Research & Innovation
Publications
Predictive value of seizure onset for gross motor dysfunction in individuals with pathogenic GABRB2 and GABRB3 variants
PMU Author
Gerhard Kluger
All Authors
Sebastian Ortiz, Leonardo Affronte, Chiara Bagliani, Serene El-kamand, Anthony Sze Hon Kan, Isabel T. Kristoffersen, Rebekka S. Dahl, Anne F. Hojte, Stephane 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 Stodberg, Rebekah V. Harris, Samuel F. Berkovic, Ingrid E. Scheffer, Mary Chebib, Elena Gardella, Philip K. Ahring, Nathan L. Absalom, Rikke S. Moller
Journal association
EPILEPSIA
Abstract
Objective: Pathogenic variants in gamma-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 similar 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.
Keywords
GENOTYPE-PHENOTYPE CORRELATION, GABA(A) receptor-related disorders, Clinical biomarker, Developmental and epileptic encephalopathy, Functional variant classification, Motor disability prediction