Fenfluramine in SCN1A-Related Genetic Epilepsy with Febrile Seizures Plus (GEFS+): Toward a Precision Therapeutic Approach

Background: SCN1A-related genetic epilepsy with febrile seizures plus (GEFS+) is characterized by marked intrafamilial phenotypic variability, ranging from asymptomatic variant carriers to severe, drug-resistant epilepsy. Methods and Results: We present a two-generation family in which two clinically affected sisters inherited a causative heterozygous SCN1A missense variant (c.3824G>A) from the mother, who likely carries the variant in a mosaic state. The proband, a 23-year-old woman, presented with a long-standing drug-resistant febrile and afebrile epilepsy with onset in early infancy, complicated by mild intellectual disability, impulse control disorder, and behavioral comorbidities, leading to a delayed genetic diagnosis in adulthood. Following insufficient control by multiple antiseizure medications, fenfluramine was introduced at age 21, resulting in complete seizure freedom sustained over two years, alongside measurable neuropsychological improvements in cognition, adaptive functioning, socialization and quality of life. Conclusions: This case highlights the importance of systematic family history and targeted genetic workup in patients with drug-resistant epilepsy, adds preliminary evidence for fenfluramine beyond Dravet and Lennox–Gastaut syndromes, and illustrates the potential of precise genetic diagnosis to guide treatment in SCN1A-related GEFS+.