Clinical Trial Readiness for the Evaluation and Treatment of Neuropsychiatric Manifestations in Tuberous Sclerosis Complex

SUMMARY ABSTRACT: Neuropsychiatric and neurodevelopmental manifestations, including closely related autism spectrum disorder (ASD), intellectual disability (ID), and other neurobehavioral difficulties, are prominent in the majority of patients with Tuberous Sclerosis Complex (TSC). Collectively, the intertwined constellation of these cognitive, neurobehavioral deficits, including sleep and sensory impairments, is referred to as TSC-associated neuropsychiatric disorders (TAND). There is a lack of TAND-specific treatments studied for use in TSC. The Developmental Synaptopathies Consortium (DSC) seeks to address this need by addressing critical gaps in clinical trial readiness for developing potential therapies (pharmacological and non-pharmacological) for TAND in TSC. Over the last five years, this has included development of the self-administered and quantified version of the TAND Checklist (TAND-SQ) in collaboration with the TANDem consortium and piloted work on novel electrophysiological biomarkers for ASD and ID in TSC. Over the next five years, we plan to validate the TAND- SQ for use in future clinical trials (AIM 1). We also will conduct the first prospective longitudinal assessment of psychiatric conditions and mental health symptoms in TSC, along with establishing the landscape of psychotropic medication use, in TSC patients with TAND (AIM 2). Finally, we will newly characterize sleep difficulties and abnormalities in sensory processing within the TAND phenotype and further develop corresponding electrophysiological biomarkers of each as potential measures of abnormal neuronal circuitry contributing to the pathobiology of TAND in TSC and their potential suitability for use in future clinical trials (AIM 3). The proposed research will also improve our understanding of the neurobiology of neurodevelopmental disorders such as ASD and ID and aid in developing treatments for these disorders more broadly.