Genetic complexity in pediatric onset epilepsy‐movement disorder syndromes: Insights from a cohort of 97 subjects

Abstract Objective Conditions presenting with both epilepsy and movement disorders (EPIMDs) range from relatively benign cases to severe developmental encephalopathies. However, the full clinical and genetic spectrum still needs to be better defined. The aim of this study is to describe the presentation of EPIMDs in pediatric patients with known genetic etiologies, correlating these features with age at onset and underlying pathological mechanisms to identify patterns that could improve patient management. Methods We retrospectively analyzed the clinical records of pediatric patients who underwent genetic testing for EPIMDs at our institution between 2009 and 2022. Genetic testing included single‐gene Sanger sequencing, multigene next‐generation sequencing panels targeting epilepsy and/or MDs, and array comparative genome hybridization. Demographic, clinical, and electroencephalography (EEG) data were collected. Statistical analyses were conducted using multivariate and cluster analyses. Results A total of 97 subjects were included. The mean age ± SD at epilepsy onset was 3.6 ± 4.4 years, whereas the mean age at MD onset was 5.2 ± 4.9 years. Based on the mechanism of genetic dysfunction, we identified six groups: transportopathies ( n = 18), synaptopathies ( n = 11), channelopathies ( n = 18), metabolic disorders ( n = 15), intracellular trafficking defects ( n = 8), and unknown/complex function disorders ( n = 27). Cluster analysis identified three distinct groups: (1) early‐onset epilepsy and paroxysmal MDs with normal intelligence quotient (IQ) and mild intellectual disability, associated with transportopathies ( n = 38); (2) early‐onset epilepsy with dystonia and myoclonus, low IQ, and developmental and epileptic encephalopathy, associated with channelopathies ( n = 31); (3) epilepsy onset between 1 and 5 years of age with developmental delay, parkinsonism, and low IQ, associated with metabolic etiology ( n = 26). Significance Our study demonstrates that, despite the phenotypic and genetic pleiotropy observed in EPIMDs, a precise characterization of semiological and cognitive features remains essential to support variant interpretation and to refine the diagnostic process and patient management in these rare conditions.