The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform
Louis J. Ptáček - One of the best experts on this subject based on the ideXlab platform.
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functional consequences of chloride channel gene clcn1 mutations causing Myotonia congenita
Neurology, 2000Co-Authors: Jie Zhang, Said Bendahhou, Michael C Sanguinetti, Louis J. PtáčekAbstract:Objective: To determine the functional consequences of missense mutations within the skeletal muscle chloride channel gene CLCN1 that cause Myotonia congenita. Background: Myotonia congenita is a genetic muscle disease associated with abnormalities in the skeletal muscle voltage-gated chloride (ClC-1) channel. In order to understand the molecular basis of this inherited disease, it is important to determine the physiologic consequences of mutations found in patients affected by it. Methods: The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations. Results: The I329T mutation shifted the voltage dependence of open probability of ClC-1 channels to the right by 192 mV, and the R338Q mutation shifted it to the right by 38 mV. In addition, the I329T ClC-1 channels deactivated to a lesser extent than normal at negative potentials. The V165G, F167L, and F413C ClC-1 channels also shifted the voltage dependence of open probability, but only by +14 to +20 mV. Conclusions: The functional consequences of these mutations form the physiologic argument that these are disease-causing mutations and could lead to Myotonia congenita by impairing the ability of the skeletal muscle voltage-gated chloride channels to maintain normal muscle excitability. Understanding of genetic and physiologic defects may ultimately lead to better diagnosis and treatment of patients with Myotonia congenita.
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mutations in the human skeletal muscle chloride channel gene clcn1 associated with dominant and recessive Myotonia congenita
Neurology, 1996Co-Authors: Jie Zhang, Robert C. Griggs, Alfred L. George, G T Fouad, J W Roberts, Hubert Kwiecinski, Anne M Connolly, Louis J. PtáčekAbstract:Myotonia, defined as delayed relaxation of muscle after contraction, is seen in a group of genetic disorders that includes autosomal dominant Myotonia congenita (Thomsen9s disease) and autosomal recessive Myotonia congenita (Becker9s disease).Both disorders are characterized electrophysiologically by increased excitability of muscle fibers, reflected in clinical Myotonia. These diseases are similar except that transient weakness is seen in patients with Becker9s, but not Thomsen9s disease. Becker9s and Thomsen9s diseases are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Genetic screening of a panel of 18 consecutive Myotonia congenita (MC) probands for mutation in CLCN1 revealed that a novel Gln-68-Stop nonsense mutation predicts premature truncation of the chloride channel protein. Four previously reported mutations, Arg-894-stop, Arg-338-Gln, Gly-230-Glu, and del 1437-1450, were also noted in our sample set. The Arg-338-Gln and Gly-230-Glu mutations were found in patients with different phenotypes from those of previous reports. Further study of the Arg-338-Gln and Gly-230-Glu alleles may shed light on variable modes of transmission (dominant versus recessive) in different families. Physiologic study of these mutations may lead to better understanding of the pathophysiology of Myotonia in these patients and of voltage-gated chloride channel structure/function relationships in skeletal muscles. NEUROLOGY 1996;47: 993-998
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Linkage of atypical Myotonia congenita to a sodium channel locus
Neurology, 1992Co-Authors: Louis J. Ptáček, Robert C. Griggs, Rabi Tawil, D. Storvick, Mark LeppertAbstract:We performed linkage analysis in a pedigree segregating an allele for autosomal dominant, painful Myotonia that is potassium sensitive and responsive to acetazolamide. This allele was tightly linked to a skeletal-muscle, sodium channel locus which is now a candidate for the site of the mutational defect in acetazolamide-responsive Myotonia congenita. Since this sodium channel locus is completely linked to the disease allele in all hyperkalemic periodic paralysis and paraMyotonia congenita pedigrees studied, the molecular alteration causing acetazolamide-responsive Myotonia congenita is likely an allelic defect in this human, skeletal-muscle, sodium channel gene.
Mark M Rich - One of the best experts on this subject based on the ideXlab platform.
