Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients
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 phe...
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2020.00646/full |
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| author | Lorenzo Maggi Raffaella Brugnoni Eleonora Canioni Paola Tonin Veronica Saletti Patrizia Sola Stefano Cotti Piccinelli Lara Colleoni Paola Ferrigno Antonella Pini Riccardo Masson Fiore Manganelli Daniele Lietti Liliana Vercelli Giulia Ricci Claudio Bruno Giorgio Tasca Antonio Pizzuti Antonio Pizzuti Alessandro Padovani Carlo Fusco Elena Pegoraro Lucia Ruggiero Sabrina Ravaglia Gabriele Siciliano Lucia Morandi Raffaele Dubbioso Tiziana Mongini Massimiliano Filosto Irene Tramacere Renato Mantegazza Pia Bernasconi |
| author_facet | Lorenzo Maggi Raffaella Brugnoni Eleonora Canioni Paola Tonin Veronica Saletti Patrizia Sola Stefano Cotti Piccinelli Lara Colleoni Paola Ferrigno Antonella Pini Riccardo Masson Fiore Manganelli Daniele Lietti Liliana Vercelli Giulia Ricci Claudio Bruno Giorgio Tasca Antonio Pizzuti Antonio Pizzuti Alessandro Padovani Carlo Fusco Elena Pegoraro Lucia Ruggiero Sabrina Ravaglia Gabriele Siciliano Lucia Morandi Raffaele Dubbioso Tiziana Mongini Massimiliano Filosto Irene Tramacere Renato Mantegazza Pia Bernasconi |
| author_sort | Lorenzo Maggi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T08:09:24Z |
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| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-11T08:09:24Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-1a3f02ad30c0483c9785aa5d4fd702c82022-12-22T01:14:55ZengFrontiers Media S.A.Frontiers in Neurology1664-22952020-07-011110.3389/fneur.2020.00646522627Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian PatientsLorenzo Maggi0Raffaella Brugnoni1Eleonora Canioni2Paola Tonin3Veronica Saletti4Patrizia Sola5Stefano Cotti Piccinelli6Lara Colleoni7Paola Ferrigno8Antonella Pini9Riccardo Masson10Fiore Manganelli11Daniele Lietti12Liliana Vercelli13Giulia Ricci14Claudio Bruno15Giorgio Tasca16Antonio Pizzuti17Antonio Pizzuti18Alessandro Padovani19Carlo Fusco20Elena Pegoraro21Lucia Ruggiero22Sabrina Ravaglia23Gabriele Siciliano24Lucia Morandi25Raffaele Dubbioso26Tiziana Mongini27Massimiliano Filosto28Irene Tramacere29Renato Mantegazza30Pia Bernasconi31Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyNeuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyNeuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalySection of Clinical Neurology, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, ItalyDevelopmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyClinica Neurologica, Azienda Ospedaliero Universitaria di Modena, Modena, ItalyUnit of Neurology, Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia, Brescia, ItalyNeuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalySC Neurologia e Stroke Unit, Azienda Ospedaliera Brotzu, Cagliari, ItalyChild Neurology and Psychiatry Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, ItalyDevelopmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, Naples, ItalyPediatric Unit, Ospedale Valduce, Como, Italy0Department of Neurosciences Rita Levi Montalcini, University of Turin, Turin, Italy1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy2Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy3Unità Operativa Complessa di Neurologia, Dipartimento di Scienze Dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy4Fondazione IRCCS Casa Sollievo della Sofferenza, Laboratory of Medical Genetics, San Giovanni Rotondo, Italy5Department of Experimental Medicine, Sapienza University of Rome, Rome, ItalyUnit of Neurology, Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia, Brescia, Italy6Dipartimento Materno-Infantile, S.C. Neuropsichiatria Infantile, Presidio Ospedaliero Provinciale Santa Maria Nuova, IRCCS di Reggio Emilia, Reggio Emilia, Italy7Department of Neurosciences, University of Padova, Padova, ItalyDepartment of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, Naples, Italy8Emergency Neurology, IRCCS Mondino Foundation, Pavia, Italy1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ItalyNeuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, Naples, Italy0Department of Neurosciences Rita Levi Montalcini, University of Turin, Turin, ItalyUnit of Neurology, Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia, Brescia, Italy9Research and Clinical Development Department, Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyNeuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyNeuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyBackground: 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.https://www.frontiersin.org/article/10.3389/fneur.2020.00646/fullmyotoniaperiodic paralysisSNELchannelopathiesvoltage-gated sodium channel NaV1.4SCN4A gene mutation |
| spellingShingle | Lorenzo Maggi Raffaella Brugnoni Eleonora Canioni Paola Tonin Veronica Saletti Patrizia Sola Stefano Cotti Piccinelli Lara Colleoni Paola Ferrigno Antonella Pini Riccardo Masson Fiore Manganelli Daniele Lietti Liliana Vercelli Giulia Ricci Claudio Bruno Giorgio Tasca Antonio Pizzuti Antonio Pizzuti Alessandro Padovani Carlo Fusco Elena Pegoraro Lucia Ruggiero Sabrina Ravaglia Gabriele Siciliano Lucia Morandi Raffaele Dubbioso Tiziana Mongini Massimiliano Filosto Irene Tramacere Renato Mantegazza Pia Bernasconi Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients Frontiers in Neurology myotonia periodic paralysis SNEL channelopathies voltage-gated sodium channel NaV1.4 SCN4A gene mutation |
| title | Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients |
| title_full | Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients |
| title_fullStr | Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients |
| title_full_unstemmed | Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients |
| title_short | Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients |
| title_sort | clinical and molecular spectrum of myotonia and periodic paralyses associated with mutations in scn4a in a large cohort of italian patients |
| topic | myotonia periodic paralysis SNEL channelopathies voltage-gated sodium channel NaV1.4 SCN4A gene mutation |
| url | https://www.frontiersin.org/article/10.3389/fneur.2020.00646/full |
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