Predictive value of seizure onset for gross motor dysfunction in individuals with pathogenic GABRB2 and GABRB3 variants.
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Ortiz Sebastian, Affronte Leonardo, Bagliani Chiara, El-Kamand Serene, Kan Anthony Sze Hon, Kristoffersen Isabel T, Dahl Rebekka S, Højte Anne F, Auvin Stéphane, Bouman Arjan, Zeidler Shimriet, Kluger Gerhard, Lesca Gaetan, Chatron Nicolas, Goke-Samar Zeynep, Papadopoulou Maria T, Terzi Matthildi Athina Papathanasiou, Schaefer Elise, de Saint Martin Anne, Baer Sarah, Al Owain Mohammed, Takroni Saud, Al-Dhalaan Hesham, Bonanni Paolo, Rossi Alessandra, Zanotta Nicoletta, Trivisano Marina, Specchio Nicola, de Dominicis Angela, Striano Pasquale, Orsini Alessandro, Mancardi Maria Margherita, Neuens Sebastian, Jennesson-Lyver Melanie, Benkel-Herrenbrueck Ira, Genevieve David, Sidlow Richard, Tezcan Kamer, Krey Ilona, Lemke Johannes R, Platzer Konrad, Lederer Damien, Talvik Inga, Vaher Ulvi, Braun Kees P J, Guerrot Anne-Marie, More Rebecca, De Wachter Matthias, Weckhuysen Sarah, Carapancea Evelina, Cilio Maria Roberta, Jacobs Julia, Sterbova Katalin, Balestrini Simona, Guerrini Renzo, Peroni Giulio, Mero Inger-Lise, ElNaggar Walaa, Elkhateeb Nour, Schmetz Ariane, Chan Denise L, Mirzaa Ghayda M, Chaumette Boris, Legrand Adrien, McTague Amy, Stödberg Tommy, Harris Rebekah V, Berkovic Samuel F, Scheffer Ingrid E, Chebib Mary, Gardella Elena, Ahring Philip K, Absalom Nathan L, Møller Rikke S
Аннотация
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 GABAA receptor-related disorders.