TY - JOUR
T1 - Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients
AU - Maggi, Lorenzo
AU - Brugnoni, Raffaella
AU - Canioni, Eleonora
AU - Tonin, Paola
AU - Saletti, Veronica
AU - Sola, Patrizia
AU - Piccinelli, Stefano Cotti
AU - Colleoni, Lara
AU - Ferrigno, Paola
AU - Pini, Antonella
AU - Masson, Riccardo
AU - Manganelli, Fiore
AU - Lietti, Daniele
AU - Vercelli, Liliana
AU - Ricci, Giulia
AU - Bruno, Claudio
AU - Tasca, Giorgio
AU - Pizzuti, Antonio
AU - Padovani, Alessandro
AU - Fusco, Carlo
AU - Pegoraro, Elena
AU - Ruggiero, Lucia
AU - Ravaglia, Sabrina
AU - Siciliano, Gabriele
AU - Morandi, Lucia
AU - Dubbioso, Raffaele
AU - Mongini, Tiziana
AU - Filosto, Massimiliano
AU - Tramacere, Irene
AU - Mantegazza, Renato
AU - Bernasconi, Pia
PY - 2020/7/29
Y1 - 2020/7/29
N2 - 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.
AB - 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.
KW - channelopathies
KW - myotonia
KW - periodic paralysis
KW - SCN4A gene mutation
KW - SNEL
KW - voltage-gated sodium channel Na1.4
UR - http://www.scopus.com/inward/record.url?scp=85089420709&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089420709&partnerID=8YFLogxK
U2 - 10.3389/fneur.2020.00646
DO - 10.3389/fneur.2020.00646
M3 - Article
AN - SCOPUS:85089420709
VL - 11
JO - Frontiers in Neurology
JF - Frontiers in Neurology
SN - 1664-2295
M1 - 646
ER -