Early biomarkers of Autism Spectrum Disorders in infants with Tuberous Sclerosis Complex

A lack of understanding regarding the underlying molecular and cellular mechanismsis a key barrier in finding effective treatments for Autism Spectrum Disorders (ASD). Single-gene disorders thathave a high prevalence of ASD provide unique opportunities to investigate the underlying biology and testtreatments for autism. Approximately 50% of individuals with Tuberous Sclerosis Complex (TSC) are alsoaffected with ASD. Since TSC can be diagnosed before or at time of birth, the natural history of ASD can beobserved prospectively in these patients to develop better tools for early detection of autism. On a molecularlevel, TSC disease manifestations result from the aberrant hyperactivity of mTOR that is caused by mutation inone of two TSC genes. Pharmacologic mTOR inhibition to correct the cellular defects in TSC is now an excitingand real possibility. To determine the potential benefit these agents may have in treating or preventing ASD, itis imperative to identify early markers of autism in infants with TSC, to avoid unnecessary risk. Accumulatingclinical and basic science evidence suggests that aberrant white matter connectivity represents a rationalcandidate as a biomarker in TSC. TSC mouse models demonstrate defects in the specification, guidance, andmyelination of axons. More importantly, several groups have reported abnormalities in the normal-appearingwhite matter of TSC patients that can be identified by MR imaging, and loss of white matter microstructuralintegrity is associated with neurological and cognitive deficits. Furthermore, there is preliminary data indicatingthat white matter integrity can be improved by treatment with mTOR inhibitors in both animal models and inTSC patients. Taken together, these findings lead to the hypothesis that longitudinal assessment of whitematter integrity and neural connectivity in TSC infants, through advanced MRI and EEG analysis, can be usedas an early biomarker of subsequent ASD in this genetic disease. This project aims to establish a consortiumof five Children’s Hospitals that are geographically-distributed throughout the US to recruit TSC patients in thefirst year of life to test this hypothesis. State of the art imaging with 3Tesla MRI scanners, advanced EEGtechnology, validated neurodevelopmental assessment tools, genetic analysis, and standardized clinicalmeasures through age 36 months will be utilized. The clinical consortium will be supported by a centralizedData Coordinating Center with experience in another rare disease (neurofibromatosis). Collaboration withLeadership Education in Neurodevelopmental and Related Disabilities (LEND) programs at each center willprovide additional interdisciplinary research training and education expertise in ASD and TSC. As a result ofthe research outlined in this project, better understanding of brain connectivity and its relationship to ASD inTSC will pave the way for new interventions for this and related causes of autism.