| Title: |
Genotype-phenotype correlations in SCN8A -related disorders reveal prognostic and therapeutic implications |
| Authors: |
Johannesen, Katrine; Liu, Yuanyuan; Koko, Mahmoud; Gjerulfsen, Cathrine; Sonnenberg, Lukas; Schubert, Julian; Fenger, Christina; Eltokhi, Ahmed; Rannap, Maert; Koch, Nils; Lauxmann, Stephan; Krüger, Johanna; Kegele, Josua; Canafoglia, Laura; Franceschetti, Silvana; Mayer, Thomas; Rebstock, Johannes; Zacher, Pia; Ruf, Susanne; Alber, Michael; Sterbova, Katalin; Lassuthová, Petra; Vlckova, Marketa; Lemke, Johannes; Platzer, Konrad; Krey, Ilona; Heine, Constanze; Wieczorek, Dagmar; Kroell-Seger, Judith; Lund, Caroline; Klein, Karl Martin; Au, P y Billie; Rho, Jong; Ho, Alice; Masnada, Silvia; Veggiotti, Pierangelo; Giordano, Lucio; Accorsi, Patrizia; Hoei-Hansen, Christina; Striano, Pasquale; Zara, Federico; Verhelst, Helene; Verhoeven, Judith; Braakman, Hilde; van der Zwaag, Bert; Harder, Aster; Brilstra, Eva; Pendziwiat, Manuela; Lebon, Sebastian; Vaccarezza, Maria; Le, Ngoc Minh; Christensen, Jakob; Grønborg, Sabine; Scherer, Stephen; Howe, Jennifer; Fazeli, Walid; Howell, Katherine; Leventer, Richard; Stutterd, Chloe; Walsh, Sonja; Gerard, Marion; Gerard, Bénédicte; Matricardi, Sara; Bonardi, Claudia; Sartori, Stefano; Berger, Andrea; Hoffman-Zacharska, Dorota; Mastrangelo, Massimo; Darra, Francesca; Vøllo, Arve; Motazacker, M Mahdi; Lakeman, Phillis; Nizon, Mathilde; Betzler, Cornelia; Altuzarra, Cecilia; Caume, Roseline; Roubertie, Agathe; Gélisse, Philippe; Marini, Carla; Guerrini, Renzo; Bilan, Frederic; Tibussek, Daniel; Koch-Hogrebe, Margarete; Perry, M Scott; Ichikawa, Shoji; Dadali, Elena; Sharkov, Artem; Mishina, Irina; Abramov, Mikhail; Kanivets, Ilya; Korostelev, Sergey; Kutsev, Sergey; Wain, Karen; Eisenhauer, Nancy; Wagner, Monisa; Savatt, Juliann; Müller-Schlüter, Karen; Bassan, Haim; Borovikov, Artem; Nassogne, Marie Cecile; Destrée, Anne; Schoonjans, an Sofie; Meuwissen, Marije; Buzatu, Marga; Jansen, Anna; Scalais, Emmanuel; Srivastava, Siddharth; Tan, Wen Hann; Olson, Heather; Loddenkemper, Tobias; Poduri, Annapurna; Helbig, Katherine; Helbig, Ingo; Fitzgerald, Mark; Goldberg, Ethan; Roser, Timo; Borggraefe, Ingo; Brünger, Tobias; May, Patrick; Lal, Dennis; Lederer, Damien; Rubboli, Guido; Heyne, Henrike; Lesca, Gaetan; Hedrich, Ulrike; Benda, Jan; Gardella, Elena; Lerche, Holger; Møller, Rikke |
| Contributors: |
The Danish Epilepsy Centre Filadelfia Dianalund, Denmark; University of Southern Denmark = Syddansk Universitet (SDU); Key Laboratory of Intelligent Perception and Image Understanding Xi’an; Xidian University; Hertie Institute for Clinical Brain Research Tubingen; Eberhard Karls Universität Tübingen = University of Tübingen; Danish Epilepsy Center Filadelfia; University Clinics Tuebingen; Max-Planck-Institut; Fondazione IRCCS Istituto Neurologico "Carlo Besta"; Instituco Neurologico C. Besta; Instituto Neurologico C. Besta; Universität Konstanz; Epilepsy Center Kleinwachau Dresden-Radeberg, Germany; University Children's Hospital, Tuebingen, Germany; First Faculty of Medicine Charles University; University Hospital Motol Prague; Leipzig University / Universität Leipzig; University Hospital Leipzig = Universitätsklinikum Leipzig; Heinrich Heine Universität Düsseldorf = Heinrich Heine University Düsseldorf; Swiss Epilepsy Centre; Oslo University Hospital Oslo; University of Calgary; V. Buzzi Children's Hospital; Università degli Studi di Milano = University of Milan (UNIMI); Civilian Hospital, Brescia, Italy; National University Hospital, Rigshospitalet, Copenhagen; Rigshospitalet Copenhagen, Denmark; Copenhagen University Hospital Denmark = Københavns Universitetshospital Danmark (KUH)-Copenhagen University Hospital Denmark = Københavns Universitetshospital Danmark (KUH); Københavns Universitet = University of Copenhagen = Université de Copenhague (UCPH); Università degli studi di Genova = University of Genoa = Université de Gênes (UniGe); G. Gaslini Institute; Gent University Hospital; Maastricht University Medical Center+ (Maastricht