Molecular and Clinical Spectrum of the Epilepsy-Dyskinesia Syndromes – A Cross-Sectional Study of 609 Patients
Abstract
Epilepsy-dyskinesia syndromes (EDS) are a complex group of neurogenetic disorders characterized by the co-occurrence of epilepsy and movement disorders. Despite their increasing clinical recognition, the molecular and clinical spectrum of EDS remain poorly understood. While numerous genetic etiologies have been implicated, systematic characterization across diverse populations is lacking. This study aimed to delineate the molecular and clinical landscape of EDS in a large, multinational cohort, focusing on movement disorder phenomenologies, genotype-phenotype correlations, and treatment responses. We conducted a multicenter, cross-sectional study involving 609 patients with childhood-onset movement disorders associated with pathogenic variants in 105 predefined genes. Clinical data were collected from over 30 centers across 25 countries using a standardized survey, capturing movement disorder phenomenologies, seizure types, developmental trajectories, motor function, and treatment outcomes. We classified EDS-associated genes into biologically meaningful groups by performing unsupervised clustering, which integrated protein-protein interactions and functional data. Genotype-phenotype correlations were assessed using a one-versus-remainder approach to quantify differential enrichment of clinical manifestations and treatment responses. Pathogenic variants were identified in 74 of the 105 predefined genes, with 12 genes accounting for two-thirds of cases. The most frequently…
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