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International Journal of Molecular... Apr 2020Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the gene encoding the alpha-subunit of...
Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the gene encoding the alpha-subunit of the voltage-gated sodium channel Na1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Na1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Na1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Na1.4 channel's co-expression with the Naβ4 peptide can generate resurgent Na currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (WT) channel. Although the decay kinetics are comparable between the mutant and WT channels, the time to the peak of resurgent Na currents in the mutant channel is significantly protracted compared with that in the WT channel. These findings suggest that the p.V445M mutation in the Na1.4 channel results in an increase of both sustained and resurgent Na currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.
Topics: Amino Acid Sequence; Animals; Asian People; CHO Cells; Channelopathies; Cricetulus; Female; Humans; Male; Mutation, Missense; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Pedigree
PubMed: 32276507
DOI: 10.3390/ijms21072593 -
Movement Disorders Clinical Practice Jul 2020
PubMed: 32626811
DOI: 10.1002/mdc3.12961 -
Psychiatria Danubina Oct 2023
Topics: Humans; Myotonia Congenita
PubMed: 37800267
DOI: No ID Found -
Acta Neurologica Belgica Jun 2022Nemaline myopathy (NM) is a congenital myopathy of great heterogeneity, characterized by the presence of rods in the cytoplasm of muscle fibers. The samples of 16...
Nemaline myopathy (NM) is a congenital myopathy of great heterogeneity, characterized by the presence of rods in the cytoplasm of muscle fibers. The samples of 16 nemaline myopathy patients diagnosed by characteristically pathological features went through whole exon sequencing. Clinico-pathological and genetic features of the cases were systematically analyzed. According to the classification of nemaline myopathy by ENMC, 8 cases are typical congenital subtype, 6 cases are childhood/juvenile onset subtype and 2 case are adult onset subtype. In histological findings, characteristic purple-colored rods are discovered under modified gömöri trichrome staining (MGT). Electron microscopy revealed the presence of high electron-dense nemaline bodies around the submucosa and the nucleus nine patients (9/16 56.3%) were detected pathogenic causative mutations, among whom mutations in the NEB gene were the most frequent (6 patients, 66.7%). KBTBD13 gene mutation was discovered in two patients and ACTA1 gene mutation was discovered in 1 patient. Nemaline myopathy is a congenital myopathy with highly clinico-pathological and genetic heterogeneity. NEB gene mutation is the most common mutation, in which splicing change c.21522 +3A > G is hotspot mutation in Chinese NM patients.
Topics: Adult; Asian People; Child; China; Humans; Muscle Proteins; Muscle, Skeletal; Muscular Diseases; Mutation; Myopathies, Nemaline; Myotonia Congenita
PubMed: 33742414
DOI: 10.1007/s13760-020-01542-9 -
Journal of Veterinary Diagnostic... Jul 2023Hereditary myotonia (HM) is characterized by delayed muscle relaxation after contraction as a result of a mutation in the gene. We describe here a complex variant in a...
Hereditary myotonia (HM) is characterized by delayed muscle relaxation after contraction as a result of a mutation in the gene. We describe here a complex variant in a mixed-breed dog with clinical and electromyographic signs of HM. Blood samples from the myotonic dog, as well as from his male littermate and parents, were analyzed via amplification of the 23 exons encoding . After sequencing the gene, a complex variant was found in exon 6 c.[705T>G; 708del; 712_732del], resulting in a premature stop codon in exon 7 and a protein that was 717 amino acids shorter than the normal CLC protein. The myotonic dog was identified as homozygous recessive for the complex variant; its parents were heterozygous, and its male littermate was homozygous wild-type. Knowledge of the mutations responsible for the development of hereditary myotonia allows greater clarification of this condition.
Topics: Animals; Dogs; Male; Chloride Channels; Dog Diseases; Exons; Mutation; Myotonia; Myotonia Congenita
PubMed: 37212506
DOI: 10.1177/10406387231176736 -
Annals of Indian Academy of Neurology 2021
PubMed: 34728966
DOI: 10.4103/aian.AIAN_970_20 -
Journal of Neuromuscular Diseases 2024The 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...
BACKGROUND
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.
METHODS
Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected.
RESULTS
A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude.
CONCLUSIONS
The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.
Topics: Adult; Female; Humans; Middle Aged; Electromyography; Italy; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Point Mutation
PubMed: 38427496
DOI: 10.3233/JND-230134 -
Frontiers in Genetics 2022Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the gene encoding skeletal muscle chloride channels. MC is characterized by delayed...
Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the gene encoding skeletal muscle chloride channels. MC is characterized by delayed muscle relaxation during contraction, resulting in muscle stiffness. There is a lack of MC case reports and data on the prevalence among Malaysians. We report a clinical case of a 50-year-old woman presents with muscle stiffness and cramp episodes that started in early childhood. She had difficulty initiating muscle movement and presented with transient muscle weakness after rest, which usually improved after repeated contraction (warm-up phenomenon). She was diagnosed with MC after myotonic discharge on electromyography (EMG). Her brother had similar symptoms; however, no additional family members showed MC symptoms. Serum creatine kinase levels were elevated in both the proband and her brother with 447 U/L and 228 U/L recorded, respectively. Genetic analysis by whole-exome sequencing (WES) revealed a previously reported pathogenic gene variant c.1667T>A (p.I556N). Genetic screening of all family members revealed that the same variant was observed in the children of both the proband and her brother; however, the children did not present with either clinical or electrophysiological MC symptoms. The multiplex ligation-dependent probe amplification (MLPA) analysis conducted identified neither exon deletion nor duplication in . In conclusion, this report describes the first case of MC in Malaysia in which incomplete penetrance observed in this family is caused by a known pathogenic variant.
PubMed: 36659963
DOI: 10.3389/fgene.2022.972007 -
Acta Myologica : Myopathies and... 2022Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the gene (OMIM #614399)....
Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the gene (OMIM #614399). Phenotypic spectrum of EMARDD is variable, ranging from severe infantile forms in which patients are ventilator-dependent and die in childhood, to milder chronic disorders with a more favorable course (mild variant, mvEMARDD). Here we describe a 22 years old boy, offspring of consanguineous parents, presenting a congenital myopathic phenotype since infancy with elbow contractures and scoliosis. The patient developed a slowly progressive muscle weakness with impaired walking, rhinolalia, dysphagia, and respiratory involvement, which required noninvasive ventilation therapy since the age of 16 years. First muscle biopsy revealed unspecific muscle damage, with fiber size variation, internal nuclei and fibrosis. Myofibrillar alterations were noted at a second muscle biopsy including whorled fibres, cytoplasmic inclusion and minicores. Exome sequencing identified a homozygous mutation in gene, c.2096G > C (p.Cys699Ser), inherited by both parents. This variant, not reported in public databases of mutations, is expected to alter the structure of the protein and is therefore predicted to be probably damaging according to ACMG classification. In conclusion, we found a new likely pathogenic mutation in , which is responsible for a progressive form of mvEMARDD with myofibrillar alterations at muscle biopsy. Interestingly, the presence of mutations has not been reported in Italian population. Early diagnosis of MEGF10 myopathy is essential in light of recent results from in vivo testing demonstrating a potential therapeutic effect of SSRIs compounds.
Topics: Humans; Deglutition Disorders; Membrane Proteins; Muscular Diseases; Myotonia Congenita; Mutation; Muscle, Skeletal
PubMed: 36349186
DOI: 10.36185/2532-1900-076 -
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