Genotype-phenotype correlations in SCN8A -related disorders reveal prognostic and therapeutic implications
Genotype-phenotype correlations in SCN8A -related disorders reveal prognostic and therapeutic implications
Abstract We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. 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 DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.
Liu Yuanyuan、Lerche Holger、Verhelst Helene、Marini Carla、Lemke Johannes R、Stutterd Chloe、Sharkov Artem、Wain Karen E、M¨1ller-Schl¨1ter Karen、Bassan Haim、Abramov Mikhail、Destr¨|e Anne、Meuwissen Marije、Buzatu Marga、Johannesen Katrine M、Koko Mahmoud、Jansen Anna、Scalais Emmanuel、Srivastava Siddharth、Loddenkemper Tobias、Poduri Annapurna、Fitzgerald Mark P、Lederer Damien、Lesca Gaetan、Schubert Julian、Eltokhi Ahmed、Koch Nils A.、Lauxmann Stephan、Rebstock Johannes、Zacher Pia、Ruf Susanne、Sterbova Katalin、Lassuthov¨￠ Petra、Vlckova Marketa、Lebon Sebastian、Scherer Stephen W、Howe Jennifer、Howell Katherine B、Borggraefe Ingo、Goldberg Ethan M、Gerard Marion、Bonardi Claudia M、Hoffman-Zacharska Dorota、Bilan Frederic、Roser Timo、Br¨1nger Tobias、Kutsev Sergey、Krey Ilona、Kroell-Seger Judith、Au PY Billie、Masnada Silvia、Veggiotti Pierangelo、van der Zwaag Bert、Harder Aster V. E.、Brilstra Eva、Pendziwiat Manuela、V?llo Arve、Motazacker M Mahdi、Lakeman Phillis、Nizon Mathilde、Betzler Cornelia、Schmidt-Petersen Mette U、Canafoglia Laura、Le Ngoc Minh、Roubertie Agathe、Savatt Juliann M、Gerard B¨|n¨|dicte、Caume Roseline、S.Verhoeven Judith、Korostelev Sergey、Helbig Katherine L、G¨|lisse Philippe、Olson Heather E、Kanivets Ilya、Mastrangelo Massimo、Klein Karl Martin、Helbig Ingo、Borovikov Artem、Koch-Hogrebe Margarete、M?ller Rikke S、May Patrick、Accorsi Patrizia、Zara Federico、Wagner Monisa、Rubboli Guido、Kr¨1ger Johanna、Altuzarra Cecilia、Lund Caroline、Perry M Scott、Gr?nborg Sabine、Striano Pasquale、Mayer Thomas、Kegele Josua、Fazeli Walid、Fenger Christina D、Rho Jong M、Sonnenberg Lukas、Giordano Lucio、Walsh Sonja、Tan Wen-Hann、Benda Jan、Mishina Irina、Alber Michael、Ichikawa Shoji、Tibussek Daniel、Darra Francesca、Hoei-Hansen Christina E、Heine Constanze、Gardella Elena、Leventer Richard、Guerrini Renzo、Rannap Maert、Gjerulfsen Cathrine E、Wieczorek Dagmar、Hedrich Ulrike BS、Dadali Elena、Nassogne Marie-Cecile、Ho Alice W、Schoonjans An-Sofie、Vaccarezza Maria、Berger Andrea、Sartori Stefano、Franceschetti Silvana、Christensen Jakob、Lal Dennis、Eisenhauer Nancy、Matricardi Sara
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenDepartment of Paediatrics, Divison of Paediatric Neurology, Gent University HospitalPediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children?ˉs Hospital, University of FlorenceInstitute of Human Genetics, University of Leipzig Hospitals and ClinicsMurdoch Children?ˉs Research Institute||Department of Pediatrics, University of Melbourne, Royal Children?ˉs HospitalGenomed||Svt. Luka?ˉs Institute of Child Neurology & EpilepsyAutism & Developmental Medicine InstituteEpilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical SchoolPediatric Neurology & Development Center Shamir Medical Center (Assaf Harofe) Be?ˉer Ya?ˉakov||Tel Aviv University, Sackler faculty of MedicineVeltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical UniversityInstitute for Pathology and GeneticsDepartment of Pediatrics and Pediatric Neurology, Antwerp University Hospital, University of AntwerpPediatric neurology, Marie Curie Hospital ¨C CHU CharleroiDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Center||Institute for Regional Health Services, University of Southern DenmarkDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenVrije Universiteit Brussel, UZ Brussel, Department of Pediatrics, Pediatric Neurology UnitPediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de LuxembourgDepartment of Neurology, Boston Children?