Genetic etiologies of epilepsies with status epilepticus

Marini C, Rosati A, Fusco L, Mastrangelo M, Izzo F, Olivotto S, Siliquini S, Cordelli DM, Mondardini MC, Vittorini R, Conio A, Battaglia DID, Pulitanò SM, Striano P, Riva A, Sartori S, Tona C, Darra F, Proietti J, Zanus C, Costa P, Parrini E, Guerrini R, Vigevano F, Bartolotta P; Italian Pediatric Status Epilepticus (IPSE) Group. Genetic Etiologies of Epilepsies With Status Epilepticus: Insights From the Italian Pediatric Status Epilepticus Group Cohort. Neurology. 2026 Apr 28;106(8):e214791. doi: 10.1212/WNL.0000000000214791. Epub 2026 Mar 31. PMID: 41915870.

Abstract

Background and objectives: Genetic factors are major contributors to pediatric epilepsy, but their role in status epilepticus (SE) remains incompletely defined. We aimed to characterize the clinical and genetic landscape of pediatric epilepsy complicated by SE in a large cohort, and to identify clinical features associated with genetic etiologies.

Methods: We conducted a retrospective, multicenter, exploratory cohort study by selecting patients aged 1 month-18 years who experienced SE from the Italian Pediatric Status Epilepticus (IPSE) group database (2010-2022). SE and epilepsy syndromes were defined according to International League Against Epilepsy criteria. From the IPSE dataset, we included only patients with epilepsy whose etiology was classified as genetic (confirmed or presumed) or nongenetic (lesional, autoimmune, metabolic-acquired, infectious, or unknown). Clinical data were collected using standardized electronic case report forms.

Results: Of 1,071 children in the IPSE cohort, 790 with SE and epilepsy were included (median age at SE onset 3.9 years, interquartile range 1.3-8.1; 44% female). A genetic etiology was confirmed or presumed in 519 (66%). Compared with those with nongenetic etiologies (n = 271), patients with genetic epilepsies presented with SE at a younger age (median 3.4 vs 4.8 years, q = 0.003) and more often had epilepsy with both focal and generalized seizures (31% vs 13%, q < 0.001). The underlying genetic abnormality was identified in 222 patients (42.7%) including 179 with confirmed single-gene pathogenic variants and 43 chromosomal alterations. Ion channel genes were most frequent (38%), with SCN1A variants accounting for 18% of confirmed single-gene cases. Neurodevelopmental and mTOR pathway genes were also frequent contributors. Logistic regression showed that younger age at SE (odds ratio [OR] 0.92, 95% CI 0.85-0.98, p = 0.020) and epilepsy with both focal and generalized seizures (OR 4.00, 95% CI 2.09-7.85, p < 0.001) were independently associated with channelopathies.

Discussion: In this large real-world cohort, two-thirds of children with epilepsy and SE had a genetic etiology, most commonly channelopathies. Younger age at SE and epilepsy with both focal and generalized seizure were linked to genetic causes. Despite limitations in testing strategies and retrospective design, these findings highlight the importance of systematic genetic investigation in pediatric epilepsies presenting SE.