Abstract
OBJECTIVE: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene in neurons. Promising disease-modifying treatments to reinstate UBE3A expression are under development and an early measure of treatment response is critical to their deployment in clinical trials. Increased delta power in EEG recordings, reflecting abnormal neuronal synchrony, occurs in AS across species and correlates with genotype. Whether delta power provides a reliable biomarker for clinical symptoms remains unknown. METHODS: We analyzed combined EEG recordings and developmental assessments in a large cohort of individuals with AS (N = 82 subjects, 133 combined EEG and cognitive assessments, 1.08-28.16 years; 32F) and evaluated delta power as a biomarker for cognitive function, as measured by the Bayley Cognitive Score. We examined the robustness of this biomarker to varying states of consciousness, recording techniques and analysis procedures. RESULTS: Delta power predicted the Bayley Scale cognitive score (P < 10(-5) , R(2) = 0.9374) after controlling for age (P < 10(-24) ), genotype:age (P < 10(-11) ), and repeat assessments (P < 10(-8) ), with the excellent fit on cross validation (R(2) = 0.95). There were no differences in model performance across states of consciousness or bipolar versus average montages (ΔAIC < 2). Models using raw data excluding frontal channels outperformed other models (ΔAIC > 4) and predicted performance in expressive (P = 0.0209) and receptive communication (P < 10(-3) ) and fine motor skills (P < 10(-4) ). INTERPRETATION: Delta power is a simple, direct measure of neuronal activity that reliably correlates with cognitive function in AS. This electrophysiological biomarker offers an objective, clinically relevant endpoint for treatment response in emerging clinical trials.