-
Muscle & Nerve Oct 2020The 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... (Review)
Review
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.
Topics: Acetazolamide; Age of Onset; Carbonic Anhydrase Inhibitors; Chloride Channels; Electrodiagnosis; Electromyography; Fatigue; Genetic Testing; Humans; Lamotrigine; Mexiletine; Muscle Weakness; Muscle, Skeletal; Myalgia; Myotonia Congenita; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Practice Guidelines as Topic; Ranolazine; Sodium Channel Blockers; Voltage-Gated Sodium Channel Blockers
PubMed: 32270509
DOI: 10.1002/mus.26887 -
Brain : a Journal of Neurology Apr 2022High-throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in...
High-throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in data interpretation and its useful translation into clinical and genetic counselling for families. Even when a plausible gene is identified with confidence, interpretation of the clinical significance and inheritance pattern of variants can be challenging. We report our approach to evaluating variants in the skeletal muscle chloride channel ClC-1 identified in 223 probands with myotonia congenita as an example of these challenges. Sequencing of CLCN1, the gene that encodes CLC-1, is central to the diagnosis of myotonia congenita. However, interpreting the pathogenicity and inheritance pattern of novel variants is notoriously difficult as both dominant and recessive mutations are reported throughout the channel sequence, ClC-1 structure-function is poorly understood and significant intra- and interfamilial variability in phenotype is reported. Heterologous expression systems to study functional consequences of CIC-1 variants are widely reported to aid the assessment of pathogenicity and inheritance pattern. However, heterogeneity of reported analyses does not allow for the systematic correlation of available functional and genetic data. We report the systematic evaluation of 95 CIC-1 variants in 223 probands, the largest reported patient cohort, in which we apply standardized functional analyses and correlate this with clinical assessment and inheritance pattern. Such correlation is important to determine whether functional data improves the accuracy of variant interpretation and likely mode of inheritance. Our data provide an evidence-based approach that functional characterization of ClC-1 variants improves clinical interpretation of their pathogenicity and inheritance pattern, and serve as reference for 34 previously unreported and 28 previously uncharacterized CLCN1 variants. In addition, we identify novel pathogenic mechanisms and find that variants that alter voltage dependence of activation cluster in the first half of the transmembrane domains and variants that yield no currents cluster in the second half of the transmembrane domain. None of the variants in the intracellular domains were associated with dominant functional features or dominant inheritance pattern of myotonia congenita. Our data help provide an initial estimate of the anticipated inheritance pattern based on the location of a novel variant and shows that systematic functional characterization can significantly refine the assessment of risk of an associated inheritance pattern and consequently the clinical and genetic counselling.
Topics: Chloride Channels; Humans; Mutation; Myotonia; Myotonia Congenita; Phenotype
PubMed: 34529042
DOI: 10.1093/brain/awab344 -
Obstetric Medicine Mar 2020Myotonic disorders represent significant risk in pregnancy due to their complexity and the risk of maternal and fetal complications. Care of these pregnancies requires... (Review)
Review
Myotonic disorders represent significant risk in pregnancy due to their complexity and the risk of maternal and fetal complications. Care of these pregnancies requires detailed pre-conception counselling, close monitoring of mother and fetus during the pregnancy and a delivery and postpartum plan involving a multidisciplinary team approach. A case of a woman with myotonia congenita diagnosed in pregnancy is presented, the general principles of care of women with myotonic disorders discussed, and care of the specific conditions in pregnancy reviewed. Not applicable.
PubMed: 32284727
DOI: 10.1177/1753495X18824238 -
Current Treatment Options in Neurology 2020This article aims to review the current and upcoming treatment options of primary muscle channelopathies including the non-dystrophic myotonias and periodic paralyses. (Review)
Review
PURPOSE OF REVIEW
This article aims to review the current and upcoming treatment options of primary muscle channelopathies including the non-dystrophic myotonias and periodic paralyses.
RECENT FINDINGS
The efficacy of mexiletine in the treatment of myotonia is now supported by two randomised placebo-controlled trials, one of which utilised a novel aggregated n-of-1 design. This has resulted in licencing of the drug via orphan drug status. There is also good evidence that mexiletine is well tolerated and safe in this patient group without the need for intensive monitoring. A range of alternative antimyotonic treatment options include lamotrigine, carbamazepine and ranolazine exist with variable evidence base. In vitro studies have shown insight into reasons for treatment failure of some medications with certain genotypes opening the era of mutation-specific therapy such as use of flecainide. In the periodic paralyses, the ability of MRI to distinguish between reversible oedema and irreversible fatty replacement makes it an increasingly useful tool to guide and assess pharmacological treatment. Unfortunately, the striking efficacy of bumetanide in hypokalaemic periodic paralysis animal models was not replicated in a recent pilot study in humans.
SUMMARY
The treatment of skeletal muscle channelopathies combines dietary and lifestyle advice together with pharmacological interventions. The rarity of these conditions remains a barrier for clinical studies but the example of the aggregated n-of-1 trial of mexiletine shows that innovative trial design can overcome these hurdles. Further research is required to test efficacy of drugs shown to have promising characteristics in preclinical experiments such as safinamide, riluzule and magnesium for myotonia or bumetanide for hypokalaemic periodic paralysis.
PubMed: 32848354
DOI: 10.1007/s11940-020-00644-2 -
Experimental Neurology Mar 2023It has long been accepted that myotonia (muscle stiffness) in patients with muscle channelopathies is due to myotonic discharges (involuntary firing of action...
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 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 from individual muscle fibers were compared to recordings of whole muscle force generation. In ClC 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, 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 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.
Topics: Mice; Animals; Myotonia; Myotonia Congenita; Muscle Contraction; Action Potentials; Muscle Fibers, Skeletal; Chloride Channels; Disease Models, Animal
PubMed: 36563835
DOI: 10.1016/j.expneurol.2022.114303 -
Muscle & Nerve Aug 2022Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal... (Observational Study)
Observational Study
INTRODUCTION/AIMS
Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research.
METHODS
Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2).
RESULTS
Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time.
DISCUSSION
Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.
Topics: Channelopathies; Chloride Channels; Hand Strength; Humans; Mutation; Myotonia; Myotonia Congenita; Myotonic Dystrophy; NAV1.4 Voltage-Gated Sodium Channel; Patient Reported Outcome Measures; Quality of Life
PubMed: 35644941
DOI: 10.1002/mus.27649 -
BMJ Case Reports May 2021
Topics: Hand Strength; Humans; Myotonia; Myotonia Congenita; Myotonic Dystrophy
PubMed: 33958356
DOI: 10.1136/bcr-2020-240779 -
Journal of Neuromuscular Diseases 2023Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride...
BACKGROUND
Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle.
OBJECTIVE
The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort.
METHODS
Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated.
RESULTS
Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment.
CONCLUSIONS
The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.
Topics: Male; Humans; Child; Adolescent; Aged; Infant; Child, Preschool; Female; Myotonia Congenita; Retrospective Studies; Chloride Channels; Mutation; Muscle, Skeletal
PubMed: 37355912
DOI: 10.3233/JND-230046