Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients.

Lorenzo Maggi,Patrizia Sola,Lucia Ruggiero,Liliana Vercelli,Raffaele Dubbioso,Veronica Saletti,Paola Tonin,Irene Tramacere,Riccardo Masson,Paola Ferrigno,Massimiliano Filosto,Renato Mantegazza,Gabriele Siciliano,Antonio Pizzuti,Antonella Pini,Lara Colleoni,Raffaella Brugnoni,Claudio Bruno,Lucia Morandi,Carlo Fusco,Fiore Manganelli,Giorgio Tasca,Elena Pegoraro,Giulia Ricci,Alessandro Padovani,Sabrina Ravaglia,Pia Bernasconi,Tiziana Mongini,Stefano Cotti Piccinelli,Daniele Lietti,Eleonora Canioni

doi:10.3389/fneur.2020.00646

Abstract

Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis.Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A.Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains.Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.

Highlights

The SCN4A gene on chromosome 17q23 encodes the α-subunit of the voltage-gated sodium channel NaV1.4, responsible for the generation of action potentials and excitation of skeletal muscle fibers
Clinical phenotypes were defined on the basis of predominant symptom; in the myotonia subgroup, we identified paramyotonia congenita (PMC) or sodium-channel myotonia (SCM) according to the presence of paradoxical myotonia or warm-up phenomenon, respectively
Phenotype concordance was observed in all families, except for the two aforementioned families including an asymptomatic subject, one family with the proband showing a neonatal SCN4A, and the mother displaying a mild SCM and two siblings carrying the p.M1592V mutation affected by Hyper/NormoPP and SCM, respectively

Summary

Introduction

The SCN4A gene on chromosome 17q23 encodes the α-subunit of the voltage-gated sodium channel NaV1.4, responsible for the generation of action potentials and excitation of skeletal muscle fibers. Mutations in SCN4A lead to changes in skeletal muscle excitability, which is connected with the activation or inactivation speed of muscle ion channels [1] These mutations are responsible for a wide spectrum of clinical manifestations, ranging from myotonia to periodic paralysis (PP) and recently discovered phenotypes such as severe neonatal episodic laryngospasms, severe fetal hypokinesia or classical congenital myopathy, myalgia, and exercise intolerance, congenital myasthenic syndrome, and sudden infant death syndrome [2,3,4]. Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A based on myotonia and paralysis features, including sodium-channel myotonia (SCM) and paramyotonia congenita (PMC) considered as non-dystrophic myotonias (NDM) and characterized by increased skeletal muscle excitability, and Hypokalemic type II (HypoPP2) and Hyperkalemic/Normokalemic PP (HyperPP/NormoPP), instead associated with reduced excitability. Only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis

Methods

Results

Conclusion