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Myotonia congenita

Chris X Dupont, Kirsten S Denman, Ahmed A Hawash, Andrew A Voss, Mark M Rich
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...
February 7, 2019: Experimental Neurology
S Portaro, A Naro, M Russo, P Bramanti, P Lauria, Giangaetano D'Aleo, G La Rosa, A Bramanti, Rocco Salvatore Calabrò
Some patients with multiple sclerosis (MS) complain of symptoms, such as myokymia, myotonia, spasms, and stiffness, which have been demonstrated to be due to a concurrent non-dystrophic myotonia, i.e. myotonia congenita or paramyotonia congenita. Beyond the known casual association between MS and non-dystrophic myotonia, a channelopathy representing a primary trait of MS rather than an epiphenomenon of demyelization (i.e., an acquired channelopathy) may exist. Indeed, the finding of MS patients with no genetic evidence of non-dystrophic myotonia but showing a clinical picture resembling this condition would support this hypothesis...
October 2018: Functional Neurology
Frantisek Cibulcik, Peter Spalek, Ivan Martinka, Jana Zidkova, Milan Grofik, Stefan Sivak, Egon Kurca
BACKGROUND: Paramyotonia congenita is a non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. This condition cannot be distinguished on the basis of symptoms and signs alone. It requires consideration of genetics as more than 100 mutations in the CLCN1 gene and at least 20 mutations in the SCN4A gene are associated with the clinical features of the non-dystrophic myotonias. Only a few families with the described features but no genetic testing have been reported in Slovakia...
January 14, 2019: Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia
Alessandro Farinato, Concetta Altamura, Paola Imbrici, Lorenzo Maggi, Pia Bernasconi, Renato Mantegazza, Livia Pasquali, Gabriele Siciliano, Mauro Lo Monaco, Christophe Vial, Damien Sternberg, Maria Rosaria Carratù, Diana Conte, Jean-François Desaphy
Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158 L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p...
January 3, 2019: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Yi-Jheng Peng, Yi-Ching Lee, Ssu-Ju Fu, Yun-Chia Chien, Yi-Fan Liao, Tsung-Yu Chen, Chung-Jiuan Jeng, Chih-Yung Tang
Mutations in the skeletal muscle-specific CLC-1 chloride channel are associated with the human hereditary disease myotonia congenita. The molecular pathophysiology underlying some of the disease-causing mutations can be ascribed to defective human CLC-1 protein biosynthesis. CLC-1 protein folding is assisted by several molecular chaperones and co-chaperones, including FK506-binding protein 8 (FKBP8). FKBP8 is generally considered an endoplasmic reticulum- and mitochondrion-resident membrane protein, but is not thought to contribute to protein quality control at the cell surface...
November 28, 2018: International Journal of Molecular Sciences
Samantha Lorusso, David Kline, Amy Bartlett, Miriam Freimer, Julie Agriesti, Ahmed A Hawash, Mark M Rich, John T Kissel, W David Arnold
INTRODUCTION: Paramyotonia congenita (PMC) is a nondystrophic myotonic disorder that is believed to be caused by a defect in Nav 1.4 sodium channel inactivation. Ranolazine, which acts by enhancing slow inactivation of sodium channels, has been proposed as a therapeutic option, but in vivo studies are lacking. METHODS: We conducted an open-label, single-center trial of ranolazine to evaluate efficacy and tolerability in patients with PMC. Subjective symptoms of stiffness, weakness, and pain as well as clinical and electrical myotonia were evaluated...
November 3, 2018: Muscle & Nerve
Kerstin Hoppe, Sunisa Chaiklieng, Frank Lehmann-Horn, Karin Jurkat-Rott, Scott Wearing, Werner Klingler
KEY POINTS: During myotonia congenita reduced chloride (Cl- ) conductance results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Repetitive contraction of myotonic muscle decreases or even abolishes myotonic muscle stiffness, a phenomenon called "warm up". Pharmacological inhibition of low Cl- channels by Anthracene-9-Carboxylic Acid from ADR muscle from mice showed a relaxation deficit at physiological conditions compared to wild-type muscle...
October 3, 2018: Journal of Physiology
Jing Miao, Xiao-Jing Wei, Xue-Mei Liu, Zhi-Xia Kang, Yan-Lu Gao, Xue-Fan Yu
BACKGROUND: Autosomal recessive Myotonia congenita (Becker's disease) is caused by mutations in the CLCN1 gene. The condition is characterized by muscle stiffness during sustained muscle contraction and variable degree of muscle weakness that tends to improve with repeated contractions. CASE PRESENTATION: A 21-year-old man presented with transient muscle stiffness since the last 10 years. He had difficulty in initiating movement and experienced muscle weakness after rest, which typically improved after repeated contraction (warm-up phenomenon)...
September 22, 2018: BMC Neurology
Concetta Altamura, Sabrina Lucchiari, Dalila Sahbani, Gianna Ulzi, Giacomo P Comi, Paola D'Ambrosio, Roberta Petillo, Luisa Politano, Liliana Vercelli, Tiziana Mongini, Maria Teresa Dotti, Rosanna Cardani, Giovanni Meola, Mauro Lo Monaco, Emma Matthews, Michael G Hanna, Maria Rosaria Carratù, Diana Conte, Paola Imbrici, Jean-François Desaphy
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...
