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PloS One 2020Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride...
Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Nav1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.
Topics: Adolescent; Adult; Aged; Amino Acid Sequence; China; Chloride Channels; Consanguinity; Conserved Sequence; Diagnosis, Differential; Female; HEK293 Cells; Humans; Hypokalemic Periodic Paralysis; Male; Middle Aged; Models, Molecular; Mutant Proteins; Mutation; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Recombinant Proteins; Exome Sequencing; Young Adult
PubMed: 32407401
DOI: 10.1371/journal.pone.0233017 -
Physiological Reviews Apr 2002Cl- channels reside both in the plasma membrane and in intracellular organelles. Their functions range from ion homeostasis to cell volume regulation, transepithelial... (Review)
Review
Cl- channels reside both in the plasma membrane and in intracellular organelles. Their functions range from ion homeostasis to cell volume regulation, transepithelial transport, and regulation of electrical excitability. Their physiological roles are impressively illustrated by various inherited diseases and knock-out mouse models. Thus the loss of distinct Cl- channels leads to an impairment of transepithelial transport in cystic fibrosis and Bartter's syndrome, to increased muscle excitability in myotonia congenita, to reduced endosomal acidification and impaired endocytosis in Dent's disease, and to impaired extracellular acidification by osteoclasts and osteopetrosis. The disruption of several Cl- channels in mice results in blindness. Several classes of Cl- channels have not yet been identified at the molecular level. Three molecularly distinct Cl- channel families (CLC, CFTR, and ligand-gated GABA and glycine receptors) are well established. Mutagenesis and functional studies have yielded considerable insights into their structure and function. Recently, the detailed structure of bacterial CLC proteins was determined by X-ray analysis of three-dimensional crystals. Nonetheless, they are less well understood than cation channels and show remarkably different biophysical and structural properties. Other gene families (CLIC or CLCA) were also reported to encode Cl- channels but are less well characterized. This review focuses on molecularly identified Cl- channels and their physiological roles.
Topics: Animals; Chloride Channels; Humans; Protein Structure, Tertiary; Receptors, GABA; Receptors, Glycine
PubMed: 11917096
DOI: 10.1152/physrev.00029.2001 -
Kidney International Mar 2000The muscle Cl- channel, ClC-1, is a member of the ClC family of voltage-gated Cl- channels. Mutations in CLCN1, the gene encoding this channel, cause two forms of... (Review)
Review
The muscle Cl- channel, ClC-1, is a member of the ClC family of voltage-gated Cl- channels. Mutations in CLCN1, the gene encoding this channel, cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). The functional characterization of these naturally occurring mutations not only allowed a better understanding of the pathophysiology of myotonia, it also provided important insights into the structure and function of the entire ClC channel family. This review describes recent experiments using a combination of cellular electrophysiology, molecular genetics, and recombinant DNA technology to study the molecular basis of ion permeation and selection in ClC-type chloride channels.
Topics: Amino Acid Sequence; Animals; Anions; Chloride Channels; Humans; Ions; Models, Biological; Mutation
PubMed: 10720929
DOI: 10.1046/j.1523-1755.2000.00915.x -
Journal of Neurology May 2021Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in...
INTRODUCTION
Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort.
METHODS
We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy.
RESULTS
70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient's perceived efficacy were mexiletine and lamotrigine.
CONCLUSION
This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.
Topics: Adult; Chloride Channels; Female; Humans; Male; Mutation; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Retrospective Studies
PubMed: 33263785
DOI: 10.1007/s00415-020-10328-1 -
Frontiers in Neurology 2020Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on...
Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on genotype-phenotype correlations are limited. In this study, clinical features and treatment patterns in genetically characterized myotonic disorders were compared. A retrospective chart review was completed in patients with genetic variants in , and to document clinical signs and symptoms, clinical testing, and antimyotonia medication use. A total of 142 patients (27 , 15 , 89 , and 11 ) were reviewed. The frequency of reported symptoms (stiffness, weakness, and pain) and electromyographic spontaneous activity were remarkably similar across genotypes. Most patients were not treated with antimyotonia agents, but those with non-dystrophic disorders were more likely to be on a treatment. Among the features reviewed, we did not identify clinical or electrophysiological differences to distinguish - and -related myotonia. Weakness and pain were more prevalent in non-dystrophic disorders than previously identified. In addition, our results suggest that medical treatments in myotonic disorders may be under-utilized.
