Clinical and genetic landscape of epilepsies with absence seizures and single-gene etiology.

objectiveTo characterize the clinical, electroencephalographic, and genetic features of epilepsies featuring absence seizures within monogenic etiology, highlighting the diagnostic, treatment and prognostic implications.

methodsWe conducted a retrospective, multicenter study including patients with monogenic epilepsies and electroencephalography (EEG)-documented absence seizures. We analyzed clinical data, electroclinical findings, neurodevelopmental outcomes, and treatment responses through standardized questionnaires and medical records. We classified genetic variants according to American College of Medical Genetics and Genomics (ACMG) guidelines and performed univariate and multivariate analyses to identify predictors of developmental outcomes.

resultsWe included 160 patients (111 female; median age at last follow-up: 13 years) with absence seizures and confirmed pathogenic or likely pathogenic monogenic variants. The most frequently implicated genes were SLC2A1, SLC6A1, SYNGAP1, CHD2, and SCN1A. Four genes-HESX1, NCKAP1, SON, STARD9-had not been previously associated with absence seizures. In 35% of patients, absence seizures were the only seizure type and in 67% were the initial manifestation. Atypical features included irregular EEG discharges (56%) eyelid myoclonia (42%), and automatisms (33%). Early-onset (before age 3) seizures occurred in 58% and was significantly associated with atypical features (p < .03). Using existing International League Against Epilepsy (ILAE) epilepsy syndrome classification, 60% of patients could not be classified. Developmental delay occurred in 54%, intellectual disability in 65%, and other neurodevelopmental comorbidities in 49%. Predictors of poor developmental outcomes included early developmental delay, drug-resistant epilepsy, and early absence onset. We found no difference in the prevalence of drug resistance across the various genetic etiologies. The most effective medications for absence seizures included valproate, ethosuximide, benzodiazepines, and lamotrigine. Disease-specific therapies (e.g., ketogenic diet in SLC2A1, stiripentol/fenfluramine in SCN1A) were effective in select cases. SIGNIFICANCE: Absence seizures are a common manifestation of different monogenic epilepsies, often associated with early onset, atypical clinical and/or EEG features, developmental delay or drug resistance. Classification models should incorporate genetic data alongside electroclinical features, especially as next-generation sequencing is increasingly used.