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Frontiers in Neurology 2020The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The...
The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The study was performed at the Neurophysiologic Division of Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome and the Children's Hospital Bambino Gesù, Rome. The treatment was accepted by 59 patients according to clinical severity, individual needs, and concerns about a chronic medication. Forty-three patients were affected by recessive congenita myotonia, 11 by sodium channel myotonia, and five by dominant congenital myotonia. They underwent clinical examination before and after starting therapy, and Electromyography (EMG). A number of recessive myotonia patients underwent a protocol of repetitive nerve stimulations, for detecting and quantifying the transitory weakness, and a modified version of the Timed Up and Go test, to document and quantify the gait impairment. Treatment duration ranged from 1 month to 20 years and the daily dosages in adults ranged between 200 and 600 mg. No patient developed cardiac arrhythmias causing drug discontinuation. Mexiletine was suspended in 13 cases (22%); in three patients, affected by Sodium Channel myotonia, because flecainide showed better efficacy; in one patient because of a gastric cancer antecedent treatment; in four patients because of untreatable dyspepsia; and five patients considered the treatment not necessary. In our experience, mexiletine is very useful and not expensive. We did not observe any hazarding cardiac arrhythmias. Dyspepsia was the most frequent dose-limiting side effect.
PubMed: 32655465
DOI: 10.3389/fneur.2020.00300 -
Movement Disorders Clinical Practice Jul 2020
PubMed: 32626811
DOI: 10.1002/mdc3.12961 -
The Turkish Journal of Pediatrics 2020Congenital Myotonia (CM) is a disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1). Mutations can be transmitted as autosomal dominant... (Review)
Review
BACKGROUND AND OBJECTIVES
Congenital Myotonia (CM) is a disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1). Mutations can be transmitted as autosomal dominant (Thomsen's disease) or recessive (Becker's disease). CM is more common in men and Becker myotonia may be 10 times more common than Thomsen myotonia. Genotypic and phenotypic characteristics of CM may vary according to geographical region and ethnicity.
METHOD
In this study, we present the genotypic and phenotypic characteristics of 20 Turkish CM patients all diagnosed by molecular genetic testing. The clinical and laboratory features of the patients with mutation in CLCN1 gene were retrospectively analyzed.
RESULTS
Eleven of the patients were female. c.1064+1G > A splice-site change, p.Arg338X (c.1012 C > T) stop codon, p.Gly190Ser (c.568_569delinsTC) missense mutations were detected. Eight of the 20 patients were found to be compatible with Becker type and 12 with Thomsen type, based on mode of inheritance, neurological examination findings and genetic test results.
CONCLUSION
The c.1064+1G > A splice-site change mutation, defined for the first time in this study, expands the spectrum of mutations in the CLCN1 gene. Thomsen type and female gender were observed to be more frequent in this series of patients from Turkey.
Topics: Chloride Channels; Female; Humans; Male; Mutation; Mutation, Missense; Myotonia Congenita; Pedigree; Retrospective Studies
PubMed: 32558419
DOI: 10.24953/turkjped.2020.03.012 -
Molecular Genetics & Genomic Medicine Aug 2020GLE1 (GLE1, RNA Export Mediator, OMIM#603371) variants are associated with severe autosomal recessive motor neuron diseases, that are lethal congenital contracture...
BACKGROUND
GLE1 (GLE1, RNA Export Mediator, OMIM#603371) variants are associated with severe autosomal recessive motor neuron diseases, that are lethal congenital contracture syndrome 1 (LCCS1, OMIM#253310) and congenital arthrogryposis with anterior horn cell disease (CAAHD, OMIM#611890). The clinical spectrum of GLE1-related disorders has been expanding these past years, including with adult-onset amyotrophic lateral sclerosis (ALS) GLE1-related forms, especially through the new molecular diagnosis strategies associated with the emergence of next-generation sequencing (NGS) technologies. However, despite this phenotypic variability, reported congenital or ALS adult-onset forms remain severe, leading to premature death.
METHODS
Through multidisciplinary interactions between our Neuropediatric and Medical Genetics departments, we were able to diagnose two siblings presenting with congenital disorder, using an NGS approach accordingly to the novel French national recommendations.
