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International Journal of Molecular... Oct 2022Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30...
Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the “typical” form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.
Topics: Brazil; Humans; Muscle Proteins; Muscle, Skeletal; Mutation; Myopathies, Nemaline; Myotonia Congenita
PubMed: 36233295
DOI: 10.3390/ijms231911995 -
The Application of Clinical Genetics 2021Becker's type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle...
BACKGROUND
Becker's type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle relaxation after voluntary contraction. It is caused by mutations in the gene, which encodes for a chloride channel mainly expressed in the striated muscle. Most cases have been reported in the European population, and only mexiletine has demonstrated a randomized placebo-controlled, double-blinded effectiveness.
CASE PRESENTATION
We present two male siblings from Colombia with Latino ancestry, without parental consanguinity, with myotonia during voluntary movements, muscle hypertrophy of lower extremities, transient weakness, and severe muscle fatigue after exercise from three years of age. A genetic panel for dystrophic muscle disorders and a muscle biopsy were both negative. Genetic testing was performed in their second decade of life. Both patients' exomic sequencing test reported the mutation c.1129C >T (p.Arg377*) affecting exon 10 of the , generating a premature stop codon. This mutation was described as pathogenic and observed in only one other patient in the United Kingdom.
CONCLUSION
To our knowledge, these are the first cases of Becker's type myotonia congenita reported in Colombia. Increasing awareness of healthcare providers for this type of disease in the region could lead to the identification of undiagnosed patients. Limited availability of medical geneticists as well as genetic testing may be the cause of the lack of previous description of cases, in addition to the delay in the diagnosis of the patients. Further epidemiological studies can reveal underdiagnosed myotonias in the country and in the Latin-American region.
PubMed: 34938096
DOI: 10.2147/TACG.S323559 -
Frontiers in Neuroscience 2022Optically pumped magnetometers (OPM) are quantum sensors that enable the contactless, non-invasive measurement of biomagnetic muscle signals, i.e., magnetomyography...
Optically pumped magnetometers (OPM) are quantum sensors that enable the contactless, non-invasive measurement of biomagnetic muscle signals, i.e., magnetomyography (MMG). Due to the contactless recording, OPM-MMG might be preferable to standard electromyography (EMG) for patients with neuromuscular diseases, particularly when repetitive recordings for diagnostic and therapeutic monitoring are mandatory. OPM-MMG studies have focused on recording physiological muscle activity in healthy individuals, whereas research on neuromuscular patients with pathological altered muscle activity is non-existent. Here, we report a proof-of-principle study on the application of OPM-MMG in patients with neuromuscular diseases. Specifically, we compare the muscular activity during maximal isometric contraction of the left rectus femoris muscle in three neuromuscular patients with severe (Transthyretin Amyloidosis in combination with Pompe's disease), mild (Charcot-Marie-Tooth disease, type 2), and without neurogenic, but myogenic, damage (Myotonia Congenita). Seven healthy young participants served as the control group. As expected, and confirmed by using simultaneous surface electromyography (sEMG), a time-series analysis revealed a dispersed interference pattern during maximal contraction with high amplitudes. Furthermore, both patients with neurogenic damage (ATTR and CMT2) showed a reduced variability of the MMG signal, quantified as the signal standard deviation of the main component of the frequency spectrum, highlighting the reduced possibility of motor unit recruitment due to the loss of motor neurons. Our results show that recording pathologically altered voluntary muscle activity with OPM-MMG is possible, paving the way for the potential use of OPM-MMG in larger studies to explore the potential benefits in clinical neurophysiology.
PubMed: 36523432
DOI: 10.3389/fnins.2022.1010242 -
Neurologia I Neurochirurgia Polska 2022In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide...
INTRODUCTION
In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis.
MATERIAL AND METHODS
We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC.
RESULTS
Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.
Topics: Female; Humans; Male; Myotonia Congenita; Sex Characteristics; Electromyography; Action Potentials; Mutation
PubMed: 35792560
DOI: 10.5603/PJNNS.a2022.0051 -
Frontiers in Pharmacology 2022Myotonia congenita (MC) is an inherited rare disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. It is caused by...
