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Frontiers in Neurology 2020The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC... (Review)
Review
The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.
PubMed: 32117034
DOI: 10.3389/fneur.2020.00076 -
Medicine Jul 2022This study aimed to characterize the genetic, pathological, and clinical alterations of 17 patients in China presenting with nondystrophic myotonia (NDM) and to analyze...
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.
Topics: Chloride Channels; Humans; Mutation; Myotonia; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel
PubMed: 35866763
DOI: 10.1097/MD.0000000000029591 -
Neuromuscular Disorders : NMD Dec 2020In 1876, two articles appeared in Germany in different medical journals under almost the same title "Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von...
In 1876, two articles appeared in Germany in different medical journals under almost the same title "Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer Disposition (Ataxia muscularis?)" by Julius Thomsen and "Tonische Krämpfe in willkürlich beweglichen Muskeln (Muskelhypertrophie?)" by Adolph Seeligmüller). The first article was by Julius Thomsen (1815-1896) from Kappeln, the second by Adolph Seeligmüller (1837-1912) from Halle (Saale). Both articles dealt with a disease that has later been referred to as myotonia congenita by Adolf Strümpell (1853-1925) in 1881. Carl Westphal (1833-1890), however, ignored the contribution of Seeligmüller and proposed to name the disease Thomsen'sche Krankheit (Thomsen disease). Despite, the temporal priority of Thomsen, the pathogenesis of the disease was more accurately described by Seeligmüller. He recognized the origin of the myotonia in voluntary muscle whereas Thomsen postulated the myotonia as a result of inherited psychological disposition. Thus, Seeligmüller's contribution to myotonia congenita has to be recognized and honored.
Topics: Germany; History, 19th Century; Myotonia Congenita
PubMed: 33221127
DOI: 10.1016/j.nmd.2020.10.004 -
Muscle & Nerve Jun 2024Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant...
INTRODUCTION/AIMS
Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage-gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease-causing variants in the CLCN1 gene have been reported. This study provides an MC genotype-phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G.
METHODS
Sanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines.
RESULTS
Sixty-one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in-cis with the c.1649C > G.
DISCUSSION
The large number of patients in whom a diagnosis was established allowed the characterization of genotype-phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.
PubMed: 38855810
DOI: 10.1002/mus.28180 -
Frontiers in Neurology 2022Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic...
INTRODUCTION
Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.
METHODS
We reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.
RESULTS
Cases 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 variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.
CONCLUSIONS
MC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.
PubMed: 35350395
DOI: 10.3389/fneur.2022.830707 -
Pflugers Archiv : European Journal of... Jul 2020In 1970, the study of the pathomechanisms underlying myotonia in muscle fibers isolated from myotonic goats highlighted the importance of chloride conductance for... (Review)
Review
In 1970, the study of the pathomechanisms underlying myotonia in muscle fibers isolated from myotonic goats highlighted the importance of chloride conductance for skeletal muscle function; 20 years later, the human ClC-1 chloride channel has been cloned; last year, the crystal structure of human protein has been solved. Over the years, the efforts of many researchers led to significant advances in acknowledging the role of ClC-1 in skeletal muscle physiology and the mechanisms through which ClC-1 dysfunctions lead to impaired muscle function. The wide spectrum of pathophysiological conditions associated with modification of ClC-1 activity, either as the primary cause, such as in myotonia congenita, or as a secondary adaptive mechanism in other neuromuscular diseases, supports the idea that ClC-1 is relevant to preserve not only for skeletal muscle excitability, but also for skeletal muscle adaptation to physiological or harmful events. Improving this understanding could open promising avenues toward the development of selective and safe drugs targeting ClC-1, with the aim to restore normal muscle function. This review summarizes the most relevant research on ClC-1 channel physiology, associated diseases, and pharmacology.
Topics: Animals; Chloride Channels; Chlorides; Humans; Muscle, Skeletal; Myotonia Congenita
PubMed: 32361781
DOI: 10.1007/s00424-020-02376-3 -
The Turkish Journal of Pediatrics 2020Congenital Myotonia (CM) is a disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1). Mutations can be transmitted as autosomal dominant... (Review)
Review
BACKGROUND AND OBJECTIVES
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.
METHOD
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.
RESULTS
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.
CONCLUSION
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.
Topics: Chloride Channels; Female; Humans; Male; Mutation; Mutation, Missense; Myotonia Congenita; Pedigree; Retrospective Studies
PubMed: 32558419
DOI: 10.24953/turkjped.2020.03.012 -
Journal of Electromyography and... Dec 2019Myotonia congenita (MC) is caused by pathogenic variants in the CLCN1 gene coding the chloride channel protein.
INTRODUCTION
Myotonia congenita (MC) is caused by pathogenic variants in the CLCN1 gene coding the chloride channel protein.
METHODS
To test the hypothesis that needle EMG could be helpful in distinguishing between the recessive and dominant MC, we performed EMG examination in 36 patients (23 men) aged 4-61 years with genetically proven MC: in 30 patients with autosomal recessive MC (Becker MC) and in 6 with autosomal dominant MC (Thomsen MC).
RESULTS
Myotonic discharges were recorded in 95.8% of examined muscles. For the whole MC group we observed a significant positive correlation between parameters of motor unit activity potentials (MUAPs) in vastus lateralis and tibialis anterior muscles and the duration of the disease. Similar correlation for biceps brachii also was found in Becker MC subgroup only.
DISCUSSION
EMG could still be helpful in diagnosis of MC and together with provocative tests might be useful in differentiation between recessive and autosomal MC.
Topics: Adolescent; Adult; Child; Child, Preschool; Diagnosis, Differential; Electromyography; Evoked Potentials, Motor; Female; Genes, Dominant; Genes, Recessive; Humans; Male; Middle Aged; Muscle, Skeletal; Mutation; Myotonia Congenita
PubMed: 31610484
DOI: 10.1016/j.jelekin.2019.102362 -
Biomedicines Sep 2023Myotonia congenita is a hereditary muscle disease mainly characterized by muscle hyperexcitability, which leads to a sustained burst of discharges that correlates with... (Review)
Review
Myotonia congenita is a hereditary muscle disease mainly characterized by muscle hyperexcitability, which leads to a sustained burst of discharges that correlates with the magnitude and duration of involuntary aftercontractions, muscle stiffness, and hypertrophy. Mutations in the chloride voltage-gated channel 1 () gene that encodes the skeletal muscle chloride channel (ClC-1) are responsible for this disease, which is commonly known as myotonic chloride channelopathy. The biophysical properties of the mutated channel have been explored and analyzed through in vitro approaches, providing important clues to the general function/dysfunction of the wild-type and mutated channels. After an exhaustive search for mutations, we report in this review more than 350 different mutations identified in the literature. We start discussing the physiological role of the ClC-1 channel in skeletal muscle functioning. Then, using the reported functional effects of the naturally occurring mutations, we describe the biophysical and structural characteristics of the ClC-1 channel to update the knowledge of the function of each of the ClC-1 helices, and finally, we attempt to point out some patterns regarding the effects of mutations in the different helices and loops of the protein.
PubMed: 37892996
DOI: 10.3390/biomedicines11102622 -
Frontiers in Neurology 2020Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC),...
Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM ( < 0.01) and in Hyper/NormoPP than in HypoPP2 ( = 0.02). Cold-induced myotonia was more frequently observed in PMC ( = 34) than in SCM ( = 23) ( = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP ( = 4), SCM ( = 5), and PMC ( = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC ( < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.
PubMed: 32849172
DOI: 10.3389/fneur.2020.00646