Characterizing Early Developmental Trajectories in Tuberous Sclerosis Complex

Background: Tuberous Sclerosis Complex (TSC) is one of the most commonly occurring genetic disorders associated with autism spectrum disorder (ASD). Up to 60% of children with TSC will meet criteria for ASD and up to 80% will experience cognitive delay. Importantly, cognitive delays and ASD often co-occur in this population, posing challenges for diagnosis, intervention targets and treatment selection. Despite hypotheses about the role of epilepsy, cortical pathology, and co-occurring genetic mutations in predicting neurodevelopmental outcomes in TSC, no single clinical factor has been identified as a consistent predictor of atypical neurodevelopment. As TSC is often diagnosed very early in life, often prenatally, allows for prospective investigation of developmental trajectories and early markers of ASD in this population.

Objectives: Modeling the approach taken in our work with infant siblings at high-risk for ASD, we conducted the first, prospective, longitudinal study of infants with TSC, mapping development from 3-6 months through to 36 months of age. Within the context of this prospective study design, we aimed to characterize early delays in cognitive development that precede, and possibly predict, the development of ASD in this high-risk population.

Methods: Infants with TSC (n = 40) and typically developing infants (n = 34) were recruited as early as 3-6 months of age and followed longitudinally until 36 months of age. For all infants, we assessed developmental functioning using the Mullen Scales of Early Learning. Social communication was assessed using the Autism Observation Scale for Infants (AOSI). At 18, 24 and 36 months a diagnostic evaluation of ASD was performed using the Autism Diagnostic Observation Schedule (ADOS). For TSC infants, detailed clinical and seizure history information was obtained at each time point.

Results: Infants with TSC show delays in cognitive development (especially in fine motor [p = .01] and visual receptions skills [p = .03]) and social communication skills (especially in visual tracking [p < .01], disengagement of attention [p < .01] and anticipatory responses [p = .02]) as early as 6 months of age, with more global delays from 9 months (all ps < .05). Infants with TSC who develop ASD (n  = 22 of 40 infants with TSC) show more cognitive impairment from 12 months of age (ps < .05) and a slowing of non-verbal skills development between 12 to 36 months of age compared to infants with TSC without ASD, even after controlling for seizure severity (slope estimate -0.80, p = .01).

Conclusions: This research has unveiled a developmental profile in TSC that is marked by prominent and early delays in non-verbal skills, regardless of ASD outcome. Declines in non-verbal skills development between 12 and 36 months in infants with TSC and ASD suggest a domain-specific pathway to ASD in this population. These findings have contributed to the development of a targeted, early intervention trial for this high-risk population.