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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 -
Neurotherapeutics : the Journal of the... Apr 2007Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some... (Review)
Review
Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed. Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.
Topics: Genotype; Humans; Muscle Proteins; Muscle, Skeletal; Mutation; NAV1.4 Voltage-Gated Sodium Channel; Paralysis, Hyperkalemic Periodic; Phenotype; Sodium Channels
PubMed: 17395131
DOI: 10.1016/j.nurt.2007.02.001 -
Annals of Neurology Sep 2017Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes...
OBJECTIVE
Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC-1 current.
METHODS
In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.
RESULTS
Intracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin-sensitive and voltage-dependent Na persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.
INTERPRETATION
This work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na current. Ann Neurol 2017;82:385-395.
Topics: Action Potentials; Animals; Disease Models, Animal; Mice; Muscle Contraction; Muscle, Skeletal; Myotonia Congenita; Sodium Channels
PubMed: 28833464
DOI: 10.1002/ana.25017 -
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 -
Journal of Korean Medical Science Dec 2009Myotonia congenita (MC) is a form of nondystrophic myotonia caused by a mutation of CLCN1, which encodes human skeletal muscle chloride channel (CLC-1). We performed...
Myotonia congenita (MC) is a form of nondystrophic myotonia caused by a mutation of CLCN1, which encodes human skeletal muscle chloride channel (CLC-1). We performed sequence analysis of all coding regions of CLCN1 in patients clinically diagnosed with MC, and identified 10 unrelated Korean patients harboring mutations. Detailed clinical analysis was performed in these patients to identify their clinical characteristics in relation to their genotypes. The CLCN1 mutational analyses revealed nine different point mutations. Of these, six (p.M128I, p.S189C, p.M373L, p.P480S, p.G523D, and p.M609K) were novel and could be unique among Koreans. While some features including predominant lower extremity involvement and normal to slightly elevated creatine kinase levels were consistently observed, general clinical features were highly variable in terms of age of onset, clinical severity, aggravating factors, and response to treatment. Our study is the first systematic study of MC in Korea, and shows its expanding clinical and genetic spectrums.
Topics: Adult; Amino Acid Sequence; Asian People; Base Sequence; Child, Preschool; Chloride Channels; DNA Mutational Analysis; Exons; Humans; Infant; Korea; Male; Molecular Sequence Data; Myotonia Congenita; Point Mutation; Protein Conformation; Young Adult
PubMed: 19949657
DOI: 10.3346/jkms.2009.24.6.1038 -
Scientific Reports Sep 2023Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum....
Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca, ATP, Mg and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca], resulting in Ca-insensitive, constitutively high P channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca], compared to wt. TM channels retained normal Mg block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis.
Topics: Animals; Mice; Ryanodine Receptor Calcium Release Channel; Dantrolene; Muscular Diseases; Cytoplasm; Myotonia Congenita; Adenosine Triphosphate
PubMed: 37670077
DOI: 10.1038/s41598-023-41801-2 -
Molecular Genetics & Genomic Medicine Feb 2021Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the...
Functional analysis of the F337C mutation in the CLCN1 gene associated with dominant myotonia congenita reveals an alteration of the macroscopic conductance and voltage dependence.
BACKGROUND
Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel have been reported and we here illustrate a novel one.
METHODS
A patient presenting the symptoms of myotonia congenita was shown to bear a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010 T > G, p.(Phe337Cys)). Confocal imaging and patch clamp recordings of transiently transfected HEK293 cells were used to functionally analyze the effect of this variant on channel properties.
RESULTS
Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. However, in patch clamp, we observed a smaller conductance for F337C at -80 mV. We also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage dependence.
CONCLUSION
To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC-1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.
Topics: Action Potentials; Cell Membrane; Chloride Channels; HEK293 Cells; Humans; Ion Channel Gating; Mutation, Missense; Myotonia Congenita; Protein Transport
PubMed: 33507632
DOI: 10.1002/mgg3.1588 -
Physiological Reviews Oct 1999By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become... (Review)
Review
By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular. Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease. A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify. It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies. Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized. Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes.
Topics: Animals; Calcium Channels; Genetic Diseases, Inborn; Humans; Ion Channels; Kidney; Muscle, Skeletal; Neurons
PubMed: 10508236
DOI: 10.1152/physrev.1999.79.4.1317 -
Acta Myologica : Myopathies and... Dec 2008This article is dedicated to our teacher, Prof. Erich Kuhn, Heidelberg, on the occasion of his 88th birthday on 23rd November 2008. In contrast to muscular dystrophies,... (Review)
Review
This article is dedicated to our teacher, Prof. Erich Kuhn, Heidelberg, on the occasion of his 88th birthday on 23rd November 2008. In contrast to muscular dystrophies, the muscle channelopathies, a group of diseases characterised by impaired muscle excitation or excitation-contraction coupling, can fairly well be treated with a whole series of pharmacological drugs. However, for a proper treatment proper diagnostics are essential. This article lists state-of-the-art diagnostics and therapies for the two types of myotonic dystrophies, for recessive and dominant myotonia congenita, for the sodium channel myotonias, for the primary dyskalemic periodic paralyses, for central core disease and for malignant hyperthermia susceptibility in detail. In addition, for each disorder a short summary of aetiology, symptomatology, and pathogenesis is provided.
Topics: Chloride Channels; Humans; Malignant Hyperthermia; Myopathy, Central Core; Myotonia; Myotonic Dystrophy; Paralysis, Hyperkalemic Periodic; Sodium Channels
PubMed: 19472919
DOI: No ID Found