Early sodium channel blocker initiation is associated with better outcomes in KCNQ2 disorders

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ID: 325607
2026
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Abstract
Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.
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Authors Charissa Millevert, Megan Hairabedian, Samuel Dahan, Johannes Lemke, Steffen Syrbe, Eugenia Roza, Raluca Ioana Teleanu, Laura Licchetta, Duccio M Cordelli, Francesca Bisulli, Trine Bjørg Hammer, Magdalena Krygier, Marta Pietruszka, Maria Mazurkiewicz-Bełdzińska, Safa Mete Dağdaş, Pinar Gencpinar, Carmen Fons, Dídac Casas‐Alba, Edward C. Cooper, Maurizio Taglialatela, Béatrice Desnous, Nathalie Villeneuve, Anne Lepine, Stéphane Auvin, Cyril Mignot, Dorothée Ville, Anne de Saint Martin, Claire Bar, C. Hachon Le Camus, Laurent Villard, Laurence Chaton, Patrick Van Bogaert, Jérémie Lefranc, Gaëtan Lesca, Silvia Napuri, Mathieu Kuchenbuch, Caroline Perriard, Blandine Dozieres, Bénédicte Héron, Annie Ting Gee Chiu, Ingrid E Scheffer, KCNQ2 study group, Pasquale Striano, Francesca Madia, Rikke S. Møller, Katrine M Johannesen, Ilona Krey, Oliver Maier, Astrid Bertsche, Pia Zacher, Dagmar Wieczorek, Margarete Koch‐Hogrebe, Tobias Bartolomaeus, Lara Heuft, Marion Heruth, Janina Gburek‐Augustat, Rebecca Gembicki, Irina Hüning, Malte Spielmann, Nienke Verbeek, Ernie Bongers, Christine Makowski, Berten Ceulemans, An‐Sofie Schoonjans, Lieven Lagae, Mathias De Wachter, Katrien Jansen, Nina Barišić, Filip Roelens, Helene Verhelst, Ana Vilan, Johanneke Harteman, Liesbeth De Waele, Damien Lederer, Antonio Gil-Nagel, Paloma Parra‐Díaz, Hilde Van Esch, Katrien Vanrykel, Jana Zarubova, Krystyna Szymańska, Jürgen Althaus, González Gutiérrez-Solana, Giulia Ventura, Pegoraro Veronica, S. Colling, Britta Hanker, Celina von Stülpnagel, Dorota Domańska‐Pakieła, Angelo Russo, Joerg Klepper, Agnes Scheuring, Esther Mutz, Eulalia Turon‐Viñas, Ivon Cuscó, Carlotta Stipa, Luca Bergonzini, Raffaella Minardi, Valentina Marchiani, Sophie Rus-Hall, Shannyn Genders
Journal Brain research
Year 2026
DOI
10.1093/brain/awag277
URL
https://doi.org/10.1093/brain/awag277
Keywords Keywords not found

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