Myotonia congenita (MC) is an inherited rare disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. It is caused by loss-of-function mutations in the skeletal muscle chloride channel ClC-1, important for the stabilization of resting membrane potential and for the repolarization phase of action potentials. Thanks to functional studies, the molecular mechanisms by which ClC-1 mutations alter chloride ion influx into the cell have been in part clarified, classifying them in "gating-defective" or "expression-defective" mutations. To date, the treatment of MC is only palliative because no direct ClC-1 activator is available. An ideal drug should be one which is able to correct biophysical defects of ClC-1 in the case of gating-defective mutations or a drug capable to recover ClC-1 protein expression on the plasma membrane for trafficking-defective ones. In this study, we tested the ability of niflumic acid (NFA), a commercial nonsteroidal anti-inflammatory drug, to act as a pharmacological chaperone on trafficking-defective MC mutants (A531V, V947E). Wild-type (WT) or MC mutant ClC-1 channels were expressed in HEK293 cells and whole-cell chloride currents were recorded with the patch-clamp technique before and after NFA incubation. Membrane biotinylation assays and western blot were performed to support electrophysiological results. A531V and V947E mutations caused a decrease in chloride current density due to a reduction of ClC-1 total protein level and channel expression on the plasma membrane. The treatment of A531V and V947E-transfected cells with 50 µM NFA restored chloride currents, reaching levels similar to those of WT. Furthermore, no significant difference was observed in voltage dependence, suggesting that NFA increased protein membrane expression without altering the function of ClC-1. Indeed, biochemical experiments confirmed that V947E total protein expression and its plasma membrane distribution were recovered after NFA incubation, reaching protein levels similar to WT. Thus, the use of NFA as a pharmacological chaperone in trafficking defective ClC-1 channel mutations could represent a good strategy in the treatment of MC. Because of the favorable safety profile of this drug, our study may easily open the way for confirmatory human pilot studies aimed at verifying the antimyotonic activity of NFA in selected patients carrying specific ClC-1 channel mutations.
PubMed: 36034862
DOI: 10.3389/fphar.2022.958196 -
Revista de Neurologia Feb 2023Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive...
INTRODUCTION
Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration.
CASES REPORT
The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker's disease and two with Thomsen's disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C).
CONCLUSIONS
the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.
Topics: Humans; Myotonia Congenita; Incidence; Chloride Channels; Mutation; Muscular Dystrophy, Duchenne; Pedigree
PubMed: 36782350
DOI: 10.33588/rn.7604.2021357 -
Frontiers in Physiology 2020Reduced Cl conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the...
Reduced Cl conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca- and voltage-activated K channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia . Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T) were monitored. Compared to wild type, fast-twitch muscle specimen of BK mice resulted in a significantly decreased T in presence of 9-AC. Paxilline significantly shortened T of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T. The currently used standard therapy for myotonia is, in some individuals, not very effective. This study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
PubMed: 33329012
DOI: 10.3389/fphys.2020.533946 -
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 -
Frontiers in Neurology 2022Non-dystrophic myotonias (NDM) encompass chloride and sodium channelopathy. Mutations in lead to either the autosomal dominant form or the recessive form of myotonia...
Non-dystrophic myotonias (NDM) encompass chloride and sodium channelopathy. Mutations in lead to either the autosomal dominant form or the recessive form of myotonia congenita (MC). The main symptom is stiffness worsening after rest and improving by physical exercise. Patients with recessive mutations often show muscle hypertrophy, and transient weakness mostly in their lower limbs. Mutations in can lead to Hyper-, Hypo- or Normo-kalemic Periodic Paralysis or to different forms of myotonia (Paramyotonia Congenita-PMC and Sodium Channel Myotonia-SCM and severe neonatal episodic laryngospasm-SNEL). SCM often presents facial muscle stiffness, cold sensitivity, and muscle pain, whereas myotonia worsens in PMC patients with the repetition of the muscle activity and cold. Patients affected by chloride or sodium channelopathies may show similar phenotypes and symptoms, making the diagnosis more difficult to reach. Herein we present a woman in whom sodium and chloride channelopathies coexist yielding a complex phenotype with features typical of both MC and PMC. Disease onset was in the second decade with asthenia, weakness, warm up and limb stiffness, and her symptoms had been worsening through the years leading to frequent heavy retrosternal compression, tachycardia, stiffness, and symmetrical pain in her lower limbs. She presented severe lid lag myotonia, a hypertrophic appearance at four limbs and myotonic discharges at EMG. Her symptoms have been triggered by exposure to cold and her daily life was impaired. All together, clinical signs and instrumental data led to the hypothesis of PMC and to the administration of mexiletine, then replaced by acetazolamide because of gastrointestinal side effects. Analysis of revealed a new variant, p.Glu1607del. Nonetheless the severity of myotonia in the lower limbs and her general stiffness led to hypothesize that the impairment of sodium channel, Nav1.4, alone could not satisfactorily explain the phenotype and a second genetic "factor" was hypothesized. was targeted, and p.Met485Val was detected in homozygosity. This case highlights that proper identification of signs and symptoms by an expert neurologist is crucial to target a successful genetic diagnosis and appropriate therapy.
PubMed: 36081873
DOI: 10.3389/fneur.2022.845383 -
Acta Neuropathologica Mar 2021Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not...
Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Connectin; Female; Humans; Infant; Male; Middle Aged; Mutation, Missense; Myotonia Congenita; Young Adult
PubMed: 33449170
DOI: 10.1007/s00401-020-02257-0