Rationale:
SCN1A-related epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet Syndrome (DS), are among the most common monogenic epilepsies. Anti-seizure medications (ASMs) can reduce seizures, however their impact on cognition and comorbidities remains unknown. Several disease-modifying treatments are undergoing clinical trials. Without understanding the natural history of these disorders, it will not be possible to measure treatment success beyond seizure control.
Methods:
Following local ethical approval, participants with a diagnosis of SCN1A-positive epilepsy were recruited from 17 UK sites. Data collection used standardised Case Report Forms designed to collect comprehensive clinical and neuropsychology data from participants with SCN1A-related epilepsy including seizure history, genetic variants, treatments, comorbidities, examination findings, investigations, biomarkers, and neuropsychology assessments. This report presents baseline clinical data from 17 months of collection. Comparisons between DS and GEFS+ used Mann-Whitney U and Fisher’s exact tests.
Results:
From November 2023 - March 2025, 120 participants with SCN1A-related epilepsy underwent baseline clinical assessment; 62(51.7%) were female, with a median age of 8 years (range 9 months–63 years). Diagnoses included DS (92;76.7%); GEFS+ (13;10.8%); unspecified SCN1A-related epilepsy (10;10.3%); and SCN1A gain-of-function phenotype (2;1.7%).
First seizures were often generalised tonic-clonic (72;60.0%) and commonly triggered by fever/illness (78;65.0%) and/or vaccination (24;20.0%). They terminated spontaneously in 59(49.2%), while 11(9.2%) required high dependency/intensive care. Median seizure onset age was 5 months (range 2-78), and most frequent subsequent seizure type was generalised tonic-clonic (109;90.8%).
Median number of current ASMs was 3 (range 0-5); most commonly sodium valproate (83;69.2%), clobazam (67;55.8%), stiripentol (55;45.8%) and fenfluramine (36;30.0%). The number of previous ASMs used ranged from 0-14 (median=1), most frequently levetiracetam (48;40.0%). DS diagnosis was associated with a higher median number of current ASMs (U=172, P=< .001) and previous ASMs (U=313, P=< .005) when compared to GEFS+ (table 1). Currently, 7(5.8%) participants were on sodium channel blockers, while 37(30.8%) were prescribed one previously. Comorbidities were frequent: 55(45.8%) reported difficulty with feeding; 61(50.8%) reported sleep problems and 64(53.3%) reported a motor disorder. Behavioural difficulties were reported by 55(45.8%). Additionally, 59(49.2%) reported features of Autistic Spectrum Disorder, while 41(34.2%) reported features of ADHD. Compared to GEFS+, participants with DS had higher rates of feeding difficulties (55.7% vs 16.7%, P=.014), sleep problems (60.2% vs 16.7%, P=.006), motor disorder (74.7% vs 9.1%, P< .001) and autistic features (66.7% vs 20.0%, P=.012), as shown in table 2.
Conclusions:
These baseline findings demonstrate the high burden of seizures and comorbidities amongst individuals with SCN1A-related epilepsy. Ongoing follow-up of this cohort will inform care standards and treatment strategies.
Funding:
The author receives funding from the SCN1A-Horizons study.