Expanding the spectrum of congenital myopathy linked to recessive mutations in
            <i>SCN4A</i>

Mercier, Sandra; Lornage, Xavière; Malfatti, Edoardo; Marcorelles, Pascale; Letournel, Franck; Boscher, Cécile; Caillaux, Gaêlle; Magot, Armelle; Böhm, Johann; Boland, Anne; Deleuze, Jean‐François; Romero, Norma B.; Péreón, Yann; Laporte, Jocelyn

doi:10.1212/wnl.0000000000003535

Cited by 13 publications

(8 citation statements)

References 7 publications

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“…Muscle biopsies were consistent with a congenital myopathy but without specific diagnostic features 6 . A second report of three brothers with compound heterozygous SCN4A mutations confirmed a very similar phenotype 25 . A much milder congenital myopathy without respiratory or bulbar compromise was subsequently reported in two brothers with compound heterozygous SCN4A mutations.…”

Section: Congenital Myopathy and Foetal Hypokinesiamentioning

confidence: 72%

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Matthews

Balestrini

Sisodiya

et al. 2020

The Lancet Child & Adolescent Health

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Voltage gated sodium channels are essential for excitability of skeletal muscle fibres and neurones. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm/stridor, congenital myasthenia and myopathy. Recent evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised brain sodium channelopathy phenotypes include several epilepsy disorders and complex encephalopathies. Together these early onset muscle and brain phenotypes have a significant morbidity and an appreciable mortality rate but there have been significant advances in understanding the pathophysiological mechanisms underlying them and these have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. Here, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We outline a diagnostic approach and review the available treatment options.

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Section: Congenital Myopathy and Foetal Hypokinesiamentioning

confidence: 72%

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Matthews

Balestrini

Sisodiya

et al. 2020

The Lancet Child & Adolescent Health

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“…This study reported 11 cases from 6 kindred, including 7 deaths during perinatal period and 4 adults presenting with congenital myopathy without myotonia. Several patients with variable myopathic traits have been since reported [214][215][216]. These cases likely represent a continuum of congenital myasthenia with the occurrence of more severe loss-of-function mutations with at least one null mutation (mutation that does not produce any functional protein) [217].…”

Section: Congenital Myopathies Related To Scn4a/cacna1smentioning

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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“…Several tests are performed to diagnose CM, including blood tests, electromyography, muscle biopsy and genetic testing. Fifteen recessive SCN4A mutations have been reported in nine unrelated kindreds with various severities of muscle weakness ranging from fetal hypokinesia (decreased or absent movements in utero ) lethal at birth to “classical” CM for 11 individuals ( Zaharieva et al, 2016 ; Gonorazky et al, 2017 ; Mercier et al, 2017 ; Sloth et al, 2018 ). Electromyographic investigations showed myopathic changes for some but not all individuals with classical CM (5 out 7).…”

Section: Loss-of-function Mutations In Scn4a and Muscle Weaknessmentioning

confidence: 99%

New Challenges Resulting From the Loss of Function of Nav1.4 in Neuromuscular Diseases

Nicole

Lory

2021

Front. Pharmacol.

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The voltage-gated sodium channel Nav1.4 is a major actor in the excitability of skeletal myofibers, driving the muscle force in response to nerve stimulation. Supporting further this key role, mutations in SCN4A, the gene encoding the pore-forming α subunit of Nav1.4, are responsible for a clinical spectrum of human diseases ranging from muscle stiffness (sodium channel myotonia, SCM) to muscle weakness. For years, only dominantly-inherited diseases resulting from Nav1.4 gain of function (GoF) were known, i.e., non-dystrophic myotonia (delayed muscle relaxation due to myofiber hyperexcitability), paramyotonia congenita and hyperkalemic or hypokalemic periodic paralyses (episodic flaccid muscle weakness due to transient myofiber hypoexcitability). These last 5 years, SCN4A mutations inducing Nav1.4 loss of function (LoF) were identified as the cause of dominantly and recessively-inherited disorders with muscle weakness: periodic paralyses with hypokalemic attacks, congenital myasthenic syndromes and congenital myopathies. We propose to name this clinical spectrum sodium channel weakness (SCW) as the mirror of SCM. Nav1.4 LoF as a cause of permanent muscle weakness was quite unexpected as the Na+ current density in the sarcolemma is large, securing the ability to generate and propagate muscle action potentials. The properties of SCN4A LoF mutations are well documented at the channel level in cellular electrophysiological studies However, much less is known about the functional consequences of Nav1.4 LoF in skeletal myofibers with no available pertinent cell or animal models. Regarding the therapeutic issues for Nav1.4 channelopathies, former efforts were aimed at developing subtype-selective Nav channel antagonists to block myofiber hyperexcitability. Non-selective, Nav channel blockers are clinically efficient in SCM and paramyotonia congenita, whereas patient education and carbonic anhydrase inhibitors are helpful to prevent attacks in periodic paralyses. Developing therapeutic tools able to counteract Nav1.4 LoF in skeletal muscles is then a new challenge in the field of Nav channelopathies. Here, we review the current knowledge regarding Nav1.4 LoF and discuss the possible therapeutic strategies to be developed in order to improve muscle force in SCW.

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Expanding the spectrum of congenital myopathy linked to recessive mutations in SCN4A

Cited by 13 publications

References 7 publications

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

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

New Challenges Resulting From the Loss of Function of Nav1.4 in Neuromuscular Diseases

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