Myotonia in a patient with a mutation in an S4 arginine residue associated with hypokalaemic periodic paralysis and a concomitant synonymous CLCN1 mutation

Thor, Michael G.; Vivekanandam, Vinojini; Sampedro‐Castañeda, Marisol; Tan, S. Veronica; Suetterlin, Karen; Sud, Richa; Durran, S.; Schorge, Stephanie; Kullmann, Dimitri M.; Hanna, Michael G.; Matthews, Emma; Männikkö, Roope

doi:10.1038/s41598-019-54041-0

Cited by 15 publications

(22 citation statements)

References 38 publications

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“…However, in both Ile215Thr and Gly241Val mutants, the shift in the voltage dependence of activation toward hyperpolarized potentials also accelerated the rate of the open-state inactivation, a mechanism consistent with a loss-of-function effect. This characteristic has already been observed by Petitprez et al ( 10), but has not been described for other mutants (13,14), which anyway showed a similar left shift for the voltage dependence of activation.…”

Section: Discussionsupporting

confidence: 69%

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4

et al. 2020

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Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Na v 1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Na v 1.4 channel. The families described have been clinically and genetically evaluated. p.Ile215Thr and p.Gly241Val lie, respectively, on extracellular and intracellular loops of the first domain of the Na v 1.4 channel. We assessed that the p.Ile215Thr mutation can be related to a founder effect in people from Southern Italy. Electrophysiological evaluation of the channel function showed that the voltage dependence of the activation for both the mutant channels was significantly shifted toward hyperpolarized potentials (Ile215Thr: −28.6 ± 1.5 mV and Gly241Val: −30.2 ± 1.3 mV vs. WT: −18.5 ± 1.3 mV). The slow inactivation was also significantly affected, whereas fast inactivation showed a different behavior in the two mutants. We characterized two novel mutations of the SCN4A gene expanding the knowledge about genetics of mild forms of myotonia, and we present, to our knowledge, the first homozygous patient with sodium channel myotonia.

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Section: Discussionsupporting

confidence: 69%

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4

et al. 2020

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“…VI: 3 was affected with concomitant mutations in both the CLCN1 and SCN4A genes. Other researchers have also reported a few patients with the same genes mutated (Table 3) [15][16][17][18]. These patients showed an atypical phenotype, suggesting that concomitant mutations may act synergistically to influence the phenotype [19].…”

Section: Discussionmentioning

confidence: 87%

Myotonia congenita and periodic hypokalemia paralysis in a consanguineous marriage pedigree: Coexistence of a novel CLCN1 mutation and an SCN4A mutation

et al. 2020

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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 Na v 1.4. 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.

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“…It is worthy to note that reports have been published regarding patients carrying both CLCN1 and SCN4A mutations or in concomitance with myotonic dystrophy nucleotide repeats, which may increase further the complexity of treatment [3,[92][93][94][95][96][97][98][99].…”

Section: O R R E C T E D P R O O Fmentioning

confidence: 99%

“…In addition, another mechanism is likely involved in the pathogenesis of hypoPP, which is the creation of an aberrant gating pore [178][179][180]. Such gating pore has been found to occur in most hypoPP channel mutants [99,[181][182][183][184][185][186], and allows small leakage cationic currents at resting membrane potential that facilitates the paradoxical depolarization at low [K + ] causing muscle weakness [15].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

Desaphy

Altamura

Vicart

et al. 2021

JND

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Background: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP. Objective: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background. Methods: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process. Results: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from DCP compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies. Conclusions: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.

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Myotonia in a patient with a mutation in an S4 arginine residue associated with hypokalaemic periodic paralysis and a concomitant synonymous CLCN1 mutation

Cited by 15 publications

References 38 publications

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4

Myotonia congenita and periodic hypokalemia paralysis in a consanguineous marriage pedigree: Coexistence of a novel CLCN1 mutation and an SCN4A mutation

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

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