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The mechanism underlying transient weakness in Myotonia congenita
2020Co-Authors: Jessica H. Myers, Chris Dupont, Ahmed A Hawash, Andrew A Voss, Kirsten Denman, Kevin R. Novak, Andrew Koesters, Manfred Grabner, Anamika Dayal, Mark M RichAbstract:Abstract In addition to the hallmark muscle stiffness, patients with recessive Myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We made intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to −25 to −35 mV in the genetic and pharmacologic models of Becker disease. Both Na+ and Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through Naγ1.4 channels is the key trigger of plateau potentials and current through Cav1.1 Ca2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in Myotonia congenita. Impact Statement Transient weakness in Myotonia congenita is caused by depolarization secondary to activation of persistent Na+ current in skeletal muscle.
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treatment of Myotonia congenita with retigabine in mice
Experimental Neurology, 2019Co-Authors: Chris Dupont, Kirsten S Denman, Ahmed A Hawash, Andrew A Voss, Mark M RichAbstract:Abstract 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. In this study, we found that retigabine greatly reduced the duration of Myotonia in vitro. Detailed study of its mechanism of action revealed that retigabine had no effect on any of the traditional measures of muscle excitability such as resting potential, input resistance or the properties of single action potentials. Instead it appears to shorten Myotonia by activating K+ current during trains of action potentials. Retigabine also greatly reduced the severity of Myotonia in vivo, which was measured using a muscle force transducer. Despite its efficacy in vivo, retigabine did not improve motor performance of mice with Myotonia congenita. There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability.
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Open-label trial of ranolazine for the treatment of Myotonia congenita
Neurology, 2017Co-Authors: W. David Arnold, Ahmed A Hawash, Mark M Rich, Kevin R. Novak, David Kline, Alan Sanderson, Amy Bartlett, John T. KisselAbstract:Objective: To determine open-label, pilot study whether ranolazine could improve signs and symptoms of Myotonia and muscle stiffness in patients with Myotonia congenita (MC). Methods: Thirteen participants were assessed at baseline and 2, 4, and 5 weeks. Ranolazine was started after baseline assessment (500 mg twice daily), increased as tolerated after week 2 (1,000 mg twice daily), and maintained until week 4. Outcomes included change from baseline to week 4 in self-reported severity of symptoms (stiffness, weakness, and pain), Timed Up and Go (TUG), hand grip and eyelid Myotonia, and Myotonia on EMG. Results: Self-reported severity of stiffness ( p p p = 0.03, p = 0.01). EMG of the abductor digiti minimi and tibialis anterior showed significantly reduced Myotonia duration ( p p Conclusions: Ranolazine appeared to be well tolerated over a period of 4 weeks in individuals with MC, and ranolazine resulted in improvement of signs and symptoms of muscle stiffness. The findings of this study suggest that ranolazine should be investigated in a larger controlled study. Classification of evidence: This study provides Class IV evidence that ranolazine improves Myotonia in Myotonia congenita.
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Sodium channel slow inactivation as a therapeutic target for Myotonia congenita.
Annals of neurology, 2015Co-Authors: Kevin R. Novak, Jennifer Norman, Jacob R. Mitchell, Martin J. Pinter, Mark M RichAbstract:Objective Patients with Myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (Myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy. Methods To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of Myotonia congenita. Results Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for Myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat Myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of Myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects. Interpretation We conclude that ranolazine has excellent therapeutic potential for treatment of patients with Myotonia congenita. Ann Neurol 2015;77:320–332.
Mark Leppert - One of the best experts on this subject based on the ideXlab platform.
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Linkage of atypical Myotonia congenita to a sodium channel locus
Neurology, 1992Co-Authors: Louis J. Ptáček, Robert C. Griggs, Rabi Tawil, D. Storvick, Mark LeppertAbstract:We performed linkage analysis in a pedigree segregating an allele for autosomal dominant, painful Myotonia that is potassium sensitive and responsive to acetazolamide. This allele was tightly linked to a skeletal-muscle, sodium channel locus which is now a candidate for the site of the mutational defect in acetazolamide-responsive Myotonia congenita. Since this sodium channel locus is completely linked to the disease allele in all hyperkalemic periodic paralysis and paraMyotonia congenita pedigrees studied, the molecular alteration causing acetazolamide-responsive Myotonia congenita is likely an allelic defect in this human, skeletal-muscle, sodium channel gene.
Coşkun Özdemir - One of the best experts on this subject based on the ideXlab platform.