ˉs Hospital and Harvard Medical SchoolDepartment of Neurology, Boston Children?ˉs Hospital and Harvard Medical SchoolDepartment of Neurology, Boston Children?ˉs Hospital and Harvard Medical School||Epilepsy Genetics Program, Boston Children?ˉs HospitalDivision of Neurology, Children?ˉs Hospital of Philadelphia||The Epilepsy Neurogenetics Initiative (ENGIN), Children?ˉs Hospital of Philadelphia||Department of Biomedical and Health Informatics (DBHi), Children?ˉs Hospital of Philadelphia||Institute of Clinical Molecular Biology, Kiel UniversityInstitute for Pathology and GeneticsDepartment of Medical Genetics, Groupement Hospitalier Est, and ERN EpiCARE, University Hospitals of Lyon (HCL)||Institut Neuromyog¨¨ne, CNRS UMR 5310 - INSERM U1217, Universit¨| de Lyon, Universit¨| Claude Bernard Lyon 1Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenInstitute for Neurobiology, University of TuebingenDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen||Institute for Neurobiology, University of TuebingenEpilepsy Center KleinwachauEpilepsy Center KleinwachauDepartment of Pediatric Neurology and Developmental Medicine, University Children?ˉs HospitalDepartment of Child Neurology, Charles University, 2nd Faculty of Medicine and University Hospital MotolDepartment of Child Neurology, Charles University, 2nd Faculty of Medicine and University Hospital MotolDepartment of Child Neurology, Charles University, 2nd Faculty of Medicine and University Hospital MotolPediatric Neurology and Neurorehabilitation Unit, Woman Mother Child Department, Lausanne University Hospital (CHUV)||University of LausanneMcLaughlin Centre and Dept. of Molecular Genetics, University of Toronto||The Centre for Applied Genomics and Dept. of Genetics and Genome Biology, The Hospital for Sick ChildrenThe Centre for Applied Genomics and Dept. of Genetics and Genome Biology, The Hospital for Sick ChildrenNeurology Department, The Royal Children?ˉs Hospital Melbourne||Murdoch Children?ˉs Research Institute||Department of Pediatrics, University of Melbourne, Royal Children?ˉs HospitalDivision of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children?ˉs Hospital, Ludwig-Maximilian-University of Munich||Comprehensive Epilepsy Center, Ludwig-Maximilian- University of MunichDivision of Neurology, Children?ˉs Hospital of Philadelphia||The Epilepsy Neurogenetics Initiative (ENGIN), Children?ˉs Hospital of PhiladelphiaGenetic DepartmenDepartment of Woman?ˉs and Child?ˉs Health, Padova University HospitalDepartment of Medical Genetics, Institute of Mother and ChildCentre Hospitalier Universitaire de PoitiersDivision of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children?ˉs Hospital, Ludwig-Maximilian-University of MunichLuxembourg Centre for Systems Biomedicine (LCSB), University LuxembourgResearch Centre for Medical GeneticsInstitute of Human Genetics, University of Leipzig Hospitals and ClinicsChildren?ˉs department, Swiss Epilepsy CentreDepartment of Medical Genetics, Alberta Children?ˉs Hospital Research Institute, University of CalgaryDepartment of Child Neurology, V. Buzzi Children?ˉs HospitalDepartment of Child Neurology, V. Buzzi Children?ˉs Hospital||Department of Biomedical and Clinical Sciences, L. Sacco, University of MilanDepartment of Genetics, University Medical Center Utrecht, Utrecht UniversityDepartment of Genetics, University Medical Center Utrecht, Utrecht UniversityDepartment of Genetics, University Medical Center Utrecht, Utrecht UniversityDepartment of Neuropediatrics, Universit?tsklinikum Schleswig Holstein Campus KielDepartment of Pediatrics, Oestfold HospitalLaboratory of Genome Diagnostics, Department of Clinical Genetics, Amsterdam UMC, University of AmsterdamAmsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research InstituteCHU Nantes, Service de G¨|n¨|tique M¨|dicaleClinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents||Research Institute ?