Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbidities when interventions are favourable. We investigated whether early EEG characteristics can be used to predict neurodevelopment in infants with TSC. The first recorded EEG of 64 infants with TSC, enrolled in the international prospective EPISTOP trial (recorded at a median gestational age 42 4/7 weeks) was first visually assessed. EEG characteristics were correlated with ASD risk based on the ADOS-2 score, and cognitive, language, and motor developmental quotients (Bayley Scales of Infant and Toddler Development III) at the age of 24 months. Quantitative EEG analysis was used to validate the relationship between EEG background abnormalities and ASD risk. An abnormal first EEG (OR = 4.1, p-value = 0.027) and more specifically a dysmature EEG background (OR = 4.6, p-value = 0.017) was associated with a higher probability of ASD traits at the age of 24 months. This association between an early abnormal EEG and ASD risk remained significant in a multivariable model, adjusting for mutation and treatment (adjusted OR = 4.2, p-value = 0.029). A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (p-value = 0.001), and motor (p-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Rome Italy

Child Neurology Unit Neuroscience and Neurorehabilitation Department Bambino Gesù Children's Hospital Rome Italy

Department of Child Neurology Brain Centre University Medical Centre Utrecht Utrecht Netherlands

Department of Child Neurology Charité University Medicine Berlin Berlin Germany

Department of Child Neurology Medical University of Warsaw Warsaw Poland

Department of Electrical Engineering STADIUS Centre for Dynamical Systems Signal Processing and Data Analytics KU Leuven Leuven Belgium

Department of Neurology and Epileptology The Children's Memorial Health Institute Warsaw Poland

Department of Paediatric Neurology Charles University 2nd Faculty of Medicine Motol University Hospital Prague Czechia

Department of Pathology Amsterdam Universitair Medisch Centrum University of Amsterdam Amsterdam Netherlands

Department of Pediatric Neurology Reference Centre for Rare Epilepsies Imagine Institute Necker Enfants Malades Hospital University Paris Descartes Paris France

Department of Pediatrics Medical University Vienna Vienna Austria

Diagnose und Behandlungszentrum für Kinder und Jugendliche Vivantes Klinikum Neuköln Berlin Germany

Harvard Medical School Brigham and Women's Hospital Boston MA United States

Institute of Heat Engineering Warsaw University and Technology Warsaw Poland

Neuroscience Unit Queensland Children's Hospital Brisbane QLD Australia

Pediatric Neurology Department of Development and Regeneration University of Leuven KU Leuven Leuven Belgium

Pediatric Neurology Unit Universitair Ziekenhuis Brussel Brussels Belgium

Stichting Epilepsie Instellingen Nederland Heemstede Netherlands

Transition Technologies Warsaw Poland

University of Queensland School of Clinical Medicine Brisbane QLD Australia

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miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex