Early Cognitive and Developmental Predictors of ASD in Infants with Tuberous Sclerosis Complex

Background: The Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 genes, and it is characterized by the widespread growth of hamartomas in multiple organ systems, including the brain. Rates of ASD in TSC range from 25-60%, much higher than the 1-2% reported in the general population. The diagnosis of TSC is often made prenatally or in early infancy, either through the visualization of cardiac rhabdomyomas or in the setting of early onset seizures and/or infantile spasms. In this setting, TSC represents a promising high-risk group for the investigation of early developmental trajectories and risk factors for ASD.

Objectives: We have performed a longitudinal, prospective study of infants with Tuberous Sclerosis Complex (TSC), with the overarching goal of defining early clinical, behavioral and biological markers of autism spectrum disorder (ASD) in this high-risk population. 

Methods: Infants with TSC and typically developing (TD) controls were recruited as early as 3 months of ages and followed longitudinally until 36 months of age. Data gathered at each time point included detailed seizure history, developmental testing using the Mullen Scales of Early Learning (MSEL), and social-communication assessments including the Autism Observation Scale of Infancy (AOSI). Several electrophysiological paradigms were also performed, with one highlighted here involving the assessment of low level visual processing using a visual evoked potential paradigm. At 18, 24 and 36 months, a diagnostic evaluation for ASD was performed using the Autism Diagnostic Observation Schedule (ADOS) and clinical assessment by a trained clinician. 

Results: Infants with TSC demonstrated delays confined to non-verbal abilities, particularly in the visual domain, through the first 6 months of life, which then generalized to more global delays by age 9 months. The delay in visual reception at 6 months was associated with electrophysiological markers, namely a longer latency of the occipital P1 component (TSC mean latency 131.8 msec, TD mean latency 120.3 msec, p=0.009). 55% (22/40) of the infants with TSC followed longitudinally were diagnosed with ASD. Both 12-month cognitive ability in all domains (verbal and non-verbal) and developmental trajectories over the second two years of life significantly differentiated the groups. More specifically, byy 12 months of age, the ASD group demonstrated significantly greater cognitive delays and a significant decline in non-verbal IQ from 12-36 months.

Conclusions: This is the first prospective study of development in infants with TSC, and it represents a timely effort to define early markers of ASD in this high-risk population. The early delay in visual reception and fine motor ability in the TSC group as a whole, coupled with the decline in non-verbal ability in infants diagnosed with ASD, suggests a domain-specific pathway to ASD that can inform more targeted interventions for these infants.