Prospective Investigation of Early Clinical Predictors of Autism Spectrum Disorders in Infants with Tuberous Sclerosis Complex: First Analysis from the Epistop Project

Background: Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that confers a high risk of early neurodevelopmental conditions. Little is known about early onset of developmental delay and of autism spectrum disorders (ASD) in this high risk population. The EPISTOP project is a multi-center prospective European study focused on evaluating clinical and molecular biomarkers of epileptogenesis and neurodevelopmental disorders in the genetic model of TSC.

Objectives: The objective of the work package 7 of EPISTOP is to identify early neurodevelopmental outcome in TSC patients in the first months of life. The main goal of this preliminary analysis is to identify early deviation in developmental trajectories and in specific skills potentially predictive of ASD onset.

Methods: 99 EPISTOP TSC subjects were prospectively followed from age of 6 months with Bayley Scales of Infant Development (BSID) for the evaluation of cognitive, language and motor level. Autism Diagnostic Observation Schedule (ADOS) was administrated from 12 months for the identification of ASD risk. All tests were repeated every 6 months up to 24 months of age. At this moment, data collection is still ongoing. We focused our analysis on the correlation with BSID sub-quotients at 6, 12 and 18 months and ASD risk based on ADOS total score at 24 months. ADOS and BSID changes over time were evaluated with paired samples t-test. Comparisons between groups were performed, as appropriate, with two-sample t test, ANOVA models, and Pearson’s correlations. An alpha level of 0.05 was used for all statistical analyses, which were performed using SPSS v.23.0 (IBM Corp., Armonk, NY, USA).

Results: Data is available for 69 children at age 6 months and 46 at 24 months. At 6 months, 20% of children showed developmental delay in cognitive and language areas, and 53% had an impairment in the motor area of the BSID. At 24 months, an increased percentage of developmental delay (30%) could be observed in all the three developmental quotients. At 6 months, no significant correlations were found between development level of the three BSID areas and ADOS total score (p 0.15). At 12 months, children with lower scores in cognitive and language quotients presented higher risk of ASD calculated on ADOS total score at 24 months (p 0.02). At 18 months, the statistical significance of this correlation increases (p 0.01) and involves all BSID subquotients.

Conclusions: Our preliminary observations show an early deviation from a normal developmental trajectory in infants with TSC in the first 6 months of life, particularly in the motor area. Impairment in cognitive and language level at 12 months could be predictive of ASD at 24 months in these high-risk children. Prospective neurodevelopmental assessment associated with a close neurological and EEG follow-up could be useful to identify early correlation between clinical and neurobiological markers of ASD, to design individualized treatment strategies and to improve both short and long term outcomes for this population.