ArticleEpilepsia2026
Predictive value of seizure onset for gross motor dysfunction in individuals with pathogenic GABRB2 and GABRB3 variants.
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74 authors.
Sebastian OrtizDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.ORCID https://orcid.org/0000-0002-3432-1932
Leonardo AffronteDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.ORCID https://orcid.org/0009-0004-7653-9907
Chiara BaglianiDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.ORCID https://orcid.org/0009-0006-6782-8912
Serene El-KamandSchool of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-6072-4102
Anthony Sze Hon KanSchool of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID https://orcid.org/0009-0008-3563-7112
Isabel T KristoffersenSchool of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID https://orcid.org/0009-0002-7788-9605
Rebekka S DahlDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.ORCID https://orcid.org/0009-0003-2672-287X
Anne F HøjteDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.
Stéphane AuvinINSERM NeuroDiderot, DMU Innov-RDB, Neurologie Pédiatrique, AP-HP, Hôpital Robert-Debré, Member of European Reference Network EpiCARE, Université de Paris, Paris, France.ORCID https://orcid.org/0000-0003-3874-9749
Arjan BoumanDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.ORCID https://orcid.org/0000-0002-9560-6333
Shimriet ZeidlerDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.ORCID https://orcid.org/0000-0001-8597-2359
Gerhard KlugerCenter for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, Germany.ORCID https://orcid.org/0000-0003-1234-994X
Gaetan LescaGenetics Department, Hospices Civils de Lyon, Member of ERN EpiCARE, Lyon, France.ORCID https://orcid.org/0000-0001-7691-9492
Nicolas ChatronGenetics Department, Hospices Civils de Lyon, Member of ERN EpiCARE, Lyon, France.ORCID https://orcid.org/0000-0003-0538-0981
Zeynep Goke-SamarDepartment of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Hôpital Femme Mère Enfant, Member of ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France.ORCID https://orcid.org/0000-0003-0901-4161
Maria T PapadopoulouDepartment of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Hôpital Femme Mère Enfant, Member of ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France.ORCID https://orcid.org/0000-0002-2076-5006
Matthildi Athina Papathanasiou TerziDepartment of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, Hôpital Femme Mère Enfant, Member of ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France.ORCID https://orcid.org/0000-0002-1964-4813
Elise SchaeferService de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Strasbourg, France.ORCID https://orcid.org/0000-0003-1004-6814
Anne de Saint MartinDepartment of Neuropediatrics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.ORCID https://orcid.org/0000-0003-4666-5369
Sarah BaerDepartment of Neuropediatrics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.ORCID https://orcid.org/0000-0003-4951-2552
Mohammed Al OwainDepartment of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Saud TakroniDepartment of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Hesham Al-DhalaanDepartment of Neuroscience, Center for Autism Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Paolo BonanniEpilepsy and Clinical Neurophysiology Unit, Scientific Institute for Research, Hospitalization and Healthcare, IRCCS, E. Medea, IRCCS Eugenio Medea, Conegliano, Italy.ORCID https://orcid.org/0000-0002-9448-9059
Alessandra RossiEpilepsy and Clinical Neurophysiology Unit, Scientific Institute for Research, Hospitalization and Healthcare, IRCCS, E. Medea, IRCCS Eugenio Medea, Conegliano, Italy.ORCID https://orcid.org/0009-0005-4098-7844
Nicoletta ZanottaUnit of Clinical Neurophysiology and Epilepsy Centre, IRCCS E. Medea, Lecco, Italy.ORCID https://orcid.org/0000-0002-2563-8209
Marina TrivisanoNeurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.ORCID https://orcid.org/0000-0002-9841-8581
Nicola SpecchioNeurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.ORCID https://orcid.org/0000-0002-8120-0287
Angela de DominicisNeurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.ORCID https://orcid.org/0000-0002-8526-1511
Pasquale StrianoDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.ORCID https://orcid.org/0000-0002-6065-1476
Alessandro OrsiniPediatric Neurology, University Hospital of Pisa, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.ORCID https://orcid.org/0000-0001-5256-6573
Maria Margherita MancardiUnit of Child Neuropsychiatry, Full Member ERN EpiCARE, IRCCS Istituto Giannina Gaslini, Genoa, Italy.ORCID https://orcid.org/0000-0001-5122-4029
Sebastian NeuensDepartment of Genetics, Hôpital Universitaire Des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.ORCID https://orcid.org/0000-0003-2979-3764
Melanie Jennesson-LyverDepartment of Pediatric Neurology, American Memorial Hospital, CHU Reims, Reims, France.ORCID https://orcid.org/0009-0005-2611-3833
Ira Benkel-HerrenbrueckSana-Krankenhaus Düsseldorf-Gerresheim, Academic Teaching Hospital der Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.ORCID https://orcid.org/0009-0005-6670-3555
David GenevieveDepartment of Clinical Genetics, Inserm U1183, Centre de Référence «Anomalies du Développement et Syndromes Malformatifs», University Hospital of Montpellier, Montpellier University, Montpellier, France.ORCID https://orcid.org/0000-0001-6928-6287
Richard SidlowDepartment of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.
Kamer TezcanDepartment of Genetics, Kaiser Permanente, Sacramento, California, USA.
Ilona KreyInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID https://orcid.org/0000-0002-9168-7615
Johannes R LemkeInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID https://orcid.org/0000-0002-4435-6610
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID https://orcid.org/0000-0001-6127-6308
Damien LedererCentre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.ORCID https://orcid.org/0000-0002-6874-6322
Inga TalvikTallin Children's Hospital, Tallin, Estonia.