RESULTS
Two siblings with very similar clinical features, meaning neuromuscular disorder of neonatal onset with progressive improvement, were examined in our Neuropediatrics department. The clinical presentation evoked initially congenital myopathy with autosomal recessive inheritance. However, additional symptoms such as mild dysmorphic features including high anterior hairline, downslanted palpebral fissures, anteverted nares, smooth philtrum with thin upper-lip, narrow mouth and microretrognathia or delayed expressive language and postnatal growth retardation were suggestive of a more complex clinical presentation and molecular diagnosis. Our NGS approach revealed an unexpected molecular diagnosis for these two siblings, meaning the presence of the homozygous c.1808G>T GLE1 variant.
CONCLUSIONS
We here report the mildest phenotype ever described, in two siblings carrying the homozygous c.1808G>T GLE1 variant, further widening the clinical spectrum of GLE1-related diseases. Moreover, by reflecting current medical practice, this case report confirms the importance of establishing regular multidisciplinary meetings, essential for discussing such difficult clinical presentations to finally enable molecular diagnosis, especially when NGS technologies are used.
Topics: Child; Child, Preschool; Diagnosis, Differential; Female; Homozygote; Humans; Male; Myotonia Congenita; Nucleocytoplasmic Transport Proteins; Pedigree; Phenotype; Point Mutation
PubMed: 32537934
DOI: 10.1002/mgg3.1277 -
Structure (London, England : 1993) Aug 2020STAC3 is a soluble protein essential for skeletal muscle excitation-contraction (EC) coupling. Through its tandem SH3 domains, it interacts with the cytosolic II-III...
STAC3 is a soluble protein essential for skeletal muscle excitation-contraction (EC) coupling. Through its tandem SH3 domains, it interacts with the cytosolic II-III loop of the skeletal muscle voltage-gated calcium channel. STAC3 is the target for a mutation (W284S) that causes Native American myopathy, but multiple other sequence variants have been reported. Here, we report a crystal structure of the human STAC3 tandem SH3 domains. We analyzed the effect of five disease-associated variants, spread over both SH3 domains, on their ability to bind to the Ca1.1 II-III loop and on muscle EC coupling. In addition to W284S, we find the F295L and K329N variants to affect both binding and EC coupling. The ability of the K329N variant, located in the second SH3 domain, to affect the interaction highlights the importance of both SH3 domains in association with Ca1.1. Our results suggest that multiple STAC3 variants may cause myopathy.
Topics: Action Potentials; Adaptor Proteins, Signal Transducing; Binding Sites; Calcium Channels, L-Type; Cell Line; Cleft Palate; Excitation Contraction Coupling; Humans; Malignant Hyperthermia; Molecular Dynamics Simulation; Mutation, Missense; Myotonia Congenita; Protein Binding; Protein Conformation, beta-Strand; src Homology Domains
PubMed: 32492370
DOI: 10.1016/j.str.2020.05.005 -
Acta Neuropathologica Aug 2020
Topics: DNA Repeat Expansion; Female; Genetic Predisposition to Disease; Humans; Male; Myotonia Congenita; Pedigree; Perilipin-4
PubMed: 32451610
DOI: 10.1007/s00401-020-02164-4 -
Molecular Genetics & Genomic Medicine Aug 2020αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that...
BACKGROUND
αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance.
METHODS
The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques.
RESULTS
CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization.
CONCLUSIONS
The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.
Topics: Cataract; Child, Preschool; Genes, Dominant; Humans; Male; Muscle, Skeletal; Mutation; Myotonia Congenita; Phenotype; Syndrome; Twins; alpha-Crystallin B Chain
PubMed: 32420686
DOI: 10.1002/mgg3.1290 -
Annals of Neurology Aug 2020Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and...
OBJECTIVE
Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy.
METHODS
We developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness.
RESULTS
As previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4-null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%.
INTERPRETATION
These data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297-308.
Topics: Animals; Anthracenes; Isometric Contraction; Mice; Mice, Knockout; Morpholines; Muscle, Skeletal; Myotonia Congenita; Pyrroles; TRPV Cation Channels
PubMed: 32418267
DOI: 10.1002/ana.25780 -
PloS One 2020Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride...
Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Nav1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.
Topics: Adolescent; Adult; Aged; Amino Acid Sequence; China; Chloride Channels; Consanguinity; Conserved Sequence; Diagnosis, Differential; Female; HEK293 Cells; Humans; Hypokalemic Periodic Paralysis; Male; Middle Aged; Models, Molecular; Mutant Proteins; Mutation; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Recombinant Proteins; Exome Sequencing; Young Adult
PubMed: 32407401
DOI: 10.1371/journal.pone.0233017 -
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