Inhibiting persistent inward sodium currents prevents myotonia

Hawash, Ahmed; Voss, Andrew A.; Rich, Mark M.

doi:10.1002/ana.25017

Cited by 18 publications

(35 citation statements)

References 37 publications

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“…Recordings were performed as previously described (Hawash, et al, 2017;Novak, et al, 2015). Briefly, prior to removal of extensor digitorum longus (EDL) muscle for recording, mice were killed by CO 2 inhalation followed by cervical dislocation.…”

Section: Electrophysiologymentioning

confidence: 99%

“…Experiments were performed on mice with homozygous null mutation for the ClCn1 gene (ClC adr mice, adr stands for arrested development of righting response) (Hawash, et al, 2017;Novak, et al, 2015). A second model of myotonia was obtained by exposing muscle from unaffected littermates to 100 μM 9-Anthracene-carboxylic acid (9AC) to acutely block ClC-1 chloride channels, which is termed 9AC-induced myotonia .…”

Section: The Mechanism Underlying Efficacy Of Retigabine Against Myotmentioning

confidence: 99%

“…We recently discovered that a small, subthreshold Na + current that lacks fast inactivation (Na persistent inward current, NaPIC), plays a central role in triggering myotonia (Hawash, et al, 2017). A theoretically attractive way to combat the depolarization triggered by activation of NaPIC is to increase resting membrane conductance.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of myotonia congenita with retigabine in mice

Dupont

Denman

Hawash

et al. 2019

Experimental Neurology

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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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Section: Electrophysiologymentioning

confidence: 99%

Section: The Mechanism Underlying Efficacy Of Retigabine Against Myotmentioning

confidence: 99%

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Treatment of myotonia congenita with retigabine in mice

Dupont

Denman

Hawash

et al. 2019

Experimental Neurology

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“…Amongst the sodium channel gain-of-function defects known to cause myotonia, a left shift of activation is especially potent (e.g., compared to the more common cause from a slower rate of inactivation) because of the effect on action potential threshold (18,19). Consequently, the trains of discharges tend to be very prolonged, lasting more than 10 s ( Figure 5C).…”

Section: Functional Defects Of L796v Mutant Channels Cause Myotonia Imentioning

confidence: 99%

Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L796V Mutation in SCN4A

et al. 2020

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The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene (SCN4A) has expanded with advancements in genetic testing. Autosomal dominant SCN4A mutations were first linked to hyperkalemic periodic paralysis, then subsequently included paramyotonia congenita, several variants of myotonia, and finally hypokalemic periodic paralysis. Biallelic recessive mutations were later identified in myasthenic myopathy and in infants showing a severe congenital myopathy with hypotonia. We report a patient with a pathogenic de novo SCN4A variant, c.2386C>G p.L796V at a highly conserved leucine. The phenotype was manifest at birth with arthrogryposis multiplex congenita, severe episodes of bronchospasm that responded immediately to carbamazepine therapy, and electromyographic evidence of widespread myotonia. Another de novo case of p.L796V has been reported with hip dysplasia, scoliosis, myopathy, and later paramyotonia. Expression studies of L796V mutant channels showed predominantly gain-of-function changes, that included defects of slow inactivation. Computer simulations of muscle excitability reveal a strong predisposition to myotonia with exceptionally prolonged bursts of discharges, when the L796V defects are included. We propose L796V is a pathogenic variant, that along with other cases in the literature, defines a new dominant SCN4A disorder of myotonic myopathy with secondary congenital joint and skeletal involvement.

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“…Ranolazine, an anti-anginal drug, demonstrated antimyotonic properties in both myotonic congenita and paramyotonia congenita model [60][61][62]. In contrast to mexiletine and lamotrigine, which enhance fast inactivation of voltage-gated sodium channels, ranolazine enhances slow inactivation and blocks persistent voltage-dependent sodium inward current [61][62][63][64][65].…”

Section: Ranolazinementioning

confidence: 99%

Treatment Updates for Neuromuscular Channelopathies

Jitpimolmard

Matthews

Fialho

2020

Curr Treat Options Neurol

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Purpose of review This article aims to review the current and upcoming treatment options of primary muscle channelopathies including the non-dystrophic myotonias and periodic paralyses. Recent findings The efficacy of mexiletine in the treatment of myotonia is now supported by two randomised placebo-controlled trials, one of which utilised a novel aggregated n-of-1 design. This has resulted in licencing of the drug via orphan drug status. There is also good evidence that mexiletine is well tolerated and safe in this patient group without the need for intensive monitoring. A range of alternative antimyotonic treatment options include lamotrigine, carbamazepine and ranolazine exist with variable evidence base. In vitro studies have shown insight into reasons for treatment failure of some medications with certain genotypes opening the era of mutation-specific therapy such as use of flecainide. In the periodic paralyses, the ability of MRI to distinguish between reversible oedema and irreversible fatty replacement makes it an increasingly useful tool to guide and assess pharmacological treatment. Unfortunately, the striking efficacy of bumetanide in hypokalaemic periodic paralysis animal models was not replicated in a recent pilot study in humans. Summary The treatment of skeletal muscle channelopathies combines dietary and lifestyle advice together with pharmacological interventions. The rarity of these conditions remains a barrier for clinical studies but the example of the aggregated n-of-1 trial of mexiletine shows that innovative trial design can overcome these hurdles. Further research is required to test efficacy of drugs shown to have promising characteristics in preclinical experiments such as safinamide, riluzule and magnesium for myotonia or bumetanide for hypokalaemic periodic paralysis.

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Inhibiting persistent inward sodium currents prevents myotonia

Cited by 18 publications

References 37 publications

Treatment of myotonia congenita with retigabine in mice

Treatment of myotonia congenita with retigabine in mice

Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L796V Mutation in SCN4A

Treatment Updates for Neuromuscular Channelopathies

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