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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 -
Journal of Genetics Sep 2019Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the gene, encoding the main skeletal muscle ion chloride channel (ClC-1)....
Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the gene, encoding the main skeletal muscle ion chloride channel (ClC-1). The clinical diagnosis of MC should be suspected in patients presenting myotonia, warm-up phenomenon, a characteristic electromyographic pattern, and/or family history. Here, we describe the largest cohort of MC Spanish patients including their relatives (up to 102 individuals). Genetic testing was performed by sequencing and multiplex ligation-dependent probe amplification (MLPA). Analysis of selected exons of the gene, causing paramyotonia congenita, was also performed. Mutation spectrum and analysis of a likely founder effect of c.180+3A>T was achieved by haplotype analysis and association tests. Twenty-eight different pathogenic variants were found in the gene, of which 21 were known mutations and seven not described. Gross deletions/duplications were not detected. Four probands had a pathogenic variant in SCN4A. Two main haplotypes were detected in c.180+3A>T carriers and no statistically significant differences were detected between case and control groups regarding the type of haplotype and its frequencies. A diagnostic yield of 51% was achieved; of which 88% had pathogenic variants in and 12% in . The existence of a c.180+3A>T founder effect remains unsolved.
Topics: Chloride Channels; Cohort Studies; Exons; Female; Founder Effect; Haplotypes; Humans; Male; Muscle, Skeletal; Mutation; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Polymorphism, Single Nucleotide; Spain
PubMed: 31544778
DOI: No ID Found -
ELife Apr 2021In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain...
In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na and Ca currents contribute to plateau potentials. Na persistent inward current (NaPIC) through Na1.4 channels is the key trigger of plateau potentials and current through Ca1.1 Ca channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.
Topics: Animals; Disease Models, Animal; Female; Male; Membrane Potentials; Mice; Myotonia Congenita; Sodium
PubMed: 33904400
DOI: 10.7554/eLife.65691 -
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 -
Obstetric Medicine Dec 2020Paramyotonia congenita is a rare autosomal dominant non-dystrophic myopathy caused by mutations in the SNC4A gene, which encodes for the voltage-gated sodium channel in...
Paramyotonia congenita is a rare autosomal dominant non-dystrophic myopathy caused by mutations in the SNC4A gene, which encodes for the voltage-gated sodium channel in skeletal muscle. Symptom onset is typically during early childhood and is characterised by myotonia followed by flaccid paralysis or weakness, usually exacerbated by repeated muscle contractions or cold temperatures. Pregnancy has been reported to increase symptoms of myotonia; however, there is limited information in the literature regarding the possible effects of paramyotonia congenita on pregnancy and labour. We present a successful case of a 20-year-old primigravida with confirmed paramyotonia congenita and review the literature regarding paramyotonia congenita during pregnancy.
PubMed: 33343696
DOI: 10.1177/1753495X18816171 -
The Journal of Pediatrics May 2022
Topics: Child; Humans; Male; Myotonia Congenita
PubMed: 34953819
DOI: 10.1016/j.jpeds.2021.12.039 -
Frontiers in Neurology 2020Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia). It is caused by mutations in the gene,...
Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia). It is caused by mutations in the gene, encoding the voltage-gated chloride channel of skeletal muscle, ClC-1. According to the pattern of inheritance, two distinct clinical forms have been described, Thomsen disease, inherited as an autosomal dominant trait and Becker disease inherited as an autosomal recessive trait. We report genetic and clinical data concerning 19 patients-13 familial and six isolated cases-all but one originating from the Campania Region, in southern Italy. Twelve patients (63.2%) present Becker type myotonia and 7 (36.8%) Thomsen type. Sex ratio M:F in Becker type is 6:6, while in Thomsen myotonia 4:3. The age of onset of the disease ranged from 2 to 15 years in Becker patients, and from 4 to 20 years in Thomsen. Overall 18 mutations were identified, 10 located in the coding part of the gene (exons 1, 3, 4, 5, 7, 8, 13, 15, 21, 22), and four in the intron part (introns 1, 2, 10, 18). All the exon mutations but two were missense mutations. Some of them, such as > > and > recurred more frequently. About 70% of mutations was inherited with an autosomal recessive pattern, two (c.86A and >) with both mechanisms. Three novel mutations were identified, never described in the literature: p.Gly276Ser, p.Phe486Ser, and p.Gln812, associated with Becker phenotype. Furthermore, we identified three mutations-c.86A>C + c.2551G > A, c.313C > T + c.501C > G and 899G > A + c.2284+5C > T, two of them inherited on the same allele, in three unrelated families. The concomitant occurrence of both clinical pictures-Thomsen and Becker-was observed in one family. Intra-familial phenotypic variability was observed in two families, one with Becker phenotype, and one with Thomsen disease. In the latter an incomplete penetrance was hypothesized.
PubMed: 32117024
DOI: 10.3389/fneur.2020.00063 -
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 -
Neuromuscular Disorders : NMD Mar 2023We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population...
We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.
Topics: Humans; Paralysis, Hyperkalemic Periodic; Hypokalemic Periodic Paralysis; Prevalence; Channelopathies; High-Throughput Nucleotide Sequencing; NAV1.4 Voltage-Gated Sodium Channel; Mutation; Muscle, Skeletal; Myotonic Disorders; Andersen Syndrome
PubMed: 36796140
DOI: 10.1016/j.nmd.2023.01.007 -
International Journal of Molecular... Aug 2021The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. has been... (Review)
Review
The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. has been implicated in a novel congenital myopathy, and in distal arthrogryposis (DA), and and in nemaline myopathy (NEM). Variants in skeletal troponin encoding genes compromise sarcomere function, e.g., by altering the Ca sensitivity of force or by inducing atrophy. Several potential therapeutic strategies are available to counter the effects of variants, such as troponin activators, introduction of wild-type protein through AAV gene therapy, and myosin modulation to improve muscle contraction. The mechanisms underlying the pathophysiological effects of the variants in skeletal troponin encoding genes are incompletely understood. Furthermore, limited knowledge is available on the structure of skeletal troponin. This review focusses on the physiology of slow and fast skeletal troponin and the pathophysiology of reported variants in skeletal troponin encoding genes. A better understanding of the pathophysiological effects of these variants, together with enhanced knowledge regarding the structure of slow and fast skeletal troponin, will direct the development of treatment strategies.
Topics: Animals; Humans; Muscle Contraction; Myotonia Congenita; Sarcomeres; Troponin
PubMed: 34502093
DOI: 10.3390/ijms22179187