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Brody disease (BD) is an "ultra-rare" human genetic disorder of skeletal muscle function due to defects in the atp2a1 gene causing deficiency of the SERCA protein, isoform1. The main clinical signs are exercise-induced stiffness and delayed muscular relaxation after physical exercises, even mild ones. No mouse model nor specific therapies exist for Brody myopathy, which is therefore considered an orphan disease. Bovine congenital pseudomyotonia (PMT) is a muscular disorder characterized by an impairment of muscle relaxation and is the only mammalian model of human BD. The pathogenetic mechanism underlying bovine PMT has been recently clarified. These findings prompted us to purpose a potential pharmacological approach addressing a specific population of BD patients who exhibit reduced expression but still exhibit activity of the SERCA1 pump. Preclinical research involving in vivo studies is essential and necessary before clinical trials can be pursued and SERCA protein shows a high degree of conservation among species. So far, the only animal models available to study BD in vivo are a group of zebrafish mutant lines known as accordion zebrafish (acc). In this paper, we focused on a comprehensive characterization of the "acctq206" zebrafish variant. Our aim was to use this mutant line as an experimental animal model for testing the novel therapeutic approach for BD.

It has long been accepted that myotonia (muscle stiffness) in patients with muscle channelopathies is due to myotonic discharges (involuntary firing of action potentials). In a previous study, we identified a novel phenomenon in myotonic muscle: development of plateau potentials, transient depolarizations to near -35 mV lasting for seconds to minutes. In the current study we examined whether plateau potentials contribute to myotonia. A recessive genetic model (ClC adr mice) with complete loss of muscle chloride channel (ClC-1) function was used to model severe myotonia congenita with complete loss of ClC-1 function and a pharmacologic model using anthracene-9-carboxylic acid (9 AC) was used to model milder myotonia congenita with incomplete loss of ClC-1 function. Simultaneous measurements of action potentials and myoplasmic Ca 2+ from individual muscle fibers were compared to recordings of whole muscle force generation. In ClC adr muscle both myotonia and plateau potentials lasted 10s of seconds to minutes. During plateau potentials lasting 1-2 min, there was a gradual transition from high to low intracellular Ca 2+ , suggesting a transition in individual fibers from myotonia to flaccid paralysis in severe myotonia congenita. In 9 AC-treated muscles, both myotonia and plateau potentials lasted only a few seconds and Ca 2+ remained elevated during the plateau potentials, suggesting plateau potentials contribute to myotonia without causing weakness. We propose, that in myotonic muscle, there is a novel state in which there is contraction in the absence of action potentials. This discovery provides a mechanism to explain reports of patients with myotonia who suffer from electrically silent muscle contraction lasting minutes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 ( RYR1 ) gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations., Competing Interests: AR, SB, UD, CB, MF, FN, LP, FP, ST, FZ No competing interests declared, (© 2022, Ruiz et al.)

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., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications., (© 2020 Wiley Periodicals, Inc.)

Patients with myotonia congenita suffer from muscle stiffness caused by muscle hyperexcitability. Although loss-of-function mutations in the ClC-1 muscle chloride channel have been known for 25 years to cause myotonia congenita, this discovery has led to little progress on development of therapy. Currently, treatment is primarily focused on reducing hyperexcitability by blocking Na + current. However, other approaches such as increasing K + currents might also be effective. For example, the K + channel activator retigabine, which opens KCNQ channels, is effective in treating epilepsy because it causes hyperpolarization of the resting membrane potential in neurons. In this study, we found that retigabine greatly reduced the duration of myotonia in vitro. Detailed study of its mechanism of action revealed that retigabine had no effect on any of the traditional measures of muscle excitability such as resting potential, input resistance or the properties of single action potentials. Instead it appears to shorten myotonia by activating K + current during trains of action potentials. Retigabine also greatly reduced the severity of myotonia in vivo, which was measured using a muscle force transducer. Despite its efficacy in vivo, retigabine did not improve motor performance of mice with myotonia congenita. There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p.Val851Met, p.Gly859Val, and p.Leu861Pro mutations reside in the CBS2 domain, while p.Pro883Thr and p.Val947Glu are in the C-terminal peptide. We showed that the functional properties of mutant channels correlated with the clinical phenotypes of affected individuals. In addition, we defined clusters of ClC-1 mutations within CBS2 and C-terminal peptide subdomains that share the same functional defect: mutations between 829 and 835 residues and in residue 883 induced an alteration of voltage dependence, mutations between 851 and 859 residues, and in residue 947 induced a reduction of chloride currents, whereas mutations on 861 residue showed no obvious change in ClC-1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the C-terminal region in ClC-1 function, and provides information to develop new antimyotonic drugs., (© 2018 Wiley Periodicals, Inc.)

