Toward better characterization and clinical trial readiness for targeting neuropsychiatric manifestations in PTEN pathogenic variants

Boston Children'S Hospital, Boston MA

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Abstract

Project Summary/Abstract PTEN hamartoma tumor syndrome (PHTS) is a collection of disorders characterized by germline mutations in the PTEN gene that encodes phosphatase and tensin homolog. Although mutations in PTEN were initially associated with a range of physical issues, our work to date has demonstrated that autism diagnosis, macrocephaly, and a broad spectrum of cognitive and behavioral issues are common among patients with PHTS. In the previous funding periods, we have characterized cross-sectional and longitudinal neuropsychiatric symptomatology (NPS) profiles of individuals with PHTS (age 3 to 45 years), completed a randomized controlled trial (RCT) examining the efficacy and safety of everolimus, an mTOR inhibitor, and gained preliminary evidence of the relationships between neurophysiological markers and clinically meaningful symptoms, emphasizing the importance of sleep and sensory dysfunctions in this group. Our increased understanding of the genetic basis of PHTS provides a unique opportunity to develop disease-specific therapeutic agents, and recent efforts highlight the need for clinical trial readiness. However, existing assessments have psychometric limitations, especially with regards to the comprehensive characterization of clinical profiles and the ability to track symptom progress in individuals with intellectual disabilities. In this proposal, we intend to develop the next generation of multimodal assessment protocols to further characterize the natural history of NPS in people with PHTS (Aim 1). We also hope to examine the neurophysiological mechanisms underpinning sleep and sensory abnormalities (Aim 2) and specifically optimize the multimodal assessment protocol from Aims 1 and 2 for quantification of change at group and individual patient levels to enable sensitive treatment tracking (Aim 3). These aims will be accomplished by recruiting 150 individuals with PHTS between over the age of 18 months who will be characterized neurocognitively cross-sectionally and longitudinally as well as 50 individuals with awake sensory EEG, sleep EEG and actigraphy. This project will be undertaken by a unique collaboration of six sites across the country and findings from this research will help better characterize individuals with PHTS and guide the design of future trials.