Ulvi VaherChildren's Clinic, Tartu University Hospital, Tartu, Estonia.ORCID https://orcid.org/0000-0002-2546-1079
Kees P J BraunDepartment of Child Neurology and Neurosurgery, University Medical Center, Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.ORCID https://orcid.org/0000-0002-6773-985X
Anne-Marie GuerrotDepartment of Genetics and Reference Center for Developmental Disorders, Inserm U1245 and CHU Rouen, Univ Rouen Normandie, Normandie Univ, Rouen, France.ORCID https://orcid.org/0000-0002-4145-7408
Rebecca MoreDépartement de Pédiatrie Néonatale Réanimation Pédiatrique, Centre Hospitalier Universitaire de Rouen, Rouen, France.
Matthias De WachterDepartment of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.ORCID https://orcid.org/0000-0002-6422-210X
Sarah WeckhuysenDepartment of Neurology, Antwerp University Hospital, Antwerp, Belgium.ORCID https://orcid.org/0000-0003-2878-1147
Evelina CarapanceaInstitute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.ORCID https://orcid.org/0000-0002-2260-3078
Maria Roberta CilioInstitute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.ORCID https://orcid.org/0000-0003-2481-8053
Julia JacobsHotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.ORCID https://orcid.org/0000-0003-1164-4699
Katalin SterbovaDepartment of Paediatric Neurology, Second Faculty of Medicine, Charles University and Motol Epilepsy Center, University Hospital Motol, Prague, Czech Republic.ORCID https://orcid.org/0000-0003-1023-5340
Simona BalestriniDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.ORCID https://orcid.org/0000-0001-5639-1969
Renzo GuerriniNeuroscience Department, Meyer Children's Hospital, European Reference Network ERN EpiCARE, Florence, Italy.ORCID https://orcid.org/0000-0002-7272-7079
Giulio PeroniNeuroscience Department, Meyer Children's Hospital, European Reference Network ERN EpiCARE, Florence, Italy.ORCID https://orcid.org/0009-0002-8414-4580
Inger-Lise MeroDepartment of Medical Genetics, Oslo University Hospital, Oslo, Norway.ORCID https://orcid.org/0009-0007-6087-7903
Walaa ElNaggarDepartment of Pediatrics, Faculty of Medicine, Cairo University, Giza, Egypt.
Nour ElkhateebDepartment of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.ORCID https://orcid.org/0000-0002-3076-3178
Ariane SchmetzInstitute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
Denise L ChanNeurology Department, Sydney Children's Hospital, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-7039-8400
Ghayda M MirzaaNorcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.ORCID https://orcid.org/0000-0003-2648-7657
Boris ChaumetteINSERM U1266, Institute of Psychiatry and Neuroscience of Paris, Université Paris Cité, Paris, France.ORCID https://orcid.org/0000-0002-1313-2788
Adrien LegrandGHU PARIS Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France.
Amy McTagueDevelopmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.ORCID https://orcid.org/0000-0002-0334-2909
Tommy StödbergDivision of Pediatric Neurology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.ORCID https://orcid.org/0000-0003-1242-5260
Rebekah V HarrisEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.ORCID https://orcid.org/0000-0002-6276-3586
Samuel F BerkovicEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.ORCID https://orcid.org/0000-0003-4580-841X
Ingrid E SchefferEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.ORCID https://orcid.org/0000-0002-2311-2174
Mary ChebibSchool of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, Australia.
Elena GardellaDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.ORCID https://orcid.org/0000-0002-7138-6022
Philip K AhringSchool of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0003-1807-3331
Nathan L AbsalomSchool of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-6084-5991
Rikke S MøllerDepartment of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Member of the European Reference Network EpiCARE, Dianalund, Denmark.ORCID https://orcid.org/0000-0002-9664-1448
Funding
Lundbeck Foundation R383-2022-276The Australian National Health & Medical Research Council APP2019780
Abstract
objectivePathogenic variants in γ-aminobutyric acid type A (GABA
methodsClinical data, including seizure onset, epilepsy syndromes, cognitive outcomes, and gross motor function classification system (GMFCS), were collected through direct interviews, physician reports, and literature review. Kruskal-Wallis, Mantel-Cox and non-parametric analysis of variance (ANOVA) with Dunn's corrected post hoc tests were used for statistical comparisons. A logistic ordinal regression model was developed to predict GMFCS outcomes based on age at seizure onset.
resultsWe analyzed a cohort of 117 individuals with pathogenic GABRB2 (n = 49) and GABRB3 (n = 68) variants. Fifty-three individuals carried GoF variants and 64 carried LoF variants. The GoF group was associated with earlier seizure onset, higher seizure frequency, and lower rates of seizure freedom. Gross motor dysfunction was markedly worse in the GoF group, with 64% classified as GMFCS IV or V (non-ambulation), compared to 7.5% in the LoF group. An inverse correlation was found between age at seizure onset and GMFCS severity in the GoF, but not the LOF group. The risk model predicted a >90% likelihood of non-ambulation for individuals with GoF variants and seizure onset before 1 month of age, decreasing to ~35% with seizure onset after 20 months. SIGNIFICANCE: We found a clear genotype-phenotype correlation in GABRB2- and GABRB3-related disorders, demonstrating that GoF variants are associated with a more severe neurodevelopmental trajectory. The age at seizure onset serves as a biomarker for predicting motor outcomes in individuals with GoF variants. These findings provide guidance regarding prognosis, need for early intervention, and data for comparison of efficacy in targeted therapeutic interventions for GABA
Indexed as
EpilepsyReceptors, GABA-ASeizuresAge of OnsetChildChild, PreschoolFemaleHumansInfantMalePredictive Value of TestsGABRB2 protein, humanGABRB3 protein, humanReceptors, GABA-Aclinical biomarkerdevelopmental and epileptic encephalopathyfunctional variant classificationGABAA receptor–related disordersgenotype–phenotype correlationmotor disability prediction
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