vividly discussed.

Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype

We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia.

A Becker myotonia patient with compound heterozygosity for CLCN1 mutations and Prinzmetal angina pectoris

Becker myotonia is a recessive muscle disease with prevalence of >1:50,000. It is caused by markedly reduced function of the chloride channel encoded by CLCN1. We describe a Polish patient with severe myotonia, transient weakness, and muscle cramps who only responds to lidocaine. In addition, the patient has Prinzmetal angina pectoris and multiple lipomatosis. He is compound heterozygeous for a novel p.W303X and a frequent p.R894X CLCN1 mutation. CLCN1 exon number variation was excluded by MLPA. His son with latent myotonia was heterozygeous for p.R894X. We discuss the potential relations of the three rare diseases and the inheritance of p.R894X.

Becker Myotonia Congenita Associated WithWolff-Parkinson-WhiteSyndrome

Becker's disease is a congenital myotonia with an autosomal recessive pattern of inheritance. Unlike myotonic dystrophy, it is not associated with cardiopathy. We present a 32-year-old man with Becker's disease diagnosed at age 11. He suffered episodes of loss of consciousness preceded by palpitations when he performed strenuous physical exercise. The electrocardiogram reveals a Wolff-Parkinson-White syndrome. Review of the literature in MEDLINE using the search terms of congenital myotonia or Becker's disease and arrhythmia or heart disease only found 2 articles on Thomsen disease but none on Becker's disease. Becker's myotonia congenita may exceptionally be associated with cardiopathy, thus patients with this disorder should have a cardiac evaluation.

Moroccan consanguineous family with Becker myotonia and review

Myotonia congenita is a genetic muscle disorder characterized by clinical and electrical myotonia, muscle hypertrophy, and stiffness. It is inherited as either autosomal-dominant or –recessive, known as Thomsen and Becker diseases, respectively. These diseases are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe muscle stiffness and pain. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, have been found in both types. We report here the case of a Moroccan consanguineous family with a myotonic autosomal-recessive condition in two children. The molecular studies showed that the patients reported here are homozygous for mutation p.Gly482Arg in the CLCN1 gene. The parents were heterozygote carriers for mutation p.Gly482Arg. This diagnosis allowed us to provide an appropriate management to the patients and to make a genetic counselling to their family.

Erratum: Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia

Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.

Clinical and molecular diagnosis of a Costa Rican family with autosomal recessive myotonia congenita (Becker disease) carrying a new mutation in the CLCN1 gene

Myotonia congenita is a muscular disease characterized by myotonia, hypertrophy, and stiffness. It is inherited as either autosomal dominant or recessive known as Thomsen and Becker diseases, respectively. Here we confirm the clinical diagnosis of a family diagnosed with a myotonic condition many years ago and report a new mutation in the CLCN1 gene. The clinical diagnosis was established using ocular, cardiac, neurological and electrophysiological tests and the molecular diagnosis was done by PCR, SSCP and sequencing of the CLCN1 gene. The proband and the other affected individuals exhibited proximal and distal muscle weakness but no hypertrophy or muscular pain was found. The myotatic reflexes were lessened and sensibility was normal. Electrical and clinical myotonia was found only in the sufferers. Slit lamp and electrocardiogram tests were normal. Two affected probands presented diminution of the sensitive conduction velocities and prolonged sensory distal latencies. The clinical spectrum for this family is in agreement with a clinical diagnosis of Becker myotonia. This was confirmed by molecular diagnosis where a new disease-causing mutation (Q412P) was found in the family and absent in 200 unaffected chromosomes. No latent myotonia was found in this family; therefore the ability to cause this subclinical sign might be intrinsic to each mutation. Implications of the structure-function-genotype relationship for this and other mutations are discussed. Adequate clinical diagnosis of a neuromuscular disorder would allow focusing the molecular studies toward the confirmation of the initial diagnosis, leading to a proper clinical management, genetic counseling and improving in the quality of life of the patients and relatives.

Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype

Mutations in the CLCN1 gene, encoding a muscle-specific chloride channel, can cause either recessive or dominant myotonia congenita (MC). The recessive form, Becker's myotonia, is believed to be caused by two loss-of-function mutations, whereas the dominant form, Thomsen's myotonia, is assumed to be a consequence of a dominant-negative effect. However, a subset of CLCN1 mutations can cause both recessive and dominant MC. We have identified two recessive and two dominant MC families segregating the common R894X mutation. Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. Variation in allelic expression has not previously been described for CLCN1, and our finding suggests that allelic variation may be an important modifier of disease progression in myotonia congenita.

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia.

Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.

Inherited ion channel disorders.

The inherited ion channel disorders (channelopathies) are a group of disorders caused by mutations in genes encoding ion channels. Ion channel disorders can affect any tissue, but the majority affect skeletal muscle or the central nervous system. These disorders include skeletal muscle sodium channelopathies causing hyperkalaemic periodic paralysis, paramyotonia congenita and potassium-aggravated myotonia. Skeletal muscle calcium channelopathies can cause hypokalaemic periodic paralysis, malignant hyperthermia and central core disease. Skeletal muscle chloride channelopathies can cause Thomsen and Becker myotonia. A neuronal sodium channelopathy causes the generalised epilepsy febrile seizures plus syndrome. Neuronal potassium channelopathies can cause familial benign neonatal convulsions and episodic ataxia type 1. Finally, neuronal calcium channelopathies can cause episodic ataxia type 2, familial hemiplegic migraine and spinocerebellar ataxia type 6. The clinical features, aetiology and pathogenesis of inherited voltage-gated ion channel disorders affecting muscle and the central nervous system are reviewed here.