Natural History of Children and Adolescents With Dravet Syndrome

Abstract

Background and Objectives Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused primarily by pathogenic variants in the voltage-gated sodium channel α subunit 1 (SCN1A) gene. Patients with DS experience refractory seizures and significant cognitive and behavioral deficits. Longitudinal studies using standardized assessments are needed to systematically document patient outcomes over time. The BUTTERFLY study aimed to assess changes in adaptive functioning and neurodevelopment over 24 months in patients with DS. Methods BUTTERFLY was a US-based multicenter, longitudinal observational study involving patients with genetically confirmed DS who were receiving standard-of-care treatment. Patients aged 2–18 years with a confirmed DS diagnosis were included. Exclusion criteria included gain-of-function SCN1A variants, current sodium channel blocker treatment, or other disorders per investigator discretion. The primary outcome measures—adaptive functioning and neurodevelopment—were assessed using Vineland Adaptive Behavior Scale, Third Edition (Vineland-3); Bayley Scales of Infant Development, Third Edition (BSID-III); and Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Assessments were conducted at baseline and at 3, 6, 12, 18, and 24 months across 15 sites. Mixed models for repeated measures were used to analyze disease progression, and comparisons were made with published standardized scores for population norms. Results Of the 36 patients enrolled, 21 completed the study. At baseline, the mean (SD) patient age was 10.8 (5.2) years, and 61.1% were female. Disease progression modeling indicated no significant improvements in 4 of the 6 Vineland-3 subdomains analyzed over 24 months. Receptive Communication (+7.24; 95% CI 1.30–13.19; p = 0.02) and Coping Skills (+4.61; 95% CI 1.14–8.08; p = 0.01) subdomains showed significant improvements. However, for Receptive Communication, this improvement translated to a magnitude of only approximately 3 months in developmental progression over the 24-month period. BSID-III and WPPSI-IV subtests did not show any significant improvement. Discussion Despite a relatively small sample size and high withdrawal rate, BUTTERFLY data reveal a widening developmental gap between patients with DS and children with typical development over 24 months. These findings reinforce the critical need for disease-modifying therapies that address the underlying genetic cause of DS to improve long-term outcomes.