PubMed: 32670189
DOI: 10.3389/fneur.2020.00593 -
Neuromuscular Disorders : NMD Nov 2021The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated.
Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Mexiletine; Middle Aged; Myotonia; Myotonia Congenita; Myotonic Disorders; Quality of Life; Treatment Outcome
PubMed: 34702654
DOI: 10.1016/j.nmd.2021.06.010 -
Brain and Behavior Jan 2021To investigate the point prevalence of hereditary neuromuscular disorders on January 1, 2020 in Northern Norway.
AIM
To investigate the point prevalence of hereditary neuromuscular disorders on January 1, 2020 in Northern Norway.
METHODS
From January 1, 1999, until January 1, 2020, we screened medical and genetic hospital records in Northern Norway for hereditary neuromuscular disorders.
RESULTS
We identified 542 patients with a hereditary neuromuscular disorder living in Northern Norway, giving a point prevalence of 111.9/100,000 on January 1, 2020. The prevalence of children (<18 years old) and adults (≥18 years old) were 57.8/100,000 and 125.1/100,000, respectively. Inherited neuropathies had a prevalence of 38.8/100,000. Charcot-Marie-Tooth and hereditary neuropathy with liability to pressure palsies had a prevalence of 29.9/100,000 and 8.3/100,000, respectively. We calculated a prevalence of 3.7/100,000 for spinal muscular atrophies and 2.4/100,000 for Kennedy disease. Inherited myopathies were found in 67.7/100,000. Among these, we registered 13.4/100,000 myotonic dystrophy type 1, 6.8/100,000 myotonic dystrophy type 2, 7.3/100,000 Duchenne muscular dystrophy, 1.6/100,000 Becker muscular dystrophy, 3.7/100,000 facioscapulohumeral muscular dystrophy, 12.8/100,000 limb-girdle muscular dystrophy, 2.5/100,000 hypokalemic periodic paralysis and 11.4/100,000 myotonia congenita.
CONCLUSION
Our total prevalence was higher than previously hypothesized in European population-based studies. The prevalence was especially high for myotonia congenita and limb-girdle muscular dystrophy. The prevalence of Charcot-Marie-Tooth polyneuropathy was higher than in most European studies, but lower than previously reported in epidemiological studies in other regions of Norway.
Topics: Adolescent; Adult; Charcot-Marie-Tooth Disease; Child; Humans; Muscular Dystrophy, Duchenne; Neuromuscular Diseases; Norway; Prevalence
PubMed: 33185984
DOI: 10.1002/brb3.1948 -
Genes Nov 2021Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to...
Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible -related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.
Topics: Animals; Cattle; Cattle Diseases; Channelopathies; Inbreeding; Mutation; Myotonia Congenita; Phenotype; Potassium Channels, Voltage-Gated
PubMed: 34828398
DOI: 10.3390/genes12111792 -
Frontiers in Neurology 2020The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The...
The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The study was performed at the Neurophysiologic Division of Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome and the Children's Hospital Bambino Gesù, Rome. The treatment was accepted by 59 patients according to clinical severity, individual needs, and concerns about a chronic medication. Forty-three patients were affected by recessive congenita myotonia, 11 by sodium channel myotonia, and five by dominant congenital myotonia. They underwent clinical examination before and after starting therapy, and Electromyography (EMG). A number of recessive myotonia patients underwent a protocol of repetitive nerve stimulations, for detecting and quantifying the transitory weakness, and a modified version of the Timed Up and Go test, to document and quantify the gait impairment. Treatment duration ranged from 1 month to 20 years and the daily dosages in adults ranged between 200 and 600 mg. No patient developed cardiac arrhythmias causing drug discontinuation. Mexiletine was suspended in 13 cases (22%); in three patients, affected by Sodium Channel myotonia, because flecainide showed better efficacy; in one patient because of a gastric cancer antecedent treatment; in four patients because of untreatable dyspepsia; and five patients considered the treatment not necessary. In our experience, mexiletine is very useful and not expensive. We did not observe any hazarding cardiac arrhythmias. Dyspepsia was the most frequent dose-limiting side effect.
PubMed: 32655465
DOI: 10.3389/fneur.2020.00300 -
Neurology India 2019
Topics: Adolescent; Humans; Male; Myotonia; Myotonia Congenita; Osteochondrodysplasias; Pedigree
PubMed: 31512670
DOI: 10.4103/0028-3886.266261