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Electrical Myotonia in heterozygous carriers of recessive Myotonia congenita
Muscle & nerve, 1999Co-Authors: Feza Deymeer, Reinhardt Rüdel, Frank Lehmann-horn, Piraye Serdaroglu, Sevinç Çakirkaya, Sandra Benz, Coşkun ÖzdemirAbstract:We investigated electrophysiologically the unaffected parents of patients with recessive Myotonia congenita. We studied 18 families, in nine of which the diagnosis was confirmed by molecular genetics. Brief myotonic discharges were present in at least one parent in 67% of the families. Fathers were more likely than mothers to show these discharges. The difficulty in distinguishing very mildly affected parents with dominant Myotonia congenita from the heterozygous carriers of recessive Myotonia congenita is stressed.
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Transient weakness and compound muscle action potential decrement in Myotonia congenita.
Muscle & nerve, 1998Co-Authors: Feza Deymeer, Reinhardt Rüdel, Frank Lehmann-horn, Piraye Serdaroglu, Sevinnç Çakirkaya, Lothar Schleithoff, Coşkun ÖzdemirAbstract:Twenty-five Turkish patients with recessive Myotonia congenita (RMC), 16 of whom had genetic confirmation, were studied. Nineteen had transient weakness. In the upper extremities, onset age of transient weakness was usually in the early teens. All untreated RMC patients had a compound muscle action potential decrement of ⩾25%, usually above 50%, with repetitive nerve stimulation at 10/s for 5 s. Patients with other nondystrophic diseases with Myotonia, except 1 patient with dominant Myotonia congenita, had no transient weakness and a CMAP decrement below 25%. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1334–1337, 1998.
Robert C. Griggs - One of the best experts on this subject based on the ideXlab platform.
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mutations in the human skeletal muscle chloride channel gene clcn1 associated with dominant and recessive Myotonia congenita
Neurology, 1996Co-Authors: Jie Zhang, Robert C. Griggs, Alfred L. George, G T Fouad, J W Roberts, Hubert Kwiecinski, Anne M Connolly, Louis J. PtáčekAbstract:Myotonia, defined as delayed relaxation of muscle after contraction, is seen in a group of genetic disorders that includes autosomal dominant Myotonia congenita (Thomsen9s disease) and autosomal recessive Myotonia congenita (Becker9s disease).Both disorders are characterized electrophysiologically by increased excitability of muscle fibers, reflected in clinical Myotonia. These diseases are similar except that transient weakness is seen in patients with Becker9s, but not Thomsen9s disease. Becker9s and Thomsen9s diseases are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Genetic screening of a panel of 18 consecutive Myotonia congenita (MC) probands for mutation in CLCN1 revealed that a novel Gln-68-Stop nonsense mutation predicts premature truncation of the chloride channel protein. Four previously reported mutations, Arg-894-stop, Arg-338-Gln, Gly-230-Glu, and del 1437-1450, were also noted in our sample set. The Arg-338-Gln and Gly-230-Glu mutations were found in patients with different phenotypes from those of previous reports. Further study of the Arg-338-Gln and Gly-230-Glu alleles may shed light on variable modes of transmission (dominant versus recessive) in different families. Physiologic study of these mutations may lead to better understanding of the pathophysiology of Myotonia in these patients and of voltage-gated chloride channel structure/function relationships in skeletal muscles. NEUROLOGY 1996;47: 993-998
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Linkage of atypical Myotonia congenita to a sodium channel locus
Neurology, 1992Co-Authors: Louis J. Ptáček, Robert C. Griggs, Rabi Tawil, D. Storvick, Mark LeppertAbstract:We performed linkage analysis in a pedigree segregating an allele for autosomal dominant, painful Myotonia that is potassium sensitive and responsive to acetazolamide. This allele was tightly linked to a skeletal-muscle, sodium channel locus which is now a candidate for the site of the mutational defect in acetazolamide-responsive Myotonia congenita. Since this sodium channel locus is completely linked to the disease allele in all hyperkalemic periodic paralysis and paraMyotonia congenita pedigrees studied, the molecular alteration causing acetazolamide-responsive Myotonia congenita is likely an allelic defect in this human, skeletal-muscle, sodium channel gene.
