Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxiaResearch in context
Hang Lyu,
Christian M. Boßelmann,
Katrine M. Johannesen,
Mahmoud Koko,
Juan Dario Ortigoza-Escobar,
Sergio Aguilera-Albesa,
Deyanira Garcia-Navas Núñez,
Tarja Linnankivi,
Eija Gaily,
Henriette J.A. van Ruiten,
Ruth Richardson,
Cornelia Betzler,
Gabriella Horvath,
Eva Brilstra,
Niels Geerdink,
Daniele Orsucci,
Alessandra Tessa,
Elena Gardella,
Zofia Fleszar,
Ludger Schöls,
Holger Lerche,
Rikke S. Møller,
Yuanyuan Liu
Affiliations
Hang Lyu
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
Christian M. Boßelmann
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
Katrine M. Johannesen
Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark; Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre (Member of the ERN EpiCARE), Dianalund, Denmark
Mahmoud Koko
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
Juan Dario Ortigoza-Escobar
Movement Disorders Unit, Institut de Recerca Sant Joan de Déu, CIBERER-ISCIII and European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain
Sergio Aguilera-Albesa
Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario de Navarra, Pamplona, Spain; Navarrabiomed-Fundación Miguel Servet, Pamplona, Spain
Deyanira Garcia-Navas Núñez
Pediatrics Department, San Pedro de Alcántara Hospital, Cáceres, Spain
Tarja Linnankivi
Department of Pediatric Neurology, New Children's Hospital and Pediatric Research Center, Epilepsia Helsinki, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Eija Gaily
Department of Pediatric Neurology, New Children's Hospital and Pediatric Research Center, Epilepsia Helsinki, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Henriette J.A. van Ruiten
Newcastle Upon Tyne Hospitals NHS Foundation Trust, Great North Children's Hospital, Newcastle upon Tyne, UK
Ruth Richardson
Northern Genetics Service, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, UK
Cornelia Betzler
Institute for Rehabilitation, Transition and Palliation, Paracelsus Medical University, Salzburg, Austria; Specialist Center for Paediatric Neurology, Neuro-Rehabilitation and Epileptology, Schön Klinik Vogtareuth, Germany
Gabriella Horvath
Adult Metabolic Diseases Clinic, BC Children's Hospital, Vancouver, Canada
Eva Brilstra
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Niels Geerdink
Department of Pediatrics, Rijnstate Hospital, Arnhem, the Netherlands
Daniele Orsucci
Unit of Neurology, San Luca Hospital, Lucca, Italy
Alessandra Tessa
IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy
Elena Gardella
Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Denmark
Zofia Fleszar
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Ludger Schöls
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Holger Lerche
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
Rikke S. Møller
Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Denmark
Yuanyuan Liu
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; Corresponding author. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Otfried-Mueller-Str. 27, D-72076, Tuebingen. Germany.
Summary: Background: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype–phenotype correlations of SCN8A-related ataxia. Methods: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. Findings: Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. Interpretation: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. Funding: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.
