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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 -
The Journal of Physiology Sep 2015Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the...
KEY POINTS
Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.
ABSTRACT
Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC-1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.
Topics: Adult; Aged; Child; Chloride Channels; Female; Genetic Association Studies; Heterozygote; Humans; Ion Channel Gating; Male; Middle Aged; Muscle, Skeletal; Mutation; Myotonia Congenita; Young Adult
PubMed: 26096614
DOI: 10.1113/JP270358 -
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 -
Frontiers in Neurology 2022Myotonia congenita is a rare neuromuscular disorder caused by mutations resulting in delayed muscle relaxation. Extramuscular manifestations are not considered to be...
Myotonia congenita is a rare neuromuscular disorder caused by mutations resulting in delayed muscle relaxation. Extramuscular manifestations are not considered to be present in chloride skeletal channelopathies, although recently some cardiac manifestations have been described. We report a family with autosomal dominant myotonia congenita and Brugada syndrome. Bearing in mind the previously reported cases of cardiac arrhythmias in myotonia congenita patients, we discuss the possible involvement of the CLCN1-gene mutations in primary cardiac arrhythmia.
PubMed: 36212636
DOI: 10.3389/fneur.2022.1011956 -
Pediatric Neurology May 2017The nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic...
BACKGROUND
The nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic myotonia and periodic paralysis.
METHODS
We identified patients with a diagnosis of muscle channelopathy from our neuromuscular database in a tertiary care pediatric center from 2005 to 2015. We then performed a retrospective review of their medical records for demographic characteristics, clinical features, investigations, treatment, and follow-up.
RESULTS
Thirty-three patients were identified. Seventeen had nondystrophic myotonia. Seven of them had chloride channelopathy (four Becker disease and three Thomsen disease). Warm-up phenomenon and muscle hypertrophy were common clinical manifestations in this subgroup. Ten patients had sodium channelopathy (four paramyotonia congenita and six other sodium channel myotonia). Stiffness of the facial muscles was an important presenting symptom, and eyelid myotonia was a common clinical finding in this subgroup. The majority of these patients had electrical myotonia. Mexiletine was effective in controlling the symptoms in patients who had received treatment. Sixteen children had periodic paralysis (four hyperkalemic periodic paralysis, eight hypokalemic periodic paralysis, and four Andersen-Tawil syndrome). Acetazolamide was commonly used to prevent paralytic attacks and was found to be effective.
CONCLUSIONS
Nondystrophic muscle channelopathies present with diverse clinical manifestations (myotonia, muscle hypertrophy, proximal weakness, swallowing difficulties, and periodic paralysis). Cardiac arrhythmias are potentially life threatening in Andersen-Tawil syndrome. Timely identification of these disorders is helpful for effective symptomatic management and genetic counseling.
Topics: Andersen Syndrome; Channelopathies; Child; Child, Preschool; Electromyography; Female; Humans; Infant; Longitudinal Studies; Male; Muscle, Skeletal; Mutation; NAV1.4 Voltage-Gated Sodium Channel; Neuromuscular Diseases; Paralysis, Hyperkalemic Periodic; Retrospective Studies
PubMed: 28325641
DOI: 10.1016/j.pediatrneurol.2017.02.006 -
PLoS Biology Apr 2019ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is...
ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia congenita, a disease impairing muscle relaxation. Here, we present the cryo-electron microscopy (cryo-EM) structure of human ClC-1, uncovering an architecture reminiscent of that of bovine ClC-K and CLC transporters. The chloride conducting pathway exhibits distinct features, including a central glutamate residue ("fast gate") known to confer voltage-dependence (a mechanistic feature not present in ClC-K), linked to a somewhat rearranged central tyrosine and a narrower aperture of the pore toward the extracellular vestibule. These characteristics agree with the lower chloride flux of ClC-1 compared with ClC-K and enable us to propose a model for chloride passage in voltage-dependent CLC channels. Comparison of structures derived from protein studied in different experimental conditions supports the notion that pH and adenine nucleotides regulate ClC-1 through interactions between the so-called cystathionine-β-synthase (CBS) domains and the intracellular vestibule ("slow gating"). The structure also provides a framework for analysis of mutations causing myotonia congenita and reveals a striking correlation between mutated residues and the phenotypic effect on voltage gating, opening avenues for rational design of therapies against ClC-1-related diseases.