UMC+); Amalia Children’s Hospital; Radboud University Medical Center Nijmegen (RadboudUMC); University Medical Center Utrecht (UMCU); Universiteit Utrecht / Utrecht University Utrecht; University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH); Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel (CAU); Department Woman-Mother-Child, CHUV, Lausanne, Switzerland; Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital Lausanne (CHUV); Université de Lausanne = University of Lausanne (UNIL); Hospital Italiano de Buenos Aires; Cleveland Clinic; Aarhus University Hospital; Copenhagen University Hospital Denmark = Københavns Universitetshospital Danmark (KUH); University of Toronto; The Hospital for sick children Toronto (SickKids); University Hospital Bonn; Universität zu Köln = University of Cologne; Royal Children's Hospital Melbourne; Murdoch Children’s Research Institute Melbourne, Australia (MCRI); University of Melbourne; University Hospital Carl Gustav Carus Dresden, Germany; Technische Universität Dresden = Dresden University of Technology (TU Dresden); Hôpital Côte de Nacre CHU Caen; CHU Caen Normandie – Centre Hospitalier Universitaire de Caen Normandie (CHU Caen Normandie); Normandie Université (NU)-Normandie Université (NU); CHRU Strasbourg; Children's Hospital G. Salesi, Ancona, Italy.; Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP); Klinikum Weiden; National Research Institute of Mother and Child Warsaw, Poland; Vittore Buzzi Children's Hospital Milano, Italy (VBCH); Università degli studi di Verona = University of Verona (UNIVR); Oestfold Hospital, Graalum, Norway; Universiteit van Amsterdam = University of Amsterdam (UvA); Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes); Epilepsy Center for Children and Adolescents; Research Institute 'Rehabilitation, Transition, Palliation, Salzburg, Austria; Hôpital Saint-Jacques CHRU de Besançon; Service de Génétique Médicale Lille; Institut de génétique médicale-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Institut des Neurosciences de Montpellier (INM); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM); CHU Montpellier = Montpellier University Hospital; Centre Hospitalier Régional Universitaire Montpellier (CHRU Montpellier); Azienda Ospedaliero Universitaria Meyer Firenze = Meyer Children's University Hospital Florence (AOU Meyer); Università degli Studi di Firenze = University of Florence = Université de Florence (UniFI); IRCCS Fondazione Stella Maris Pisa; Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers La Milétrie ); Center for Pediatric and Teenage Health Care, Sankt Augustin, Germany; Vestische Kinder- und Jugendklinik, Datteln, Germany; Justin Neurosciences Center, Fort Worth, USA; Ambry Genetics Aliso Viejo, CA, USA; Research Centre for Medical Genetics Moscow, Russia (RCMG); Pirogov Russian National Research Medical University; Svt. Luka's Institute of Child Neurology and Epilepsy; I.M. Sechenov First Moscow State Medical University Moscow, Russia (MSMU); Geisinger Autism & Developmental Medicine Institute Danville, PA, USA (ADMI); Medizinische Hochschule Brandenburg Theodor Fontane / Brandenburg Medical School Theodor-Fontane (MHB Theodor Fontane); Sackler Faculty of Medicine; Tel Aviv University (TAU); Cliniques Universitaires Saint-Luc Bruxelles; Université Catholique de Louvain = Catholic University of Louvain (UCL); Institute for Pathology and Genetics, Gosselies, Belgium |
| Source: |
ISSN: 0006-8950. |
| Publisher Information: |
CCSD; Oxford University Press |
| Publication Year: |
2022 |
| Collection: |
Université de Montpellier: HAL |
| Subject Terms: |
SCN8A; epilepsy; genetics; personalized medicine; [SDV]Life Sciences [q-bio] |
| Description: |
International audience ; Abstract We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/34431999; PUBMED: 34431999; PUBMEDCENTRAL: PMC10147326 |
| DOI: |
10.1093/brain/awab321 |
| Availability: |
https://inserm.hal.science/inserm-04956794; https://doi.org/10.1093/brain/awab321 |
| Accession Number: |
edsbas.EEF849C3 |
| Database: |
BASE |