DESCRIPTION (provided by applicant): Fragile X syndrome (fraX) is the most common known cause of inherited mental impairment with well over 100,000 individuals affected in the U.S. Mutations in the FMR1 gene give rise to a clinical phenotype that includes increased risk for aberrant cognitive, behavioral and emotional function. The major emphasis of the 5-year study proposed in this application is a prospective, longitudinal extension o the work completed during the current grant period, during which key cognitive, behavioral, neuroendocrinological, genetic and environmental data were collected from 120 families across the U.S. and Canada, each having a child proband affected with fraX and a typically developing sibling. To the best of our knowledge, this study would be the first longitudinal investigation of a large, school-age fraX cohort in which both biological and environmental factors contributing to clinical outcome were assessed on a prospective basis. We also propose to extend our investigation into the neurobiology of this disorder using advanced brain imaging techniques. Specifically, longitudinal imaging studies will be used to explicate the developmental trajectory of brain structure and function in children with fraX as compared to key control groups. Specific Aims: 1) 10 use a longitudinal, prospective experimental design (with "Time 1" and "Time 2? assessments) to elucidate the developmental trajectory of cognitive, behavioral and emotional development in probands with fraX compared to their like-gender siblings; 2) to specify the longitudinal trajectory of hypothalamic-pituitary-adrenal (HPA) function and measures of FMR1 gene expression in probands with fraX; and 3) to utilize neuromaging techniques to specify the trajectory of brain structure and function in children with fraX compared to specific age-, gender-, handedness-, SES- and lQ-matched control groups. Although knowledge of cognition, behavior and the brain in children and adults with fraX has grown considerably over the past 20 years, longitudinal data from school-age children with this condition are limited. Cross-sectional findings and limited longitudinal data to date support the hypothesis that an age-related decline in standardized cognitive and adaptive behavioral scores occurs among school-age children with fraX. However, many questions remain unanswered regarding this phenomenon, in particular as related to extent, timing and neural basis. These unanswered questions offer a compelling rationale for conducting a longitudinal study of a large group of school-age boys and girls with fraX as proposed in this application.