Dravet Syndrome (DS) is a severe, lifelong epileptic encephalopathy caused primarily by SCN1A mutations, characterised by treatment-resistant seizures, cognitive impairment, and elevated risk of sudden unexpected death in epilepsy (SUDEP). While paediatric populations have been extensively studied, adults with DS remain understudied, despite persistent and evolving sleep disturbances that exacerbate seizure frequency, cognitive decline, and mortality risk. Sleep-wake dysregulation in DS may reflect intrinsic circadian rhythm disruption, affecting hormonal cycles, seizure susceptibility, and response to therapies.
The DS-COMBINE study integrates longitudinal, multi-modal assessments to define sleep-circadian architecture and its molecular underpinnings in adults with DS. WP1 combines actigraphy, digital sleep diaries, environmental biosensors, and salivary dim light melatonin onset (DLMO) and cortisol profiling to characterise individual sleep patterns, circadian phase, temporal seizure clustering and therapeutic timing. WP2 extends these data with high-resolution time-resolved saliva transcriptomics to identify circadian-oscillatory genes, integrating molecular, behavioural, and clinical data to develop predictive multi-modal models of sleep-circadian disruption, seizure risk, and chronotherapeutic responsiveness. Medication timing and melatonin supplementation are synchronised with circadian and seizure metrics to investigate chronotherapy potential. WP3 ensures robust project governance, patient and public involvement, and data management to support FAIR-compliant, high-integrity datasets.
By mapping molecular and behavioural circadian signatures, DS-COMBINE will identify biomarkers predictive of sleep fragmentation, seizure susceptibility, and ASM timing efficacy. The integration of home-based monitoring, longitudinal diaries, and molecular profiling allows classification of participants by circadian disruption severity and enables personalised chronotherapy strategies.
This project will generate the first comprehensive, phase-aligned framework linking sleep, circadian biology, seizures, and medication timing in adults with DS. Findings will inform precision treatment, optimise sleep and seizure control, and provide mechanistic insight to reduce SUDEP risk, supporting future translational interventions and improving long-term health outcomes in this vulnerable population.