Background: The central nervous system involvement, in terms of a maladaptive sensory-motor plasticity, is well known in patients with dystrophic myotonias (DMs). To date, there are no data suggesting a central nervous system involvement in non-dystrophic myotonias (NDMs)., Objective: To investigate sensory-motor plasticity in patients with Myotonia Congenita (MC) and Paramyotonia Congenita (PMC) with or without mexiletine., Methods: Twelve patients with a clinical, genetic, and electromyographic evidence of MC, fifteen with PMC, and 25 healthy controls (HC) were included in the study. TMS on both primary motor cortices (M1) and a rapid paired associative stimulation (rPAS) paradigm were carried out to assess M1 excitability and sensory-motor plasticity., Results: patients showed a higher cortical excitability and a deterioration of the topographic specificity of rPAS aftereffects, as compared to HCs. There was no correlation among neurophysiological and clinical-demographic characteristics. Noteworthy, the patients who were under mexiletine showed a minor impairment of the topographic specificity of rPAS aftereffects as compared to those who did not take the drug., Conclusion: our findings could suggest the deterioration of cortical sensory-motor plasticity in patients with NDMs as a trait of the disease.

Mexiletine is the only drug with proven effect for treatment of non-dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non-dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non-dystrophic myotonias. In this, randomized double-blind, placebo-controlled, two-period cross-over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8-week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013-003309-24). We included 26 patients (10 females, 16 males, age: 19-74 years) from 13 November 2013 to 6 July 2015. Twenty-two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5-1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2-1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient-related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment-naive patients with non-dystrophic myotonias., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life., Methods: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration., Results: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels., Discussion: Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.

Objective: To determine open-label, pilot study whether ranolazine could improve signs and symptoms of myotonia and muscle stiffness in patients with myotonia congenita (MC)., Methods: Thirteen participants were assessed at baseline and 2, 4, and 5 weeks. Ranolazine was started after baseline assessment (500 mg twice daily), increased as tolerated after week 2 (1,000 mg twice daily), and maintained until week 4. Outcomes included change from baseline to week 4 in self-reported severity of symptoms (stiffness, weakness, and pain), Timed Up and Go (TUG), hand grip and eyelid myotonia, and myotonia on EMG., Results: Self-reported severity of stiffness ( p < 0.0001) and weakness ( p < 0.01) was significantly improved compared with baseline. TUG and grip myotonia times were reduced ( p = 0.03, p = 0.01). EMG of the abductor digiti minimi and tibialis anterior showed significantly reduced myotonia duration ( p < 0.001, p < 0.01) at week 4. No participant discontinued ranolazine because of side effects., Conclusions: Ranolazine appeared to be well tolerated over a period of 4 weeks in individuals with MC, and ranolazine resulted in improvement of signs and symptoms of muscle stiffness. The findings of this study suggest that ranolazine should be investigated in a larger controlled study., Classification of Evidence: This study provides Class IV evidence that ranolazine improves myotonia in myotonia congenita., (© 2017 American Academy of Neurology.)

Objective: To investigate the cause of transient weakness in myotonia congenita (MC) and the mechanism of action of mexiletine in reducing weakness., Methods: The changes in neuromuscular excitability produced by 1min of maximal voluntary contractions (MVC) were measured on the amplitude of compound muscle action potentials (CMAP) in two patients with either recessive or dominant MC, compared to control values obtained in 20 healthy subjects. Measurements were performed again in MC patients after mexiletine therapy., Results: Transient reduction in maximal CMAP amplitude lasting several minutes after MVC was evident in MC patients, whereas no change was observed in controls. Mexiletine efficiently reduced this transient CMAP depression in both patients., Discussion: Transient CMAP depression following sustained MVC may represent the electrophysiological correlate of the weakness clinically experienced by the patients. In MC, the low chloride conductance could induce self-sustaining action potentials after MVC, determining progressive membrane depolarization and a loss of excitability of muscle fibers, thus resulting in transient paresis. Mexiletine may prevent conduction block due to excessive membrane depolarization, thus reducing the transient CMAP depression following sustained MVC., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objective: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype., Methods: Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp., Results: The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition., Conclusions: Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual., (© 2016 American Academy of Neurology.)

