Predictive value of seizure onset for gross motor dysfunction in individuals with pathogenic GABRB2 and GABRB3 variants
Year: 2026
Type: article
Study design: Observational Study
Abstract: Objective Pathogenic variants in γ‐aminobutyric acid type A (GABA A ) receptor genes have been associated with a wide spectrum of neurological disorders. We aimed to delineate the clinical trajectories associated with gain‐of‐function (GoF) and loss‐of‐function (LoF) variants in GABRB2 and GABRB3 , and to develop a risk‐prediction model for gross motor dysfunction based on age at seizure onset. Methods Clinical 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. Results We 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 A receptor–related disorders.
Source: Epilepsia
Authors: Sebastian Ortiz, Leonardo Affronte, Chiara Bagliani, Serene El‐Kamand, Anthony Sze Hon Kan, Isabel T. Kristoffersen, Rebekka S. Dahl, Anne F. Højte, Stéphane Auvin, Arjan Bouman, Shimriet Zeidler, Gerhard Kluger, Gaetan Lesca, Nicolas Chatron, Zeynep Goke‐Samar, Maria T. Papadopoulou, Matthildi Athina Papathanasiou Terzi, Elise Schaefer, Anne de Saint Martin, Sarah Baer, Mohammed Al Owain, Saud Takroni, Hesham Al‐Dhalaan, Paolo Bonanni, Alessandra Rossi, Nicoletta Zanotta, Marina Trivisano, Nicola Specchio, Angela de Dominicis, Pasquale Striano, Alessandro Orsini, Maria Margherita Mancardi, Sebastian Neuens, Melanie Jennesson‐Lyver, Ira Benkel‐Herrenbrueck, David Genevieve, Richard Sidlow, Kamer Tezcan, Ilona Krey, Johannes R. Lemke, Konrad Platzer, Damien Lederer, Inga Talvik, Ulvi Vaher, Kees P. J. Braun, Anne‐Marie Guerrot, Rebecca More, Matthias De Wachter, Sarah Weckhuysen, Evelina Carapancea, Maria Roberta Cilio, Julia Jacobs, Katalin Sterbova, Simona Balestrini, Renzo Guerrini, Giulio Peroni, Inger‐Lise Mero, Walaa ElNaggar, Nour Elkhateeb, Ariane Schmetz, Denise L. Chan, Ghayda M. Mirzaa, Boris Chaumette, Adrien Legrand, Amy McTague, Tommy Stödberg, Rebekah V. Harris, Samuel F. Berkovic, Ingrid E. Scheffer, Mary Chebib, Elena Gardella, Philip K. Ahring, Nathan L. Absalom, Rikke S. Møller
Institutions: University of Southern Denmark, Filadelfia, Istituto Giannina Gaslini, University of Genoa, The University of Sydney, Inserm, Université Paris Cité, Hôpital Robert-Debré, NeuroDiderot, Erasmus MC, Schön Klinik Vogtareuth, Lyon 1 Université, Centre National de la Recherche Scientifique, Hospices Civils de Lyon, ERN EpiCARE, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, Hôpital Femme Mère Enfant, Centre de Recherche en Neurosciences de Lyon, Institut de génétique et de biologie moléculaire et cellulaire, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, King Faisal Specialist Hospital & Research Centre, IRCCS Eugenio Medea, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria Pisana, Université Libre de Bruxelles, Queen Fabiola Children's University Hospital, Centre Hospitalier Universitaire de Reims, Heinrich Heine University Düsseldorf, Université de Montpellier, Centre Hospitalier Universitaire de Montpellier, Children's Hospital Central California, Kaiser Permanente, Kaiser Permanente Sacramento Medical Center, University Hospital Leipzig, Leipzig University, Institute of Pathology and Genetics, Tartu University Hospital, Utrecht University, University Medical Center Utrecht, Université de Rouen Normandie, Centre Hospitalier Universitaire de Rouen, University of Antwerp, Antwerp University Hospital, VIB-UAntwerp Center for Molecular Neurology, UCLouvain, University of Calgary, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Charles University, University Hospital in Motol, Meyer Children's Hospital, UCL Queen Square Institute of Neurology, University College London, Oslo University Hospital, Cairo University, Cambridge University Hospitals NHS Foundation Trust, Düsseldorf University Hospital, UNSW Sydney, Sydney Children's Hospital, University of Washington, Norcliffe Foundation, Seattle Children's Research Institute, Institut de Psychiatrie et Neurosciences de Paris, GHU Paris psychiatrie & neurosciences, Great Ormond Street Hospital, Karolinska University Hospital, Karolinska Institutet, The University of Melbourne, Austin Health, Royal Children's Hospital, Florey Institute of Neuroscience and Mental Health, Murdoch Children's Research Institute, Western Sydney University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,360
Award: G8103534029
OpenAlex ID: W7125936321