Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6-24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development-BSID, and Autism Diagnostic Observation Schedule-ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy-Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6-12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies.

Amsterdam UMC University of Amsterdam Department of The Netherlands

Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Via Montpellier 1 00133 Rome Italy

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Via Montpellier 1 00133 Rome Italy Child Neurology Unit Neuroscience and Neurorehabilitation Department Bambino Gesù Children's Hospital IRCCS P zza S Onofrio 4 00165 Rome Italy

Department of Biomedicine and Prevention Tor Vergata University of Rome Via Montpellier 1 00133 Rome Italy

Department of Biomedicine and Prevention Tor Vergata University of Rome Via Montpellier 1 00133 Rome Italy Department of Biotechnological and Applied Clinical Sciences University of L'Aquila 67100 L'Aquila Italy

Department of Child Neurology Brain Center University Medical Center Utrecht 3584 Utrecht The Netherlands

Department of Child Neurology Charité University Medicine Berlin Augustenburger Platz 1 13353 Berlin Germany

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven 3000 Leuven Belgium

Department of Neurology and Epileptology The Children's Memorial Health Institute Al Dzieci Polskich 20 04 730 Warsaw Poland

Department of Neurology and Epileptology The Children's Memorial Health Institute Al Dzieci Polskich 20 04 730 Warsaw Poland Department of Child Neurology Medical University of Warsaw Warsaw Poland Zwirki i Wigury 63A 02 091 Warsaw Poland

Department of Pediatric Neurology Reference Centre for Rare Epilepsies Necker Enfants Malades Hospital University Paris Descartes Imagine Institute 75015 Paris France

Department of Pediatrics University Hospital Vienna 1090 Vienna Austria

Diagnose und Behandlungszentrum für Kinder und Jugendliche Vivantes Klinikum Neuköln 12351 Berlin Germany

Motol University Hospital Charles University 150 06 Prague Czech Republic

Neuroscience Unit Queensland Children's Hospital 501 Stanley Street South Brisbane QLD 4101 Australia School of Clinical Medicine University of Queensland St Lucia QLD 4072 Australia

Pediatric Neurology Unit UZ Brussel 1050 Brussels Belgium

Warsaw University of Technology Institute of Heat Engineering 00 661 Warsaw Poland Transition Technologies ul Pawia 5 01 030 Warsaw Poland

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