Sodium channel myotonias are inherited muscle diseases linked to mutations in the voltage-gated sodium channel. These diseases may also affect newborns with variable symptoms. More recently, severe neonatal episodic laryngospasm (SNEL) has been described in a small number of patients. A timely diagnosis of SNEL is crucial because a specific treatment is now available that will likely reduced laryngospasm and improve vital and cerebral outcomes. We report here on an 8-year-old girl who had presented, at birth, with SNEL who subsequently developed myotonia permanens starting at age 3 years. Results of molecular analysis revealed a de novo SCN4A G1306E mutation. The girl was treated with carbamazepine, acetazolamide, and mexiletine, with little improvement; after switching her treatment to flecainide, she experienced a dramatic reduction in muscle stiffness and myotonic symptoms as well as an improvement in behavior., (Copyright © 2016 by the American Academy of Pediatrics.)

Objective: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy., Methods: To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of myotonia congenita., Results: Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects., Interpretation: We conclude that ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita., (© 2014 American Neurological Association.)

Objective: We aim to demonstrate the effect of mexiletine on the compound muscle action potential (CMAP) amplitude transitory depression (TD) in a cohort of patients with recessive myotonia congenita., Methods: We evaluated 21 patients with recessive myotonia congenita referred to our institute from 1990 to 2013 and treated with mexiletine chlorhydrate. All patients underwent prolonged 3 Hz repetitive nerve stimulation (3 Hz-PLRS) before and after the beginning of treatment., Results: We observed in all subjects a reduction of CMAP amplitude TD after the beginning of treatment. The mean value of the TD nadir before starting mexiletine treatment was -62.0% and reduced to -28.8% after the therapy was started (51.6% reduction, p<0.001)., Conclusions: The 3 Hz-PLRS is configured as a neurophysiological test able to indirectly detect and quantify, through the measurement of TD, the clinical phenomenon of the transitory weakness that occurs in myotonic syndromes due to CLCN1 mutations., Significance: This neurophysiological test might be considered a helpful tool to assess the effect of anti-myotonic drugs, as mexiletine, in recessive myotonia congenita., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. Focal paresis has sometimes already been described. We report a case with atypical clinical manifestation comprising paramyotonia and cold-induced persistent and focal paralysis. A 27-year-old woman presented with paramyotonia congenita since her childhood. She experienced during her childhood one brief episode of generalised weakness. At the age of 27, she experienced a focal paresis lasting for several months. The known mutation p.Val1293Ile was found in the muscle sodium channel gene (SCN4A). Channel inactivation is involved in most Na(+) channelopathies. Fast inactivation is known to be responsible for the myotonia phenotype. We hypothesise that the V1293I mutation may also alter the slow inactivation in specific conditions, for example, prolonged cold exposure or prolonged and intensive exercise. This observation broadens the spectrum of clinical manifestations of this sodium channel mutation., (2014 BMJ Publishing Group Ltd.)

Introduction: Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected., Methods: MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls., Results: MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation., Conclusions: MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve., (Copyright © 2013 Wiley Periodicals, Inc.)

Although the sodium channel blocker mexiletine is considered the first-line drug in myotonia, some patients experiment adverse effects, while others do not gain any benefit. Other antimyotonic drugs are thus needed to offer mexiletine alternatives. In the present study, we used a previously-validated rat model of myotonia congenita to compare six marketed sodium channel blockers to mexiletine. Myotonia was induced in the rat by injection of anthracen-9-carboxylic acid, a muscle chloride channel blocker. The drugs were given orally and myotonia was evaluated by measuring the time of righting reflex. The drugs were also tested on sodium currents recorded in a cell line transfected with the human skeletal muscle sodium channel hNav1.4 using patch-clamp technique. In vivo, carbamazepine and propafenone showed antimyotonic activity at doses similar to mexiletine (ED50 close to 5mg/kg); flecainide and orphenadrine showed greater potency (ED50 near 1mg/kg); lubeluzole and riluzole were the more potent (ED50 near 0.1mg/kg). The antimyotonic activity of drugs in vivo was linearly correlated with their potency in blocking hNav1.4 channels in vitro. Deviation was observed for propafenone and carbamazepine, likely due to pharmacokinetics and multiple targets. The comparison of the antimyotonic dose calculated in rats with the current clinical dose in humans strongly suggests that all the tested drugs may be used safely for the treatment of human myotonia. Considering the limits of mexiletine tolerability and the occurrence of non-responders, this study proposes an arsenal of alternative drugs, which may prove useful to increase the quality of life of individuals suffering from non-dystrophic myotonia. Further clinical trials are warranted to confirm these results., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Botulinum toxin (BT) is a potent local muscle relaxant with analgetic properties. Myotonia congenita (MC) is a genetic disorder producing muscle rigidity and pain. BT injected into the trapezius produced mild paresis, but no effect on rigidity and pain. There were no signs of systemic effects. Lack of BT efficacy on MC rigidity confirms its origin from muscle membrane dysfunction rather than from inappropriate neuromuscular activation. Lack of BT efficacy on pain could be caused by lack of anti-rigidity effect. It could also be due to separate non-muscular pain mechanisms unresponsive to BT.

Myotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We report a 4-generation Turkish family with 10 affected members presenting with myotonia and potassium- and exercise-induced paralytic attacks. The clinical presentation was neither typical for the chloride channel myotonias Thomsen and Becker nor for the separate sodium channel myotonia entities potassium-aggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. It is best described by a combination of potassium-aggravated myotonia and hyperkalemic periodic paralysis. We excluded exonic chloride channel mutations including CLCN1 exon deletion/duplication by MLPA. Instead we identified a novel p.N440K sodium channel mutation that is located at the inner end of segment S6 of repeat I. We discuss the genotype phenotype relation.

A 28-year-old male had history of stiffness in limb muscles, with hypertrophy of most muscle groups and both action and percussion myotonia. We report a very interesting rare family of brothers and sister of myotonia congenita, conforming to autosomal recessive transmission (Becker's variety) with Herculean appearance.

Myotonia congenita is a nondystrophic muscle disorder characterized by muscle stiffness and muscle hypertrophy. The disorder can be inherited in an autosomal-dominant (Thomsen disease) or autosomal-recessive (Becker disease) manner. Both forms of myotonia congenita are attributable to mutations in the CLCN1 gene. Treatment with a variety of medications has led to long-term improvement in the clinical course of affected individuals. We describe a Honduran boy with myotonia congenita and a novel p.L287I mutation in the CLCN1 gene. The patient's unaffected father carries the same mutation, most likely reflecting autosomal-recessive myotonia congenita, with an inability to find a second mutation. The patient received carbamazepine treatment for 1 year, resulting in decreased muscle stiffness, increased strength, and improved quality of life in school and with peers., (Copyright 2010 Elsevier Inc. All rights reserved.)

In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to repetitive action potentials, stiffness, and delayed relaxation. This constellation of features, collectively known as myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (ClC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3' splice site of ClC-1 exon 7a reversed the defect of ClC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in ClC-1 mRNA, upregulated the level of ClC-1 mRNA, increased the expression of ClC-1 protein in the surface membrane, normalized muscle ClC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of ClC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM.

Myotonia congenita is a rare disease of skeletal muscle characterized by painless myotonia, generalized muscular hypertrophy and a non-progressive course. We report a 10-year-old girl with myotonia, "Herculean appearance" and electromyographic confirmation of myotonic discharges. There was a dramatic response to carbamazepine. The aim of this report is to make the readers aware of this entity which can be easily controlled with medication and also prevented by genetic counseling.

Introduction: The word myotonia was used for the first time by Strümpell in 1891. Diseases associated with this symptom are called myotonias. They are classified on the basis of their clinical features in: congenita myotonia, paramyotonia congenita, myotonic dystrophy and Schwartz-Jampel syndrome. Becker's myotonia is a generalized congenita nondystrophic myotonia transmitted as an autosomal recessive trait and caused by allelic mutation of the gene encoding the chloride channel CLC-1 of the skeletal muscle fiber surface membrane, localized on chromosome 7q35. At the present time, nondystrophic myotonias are referred as channelopathies., Clinical Case: We describe a case of generalized myotonia in a Peruvian young male, descending of Europeans, without familial history., Conclusions: We discuss his clinical symptoms, laboratory and electrophysiologic findings, differential diagnosis, and response to the treatment with carbamazepine. We report the first case of Becker's myotonia in Peru.

Tocainide is effective in the symptomatic treatment of myotonic syndromes for its ability to reduce the high frequency discharges of action potentials typical of the disease, by blocking voltage-gated sodium channels. However, its use is restricted by serious side effects. In spite of its chiral structure, tocainide is clinically used as a racemic mixture. Since the optical isomers may differ in their efficacy and toxicity, the present study was aimed at evaluating the antimyotonic activity of the pure R(-) and S(+) enantiomers of tocainide, on the abnormal membrane hyperexcitability of external intercostal muscle fibers of congenitally myotonic goats. The excitability parameters were recorded in vitro by means of the standard two-microelectrode current-clamp technique before and after the addition of the compounds. The R(-) enantiomer of tocainide at concentrations as low as 10 microM potently counteracted the abnormal excitability of myotonic fibers, by increasing the threshold current, and decreasing the latency of the action potential and firing capability. Also, this concentration of R-(-) tocainide almost completely abolished the abnormal spontaneous electrical activity occurring in about 70-80% of the myotonic fiber. The S(+) enantiomer was remarkably less potent since up to 100 microM did not restore the normal excitability pattern. The results show that most of the antimyotonic activity of tocainide resides in the R(-) enantiomer suggesting that its clinical use may allow a significant reduction of the doses and possibly of the side effects.

Purpose: To describe two cases of competitive hockey players whose performance was impaired by generalized painless muscle stiffness. They were each found to have a separate type of myotonia., Case Summary: The first hockey player experienced stiffness only when initiating activity after a period of inactivity. He had a family history of muscle stiffness, grip myotonia clinically, and electrophysiologic findings of myotonic discharges. He had myotonia congenita. The stiffness in the second case was episodic and occurred during bouts of intense physical activity. The legs, arms, and neck were affected. Myotonia fluctuans was the probable diagnosis. Both cases responded well to Mexiletine., Discussion: The etiology, classification, and clinical presentation of myotonia are discussed., Relevance: Because of the musculoskeletal nature of our practice, sport medicine clinicians should be aware of myotonic disorders so they can be recognized and appropriately treated.

Myotonia is the phenomenon of decrease of muscular relaxation rate, after either a contraction or a mechanical or electrical stimulus. Congenital myotonias are hereditary affections and do not present muscular dystrophy. The current trend is to group them as ionic channels diseases, together with the periodic paralysis. The authors accompanied the cases of seven patients, six males and one female, with ages ranging from 16 to 48 years (average 27 years) and onset of symptoms between 1 and 10 years (average 5 years). These patients presented a myotonic phenomenon unleashed by intensive contraction and global muscular hypertrophy. Three patients were diagnosed as cases of Becker type generalized myotonia because they presented a recessive autosomic heredity and/or transient episodes of muscular weakness. Two patients fitted the description of Thomsen congenital myotonia, with a pattern of dominating autosomic heredity and/or absence of weakness episodes or worsening factors for their condition. Two patients presented fluctuating myotonia, which because worse in cold weather or at potassium intake. The clinical diagnosis was confirmed through complementary tests (electroneuromyography, muscle biopsy and DNA study). Each of the patients made use of different drugs, in the search of optimal lessening of their myotonia. There were five reports of amelioration with the use of diphenilhydantoine; one report with the use of carbamazepine; three reports with the use of acetazolamide; one report with the use of a calcium channel blocker; one report with the use of a beta-adrenergic; one report with the use of thiazide; and none with the use of quinidine/procainamide.

Hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) are genetic muscle disorders sharing the common features of myotonia and episodic weakness. In hyperKPP, patient symptoms and signs are worsened by elevated serum potassium, whereas in PC, muscle cooling exacerbates the condition. There are patients in whom features of both hyperKPP and PC are present. These diseases result from molecular alterations in the adult skeletal muscle sodium channel. This report summarizes our sodium channel mutation analysis in 25 families with hyperKPP and PC. We also report the putative disease-causing mutation in acetazolamide-responsive myotonia congenita, a related disease in which myotonia is worsened by potassium but in which episodic weakness does not occur. This missense mutation (I1160V) occurs at a very highly conserved position in the sodium channel, cosegregates with the disease, and was not present in any of a large panel of normal DNAs. Electrophysiologic characterization of specific mutations will lead to better understanding of the biophysics of this voltage-gated ion channel.

The diagnosis of paramyotonia congenita (PC) can be aided by demonstrating a decrease in compound motor action potential amplitude after exercise and a decrement on repetitive stimulation, following cold exposure. We report a patient with PC who presented with complaints of cold-induced hand and jaw stiffening, in the absence of any episodes of weakness. Treatment with mexiletine led to resolution of the abnormalities exhibited during a short exercise test and repetitive stimulation following ice bath immersion. Molecular genetic analysis revealed a missense mutation (cytosine to thymidine) on chromosome 17 in the alpha-subunit of the skeletal muscle sodium channel gene that results in the replacement of threonine with methionine. This case demonstrates that, despite the absence of weakness, the short exercise test following cold exposure can be used to confirm the diagnosis of PC in patients without episodic weakness. Furthermore, improvement of the electrophysiologic abnormalities with mexiletine was documented, corresponding with clinical improvement.

