Epilepsia open · 2026
Shared molecular pathways in pediatric genetic epilepsies: Insights from a single-center cohort of 80 patients.
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Hecher Laura, Woidy Mathias, Plein Franziska, Bierhals Tatjana, Elsner Leonie von, Herget Theresia, Hempel Maja, Kortüm Fanny, Grinstein Lev, Cramer Julia V, Johannsen Jessika, Denecke Jonas
Аннотация
OBJECTIVE: Genetic epilepsies in childhood are highly heterogeneous, and approaches to identify shared biological mechanisms across distinct genetic etiologies remain limited. We aimed to investigate whether genes associated with pediatric genetic epilepsies in our heterogeneous cohort converge on common functional pathways.
METHODS: We conducted a single-center retrospective study involving 80 children who met the International League Against Epilepsy (ILAE) criteria for epilepsy with a confirmed monogenetic etiology, with or without other neurological conditions. These children were part of a cohort of pediatric patients with a broad spectrum of neurological disorders that had been genetically diagnosed using trio-based whole-exome sequencing. Clinical data were systematically collected. Gene Ontology (GO)-based enrichment analysis was performed to explore functional convergence.
RESULTS: The cohort comprised 80 patients (39% female, 61% male) with a median age at seizure onset of seven months and included 66 distinct disease-causing genes and four pathogenic copy number variants. Despite marked genetic heterogeneity, enrichment analyses revealed convergence in functional pathways related to synaptic signaling, membrane channels and transport processes, and neurodevelopmental and neuronal plasticity pathways. Age-stratified analyses suggested variation in the relative contribution of these pathways across developmental stages, while no significant differences were observed with respect to neurodevelopmental delay or neuroimaging abnormalities.
SIGNIFICANCE: These findings demonstrate shared molecular pathways across clinically and genetically diverse pediatric neurological conditions associated with epilepsies and support a pathway-oriented perspective that may complement gene-based classification and inform future therapeutic strategies.
PLAIN LANGUAGE SUMMARY: Childhood epilepsies caused by genetic changes can arise from many different genes, making them difficult to understand and classify. In this study, we analyzed 80 children with genetically confirmed epilepsy and found that, despite different genetic causes, many of the affected genes are involved in similar biological processes, particularly those related to brain signaling and development. These findings suggest that different genetic epilepsies may share common underlying mechanisms. A better understanding of these shared pathways may help improve how epilepsy is classified and treated in the future.
METHODS: We conducted a single-center retrospective study involving 80 children who met the International League Against Epilepsy (ILAE) criteria for epilepsy with a confirmed monogenetic etiology, with or without other neurological conditions. These children were part of a cohort of pediatric patients with a broad spectrum of neurological disorders that had been genetically diagnosed using trio-based whole-exome sequencing. Clinical data were systematically collected. Gene Ontology (GO)-based enrichment analysis was performed to explore functional convergence.
RESULTS: The cohort comprised 80 patients (39% female, 61% male) with a median age at seizure onset of seven months and included 66 distinct disease-causing genes and four pathogenic copy number variants. Despite marked genetic heterogeneity, enrichment analyses revealed convergence in functional pathways related to synaptic signaling, membrane channels and transport processes, and neurodevelopmental and neuronal plasticity pathways. Age-stratified analyses suggested variation in the relative contribution of these pathways across developmental stages, while no significant differences were observed with respect to neurodevelopmental delay or neuroimaging abnormalities.
SIGNIFICANCE: These findings demonstrate shared molecular pathways across clinically and genetically diverse pediatric neurological conditions associated with epilepsies and support a pathway-oriented perspective that may complement gene-based classification and inform future therapeutic strategies.
PLAIN LANGUAGE SUMMARY: Childhood epilepsies caused by genetic changes can arise from many different genes, making them difficult to understand and classify. In this study, we analyzed 80 children with genetically confirmed epilepsy and found that, despite different genetic causes, many of the affected genes are involved in similar biological processes, particularly those related to brain signaling and development. These findings suggest that different genetic epilepsies may share common underlying mechanisms. A better understanding of these shared pathways may help improve how epilepsy is classified and treated in the future.