°RehabilitationDepartment of Neurology, Aarhus University HospitalDepartment of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo BestaCenter for Pediatric Neurology, Cleveland ClinicNM, Univ MontpellierAutism & Developmental Medicine InstituteGenetic DepartmentCHU Lille, Clinique de G¨|n¨|tiqueAcedemic Center for Epileptology, Kempenhaeghe/Maastricht University Medical CenterSvt. Luka?ˉs Institute of Child Neurology & Epilepsy||I.M. Sechenov First Moscow State Medical UniversityDivision of Neurology, Children?ˉs Hospital of Philadelphia||The Epilepsy Neurogenetics Initiative (ENGIN), Children?ˉs Hospital of PhiladelphiaNM, Univ MontpellierDepartment of Neurology, Boston Children?ˉs Hospital and Harvard Medical School||Epilepsy Genetics Program, Boston Children?ˉs HospitalSvt. Luka?ˉs Institute of Child Neurology & Epilepsy||Russian Medical Academy Continuous Professional EeducationPediatric Neurology Unit, Vittore Buzzi HospitalDepartments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children?ˉs Hospital Research Institute, Cumming School of Medicine, University of CalgaryDivision of Neurology, Children?ˉs Hospital of Philadelphia||The Epilepsy Neurogenetics Initiative (ENGIN), Children?ˉs Hospital of Philadelphia||Department of Biomedical and Health Informatics (DBHi), Children?ˉs Hospital of Philadelphia||Department of Neurology, University of Pennsylvania, Perelman School of Medicine||Institute of Clinical Molecular Biology, Kiel University||Department of Neuropediatrics, Kiel UniversityResearch Centre for Medical GeneticsVestische Kinder- und JugendklinikDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Center||Institute for Regional Health Services, University of Southern DenmarkGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicChild Neuropsychiatric Unit, Civilian HospitalIRCCS ?°G. Gaslini?± InstituteAutism & Developmental Medicine InstituteDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Center||University of CopenhagenDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenDepartment of Pediatrics, St. Jacques HospitalNational Centre for Rare Epilepsy-Related Disorders, Oslo University HospitalJustin Neurosciences Center, Cook Children?ˉs Medical CenterCenter for Rare Diseases, Department of Pediatrics and Department of Clinical Genetics, Copenhagen University Hospital RigshospitaletDepartment of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genoa||IRCCS ?°G. Gaslini?± InstituteEpilepsy Center KleinwachauDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenDepartment of Neuropediatrics, University Hospital Bonn||Institute for Molecular and Behavioral Neuroscience, University of CologneDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy CenterSection of Pediatric Neurology, Alberta Children?ˉs Hospital, Cumming School of Medicine, University of CalgaryDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen||Institute for Neurobiology, University of TuebingenChild Neuropsychiatric Unit, Civilian HospitalDepartment of Neuropediatrics, Children?ˉs hospital, University Hospital Carl Gustav Carus, Technical UniversityDepartment of Genetics, Boston Children?ˉs HospitalInstitute for Neurobiology, University of TuebingenResearch Centre for Medical GeneticsDepartment of Pediatric Neurology and Developmental Medicine, University Children?ˉs HospitalDepartment of Clinical DiagnosticsCenter for Pediatric and Teenage Health Care, Child Neurology,Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Pediatrics, Copenhagen University Hospital||Department of Clinical Medicine, University of CopenhagenInstitute of Human Genetics, University of Leipzig Hospitals and ClinicsDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Center||Institute for Regional Health Services, University of Southern DenmarkNeurology Department, The Royal Children?