Topics: Amino Acid Sequence; Cell Membrane; Chloride Channels; Cryoelectron Microscopy; Humans; Ion Channel Gating; Kinetics; Membrane Potentials; Models, Molecular
PubMed: 31022181
DOI: 10.1371/journal.pbio.3000218 -
Frontiers in Pharmacology 2021The voltage-gated sodium channel Na1.4 is a major actor in the excitability of skeletal myofibers, driving the muscle force in response to nerve stimulation. Supporting... (Review)
Review
The voltage-gated sodium channel Na1.4 is a major actor in the excitability of skeletal myofibers, driving the muscle force in response to nerve stimulation. Supporting further this key role, mutations in , the gene encoding the pore-forming α subunit of Na1.4, are responsible for a clinical spectrum of human diseases ranging from muscle stiffness (sodium channel myotonia, SCM) to muscle weakness. For years, only dominantly-inherited diseases resulting from Na1.4 gain of function (GoF) were known, , non-dystrophic myotonia (delayed muscle relaxation due to myofiber hyperexcitability), and hyperkalemic or hypokalemic periodic paralyses (episodic flaccid muscle weakness due to transient myofiber hypoexcitability). These last 5 years, mutations inducing Na1.4 loss of function (LoF) were identified as the cause of dominantly and recessively-inherited disorders with muscle weakness: periodic paralyses with hypokalemic attacks, congenital myasthenic syndromes and congenital myopathies. We propose to name this clinical spectrum sodium channel weakness (SCW) as the mirror of SCM. Na1.4 LoF as a cause of permanent muscle weakness was quite unexpected as the Na current density in the sarcolemma is large, securing the ability to generate and propagate muscle action potentials. The properties of LoF mutations are well documented at the channel level in cellular electrophysiological studies However, much less is known about the functional consequences of Na1.4 LoF in skeletal myofibers with no available pertinent cell or animal models. Regarding the therapeutic issues for Na1.4 channelopathies, former efforts were aimed at developing subtype-selective Na channel antagonists to block myofiber hyperexcitability. Non-selective, Na channel blockers are clinically efficient in SCM and , whereas patient education and carbonic anhydrase inhibitors are helpful to prevent attacks in periodic paralyses. Developing therapeutic tools able to counteract Na1.4 LoF in skeletal muscles is then a new challenge in the field of Na channelopathies. Here, we review the current knowledge regarding Na1.4 LoF and discuss the possible therapeutic strategies to be developed in order to improve muscle force in SCW.
PubMed: 34671263
DOI: 10.3389/fphar.2021.751095 -
Frontiers in Pharmacology 2017The discovery of ClC proteins at the beginning of the 1990s was important for the development of the Cl transport research field. ClCs form a large family of proteins... (Review)
Review
The discovery of ClC proteins at the beginning of the 1990s was important for the development of the Cl transport research field. ClCs form a large family of proteins that mediate voltage-dependent transport of Cl ions across cell membranes. They are expressed in both plasma and intracellular membranes of cells from almost all living organisms. ClC proteins form transmembrane dimers, in which each monomer displays independent ion conductance. Eukaryotic members also possess a large cytoplasmic domain containing two CBS domains, which are involved in transport modulation. ClC proteins function as either Cl channels or Cl/H exchangers, although all ClC proteins share the same basic architecture. ClC channels have two gating mechanisms: a relatively well-studied fast gating mechanism, and a slow gating mechanism, which is poorly defined. ClCs are involved in a wide range of physiological processes, including regulation of resting membrane potential in skeletal muscle, facilitation of transepithelial Cl reabsorption in kidneys, and control of pH and Cl concentration in intracellular compartments through coupled Cl/H exchange mechanisms. Several inherited diseases result from C1C gene mutations, including myotonia congenita, Bartter's syndrome (types 3 and 4), Dent's disease, osteopetrosis, retinal degeneration, and lysosomal storage diseases. This review summarizes general features, known or suspected, of ClC structure, gating and physiological functions. We also discuss biophysical properties of mammalian ClCs that are directly involved in the pathophysiology of several human inherited disorders, or that induce interesting phenotypes in animal models.
PubMed: 28386229
DOI: 10.3389/fphar.2017.00151 -
Channels (Austin, Tex.) 2015Myotonia congenita belongs to the group of non-dystrophic myotonia caused by mutations of CLCN1gene, which encodes human skeletal muscle chloride channel 1. It can be...
Myotonia congenita belongs to the group of non-dystrophic myotonia caused by mutations of CLCN1gene, which encodes human skeletal muscle chloride channel 1. It can be inherited either in autosomal dominant (Thomsen disease) or recessive (Becker disease) forms. Here we have sequenced all 23 exons and exon-intron boundaries of the CLCN1 gene, in a panel of 5 unrelated Chinese patients with myotonia congenita (2 with dominant and 3 with recessive form). In addition, detailed clinical analysis was performed in these patients to summarize their clinical characteristics in relation to their genotypes. Mutational analyses revealed 7 different point mutations. Of these, we have found 3 novel mutations including 2 missense (R47W, V229M), one splicing (IVS19+2T>C), and 4 known mutations (Y261C,G523D, M560T, G859D). Our data expand the spectrum of CLCN1 mutations and provide insights for genotype-phenotype correlations of myotonia congenita in the Chinese population.
Topics: Adolescent; Adult; Child; Child, Preschool; Chloride Channels; Female; Humans; Infant; Male; Mutation, Missense; Myotonia Congenita; Point Mutation; RNA Splicing
PubMed: 26260254
DOI: 10.1080/19336950.2015.1075676