September 2018: Human Mutation
Pia R Quitt, Marjo K Hytönen, Kaspar Matiasek, Marco Rosati, Andrea Fischer, Hannes Lohi
An eight week old Labrador Retriever puppy presented with stiff-legged robotic gait. Abnormal gait was most evident after rest and improved with prolonged activity. On occasions, initiation of sudden movements would result in collapse with rigidity of the trunk and stiff extended limbs for several seconds. Other clinical signs were excitement-induced upper airway stridor and oropharyngeal dysphagia. Myotonia congenita was diagnosed based on clinical signs, abundant myotonic discharges on electromyography and exclusion of structural myopathies on histology...
July 2018: Neuromuscular Disorders: NMD
Feng Jing, Haijiang Li, Dan Yang, Tao Chen, Yuexian Liu, Lidan Yu
OBJECTIVE: To detect potential mutations of chloride channel l (CLCN1) gene in a family affected with myotonia congenita. METHODS: Clinical data of the proband and her parents and brother was collected. The coding regions of the CLCN1 gene were subjected to PCR and Sanger sequencing. RESULTS: Two missense mutations (c.937G>A and c.1205C>T), which were respectively located within exons 8 and 11 of the CLCN1 gene, were identified in the proband...
June 10, 2018: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Simona Portaro, Antonino Naro, Alessia Bramanti, Antonino Leo, Alfredo Manuli, Tina Balletta, Antonia Trinchera, Placido Bramanti, Rocco Salvatore Calabrò
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...
2018: Restorative Neurology and Neuroscience
Simona Portaro, Alberto Cacciola, Antonino Naro, Demetrio Milardi, Rosa Morabito, Francesco Corallo, Silvia Marino, Alessia Bramanti, Emanuela Mazzon, Rocco Salvatore Calabrò
RATIONALE: Myotonia congenita (MC) is a non-dystrophic myotonia inherited either in dominant (Thomsen) or recessive (Becker) form. MC is due to an abnormal functioning of skeletal muscle voltage-gated chloride channel (CLCN1), but the genotype/phenotype correlation remains unclear. PATIENT CONCERNS: A 48-year-old man, from consanguineous parents, presented with a fixed muscle weakness, muscle atrophy, and a cognitive impairment. Notably, his brother presented the same mutation but with a different phenotype, mainly involving cognitive function...
June 2018: Medicine (Baltimore)
David J Coote, Mark R Davis, Macarena Cabrera, Merrilee Needham, Nigel G Laing, Kristen J Nowak
No abstract text is available yet for this article.
July 2018: European Journal of Human Genetics: EJHG
B C Stunnenberg, J Raaphorst, J C W Deenen, T P Links, A A Wilde, D J Verbove, E J Kamsteeg, A van den Wijngaard, C G Faber, G J van der Wilt, B G M van Engelen, G Drost, H B Ginjaar
Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100...
May 2018: Neuromuscular Disorders: NMD
C Altamura, G F Mangiatordi, O Nicolotti, D Sahbani, A Farinato, F Leonetti, M R Carratù, D Conte, J-F Desaphy, P Imbrici
BACKGROUND AND PURPOSE: Although chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is limited. ClC-1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC-1 blockers have been discovered, such as anthracene-9-carboxylic acid (9-AC) and niflumic acid (NFA), whereas no activator exists...
May 2018: British Journal of Pharmacology
Ibrahim Sahin, Haktan B Erdem, Huseyin Tan, Abdulgani Tatar
Myotonia congenita is an inherited muscle disease present from childhood that is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness; moreover, skeletal striated muscle groups may be involved. Myotonia congenita occurs due to chloride (Cl) channel mutations that reduce the stabilizing Cl conductance, and it is caused by mutations in the CLCN1 gene. This paper describes four patients from two different healthy consanguineous Turkish families with muscle stiffness and easy fatigability...
February 26, 2018: Acta Neurologica Belgica
Yang-Qi Xu, Xiao-Li Liu, Xiao-Jun Huang, Wo-Tu Tian, Hui-Dong Tang, Li Cao
No abstract text is available yet for this article.
February 20, 2018: Chinese Medical Journal
Héctor Gaitán-Peñas, Mercedes Armand-Ugón, Alfons Macaya, Raúl Estévez
INTRODUCTION: Mutations in CLCN1 cause recessive or dominant forms of myotonia congenita (MC). Some mutations have been found to exhibit both patterns of inheritance but the mechanism explaining this behavior is unknown. METHODS: A known recessive missense mutation, A493E, was identified in a family with dominant MC. The mutant p.A493E alone or in co-expression with wild-type (WT) ClC-1 was expressed in Xenopus oocytes. Currents were measured and biochemical assays were performed...
February 9, 2018: Muscle & Nerve
Rosangela Ferese, Veronica Albano, Mattia Falconi, Federico Iacovelli, Rosa Campopiano, Simona Scala, Anna Maria Griguoli, Anderson Gaglione, Emiliano Giardina, Stefania Zampatti, Marianna Storto, Francesco Fornai, Carmelo D'Alessio, Giuseppe Novelli, Stefano Gambardella
No abstract text is available yet for this article.
December 1, 2017: Archives Italiennes de Biologie
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