ˉs Hospital Melbourne||Murdoch Children?ˉs Research Institute||Department of Pediatrics, University of Melbourne, Royal Children?ˉs HospitalIRCCS Stella MarisDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy CenterInstitute of Human Genetics, University Clinic, Heinrich-Heine-UniversityDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuebingenResearch Centre for Medical Genetics||Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical UniversityPediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Universit¨| Catholique de LouvainSection of Pediatric Neurology, Alberta Children?ˉs Hospital, Cumming School of Medicine, University of CalgaryDepartment of Pediatrics and Pediatric Neurology, Antwerp University Hospital, University of AntwerpDepartment of Pediatric Neurology, Hospital Italiano de Buenos AiresDepartment of NeuropediatricsChild Neurology and Clinical Neurophysiology Unit, Padova University HospitalDepartment of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo BestaDepartment of Neurology, Aarhus University HospitalLuxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg||Epilepsy Center, Neurological Institute, Cleveland Clinic||Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T.||Cologne Center for Genomics (CCG), University of CologneAutism & Developmental Medicine InstituteChild Neurology and Psychiatry Unit, Children?ˉs Hospital G. Salesi
神经病学、精神病学基础医学医学研究方法
Liu Yuanyuan,Lerche Holger,Verhelst Helene,Marini Carla,Lemke Johannes R,Stutterd Chloe,Sharkov Artem,Wain Karen E,M¨1ller-Schl¨1ter Karen,Bassan Haim,Abramov Mikhail,Destr¨|e Anne,Meuwissen Marije,Buzatu Marga,Johannesen Katrine M,Koko Mahmoud,Jansen Anna,Scalais Emmanuel,Srivastava Siddharth,Loddenkemper Tobias,Poduri Annapurna,Fitzgerald Mark P,Lederer Damien,Lesca Gaetan,Schubert Julian,Eltokhi Ahmed,Koch Nils A.,Lauxmann Stephan,Rebstock Johannes,Zacher Pia,Ruf Susanne,Sterbova Katalin,Lassuthov¨￠ Petra,Vlckova Marketa,Lebon Sebastian,Scherer Stephen W,Howe Jennifer,Howell Katherine B,Borggraefe Ingo,Goldberg Ethan M,Gerard Marion,Bonardi Claudia M,Hoffman-Zacharska Dorota,Bilan Frederic,Roser Timo,Br¨1nger Tobias,Kutsev Sergey,Krey Ilona,Kroell-Seger Judith,Au PY Billie,Masnada Silvia,Veggiotti Pierangelo,van der Zwaag Bert,Harder Aster V. E.,Brilstra Eva,Pendziwiat Manuela,V?llo Arve,Motazacker M Mahdi,Lakeman Phillis,Nizon Mathilde,Betzler Cornelia,Schmidt-Petersen Mette U,Canafoglia Laura,Le Ngoc Minh,Roubertie Agathe,Savatt Juliann M,Gerard B¨|n¨|dicte,Caume Roseline,S.Verhoeven Judith,Korostelev Sergey,Helbig Katherine L,G¨|lisse Philippe,Olson Heather E,Kanivets Ilya,Mastrangelo Massimo,Klein Karl Martin,Helbig Ingo,Borovikov Artem,Koch-Hogrebe Margarete,M?ller Rikke S,May Patrick,Accorsi Patrizia,Zara Federico,Wagner Monisa,Rubboli Guido,Kr¨1ger Johanna,Altuzarra Cecilia,Lund Caroline,Perry M Scott,Gr?nborg Sabine,Striano Pasquale,Mayer Thomas,Kegele Josua,Fazeli Walid,Fenger Christina D,Rho Jong M,Sonnenberg Lukas,Giordano Lucio,Walsh Sonja,Tan Wen-Hann,Benda Jan,Mishina Irina,Alber Michael,Ichikawa Shoji,Tibussek Daniel,Darra Francesca,Hoei-Hansen Christina E,Heine Constanze,Gardella Elena,Leventer Richard,Guerrini Renzo,Rannap Maert,Gjerulfsen Cathrine E,Wieczorek Dagmar,Hedrich Ulrike BS,Dadali Elena,Nassogne Marie-Cecile,Ho Alice W,Schoonjans An-Sofie,Vaccarezza Maria,Berger Andrea,Sartori Stefano,Franceschetti Silvana,Christensen Jakob,Lal Dennis,Eisenhauer Nancy,Matricardi Sara.Genotype-phenotype correlations in SCN8A -related disorders reveal prognostic and therapeutic implications[EB/OL].(2025-03-28)[2025-06-21].https://www.medrxiv.org/content/10.1101/2021.03.22.21253711.点此复制
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