Carbonic anhydrase inhibitors can cause nephrolithiasis. We studied 20 patients receiving long-term carbonic anhydrase inhibitor treatment for periodic paralysis and myotonia. Three patients on acetazolamide (15%) developed renal calculi. Extracorporeal lithotripsy successfully removed a renal calculus in one patient and surgery removed a staghorn calculus in another, permitting continued treatment. Renal function remained normal in all patients. Nephrolithiasis is a complication of acetazolamide but does not preclude its use.

A case with the combination of hypothyroidism and true myotonia is reported, in which the latter first became manifest clinically together with the thyroid disorder and improved with L-thyroxine therapy. The hypothyroidism itself caused very few symptoms, and the diagnosis was not made until examination for myotonia. The effect of each disorder on muscle function seems to be additive.

The effects of disopyramide, phenytoin, mexiletine, and tocainide were compared in 30 patients with myotonic disorders. The severity of myotonia was assessed by clinical and electromyographic criteria at the end of each treatment phase lasting four weeks. Mexiletine (MXT) and tocainide (TCD) were found to be the most potent antimyotonic agents. The antimyotonic efficacy of MXT and TCD is explained by their fast-blocking effect on voltage-dependent sodium channels in the muscle membrane. The benefits of myotonia control with pharmacological agents must be weight against the risk of therapy in the individual patient. Because of the risks of hematologic problems, TCD is not recommended by us for the treatment of myotonia.

A sporadic event of myotonia congenita in a infant admitted to the Paediatric Clinic for frequent crises of apnoea, cyanosis, vomiting and difficult feeding is reported. EMG analysis was consistent with the dominant variety of myotonia congenita. Mexiletine therapy showed excellent results in reducing myotonic activity. It is worthwhile stressing that early symptoms may go unnoticed or may be misinterpreted and that information on the genetic form of the disease can be obtained also from the EMG analysis through a repetitive stimulation test.

A 3 year, 10 month old male with myotonia congenita (Thomsen's disease) was placed on dantrolene sodium, which successfully abolished the myotonic phenomenon. Dantrolene sodium might therefore be a useful medicine for patients with Thomsen's disease who do not respond to other medicines, such as carbamazepine (CBZ), with a decrease in the myotonic phenomenon.

There are two types of MC, autosomal dominant and autosomal recessive (also called recessive generalized myotonia), both with the predominant clinical feature of diffuse myotonia. Recessive MC patients have more weakness than patients with dominant MC. MC patients of both types have a normal life span. Ongoing genetic studies have not as yet identified any chromosomal linkage. Electrophysiologically and pathophysiologically, there is no difference between these two types. The major pathophysiologic abnormality is decreased membrane chloride conductance. Treatment of myotonia is not always necessary, but when it is, the most effective medications are those that stabilize the muscle membrane. Phenytoin is frequently the first choice because it has more benign side effect profile than other drugs and a reasonable response rate.

This report describes 5 out of 8 siblings who were the first cases of myotonia congenita diagnosed in our department. The parents were first cousins. Neither the parents, nor the other family members have myotonia. The affected siblings 4 boys and 1 girl, all showed a very typical myotonia especially after prolonged rest, and it could be worked off with continuing activity. They had a muscular looking body or a herculean proportion. The diagnosis were based upon family history, clinical findings of percussion myotonia, had grip myotania, prominent muscular hypertrophy and confirmed by electromyographic examination revealing myotonic discharges. Since there were some functional impairments, these patients were treated with diphenylhydantoin and then with quinine sulphate, with good results. The patients related parents were much likely to be heterozygous for the same harmful recessive genes, because they had common ancestor. The role of marriage counseling is important in this kind of inherited disease, to prevent the occurrence of this inherited disorder in the next generations.

In a family in which myotonia congenita was found in five generations, both great-grandparents of the index case were affected. In subsequent generations mild and severely affected cases were clearly segregated down parallel lines of this family. The grandmother of the index case had noted improvement with an antihistamine. When the index case was prescribed trimeprazine, she showed a striking reduction in severity of symptoms. Antihistamines seem to deserve further evaluation as a safe and effective treatment for myotonia congenita.