The aim of this study is to investigate relations between molecular genetic and brain abnormalities underlying social-emotional and cognitive functioning in adult males with the fragile X premutation. The fragile X premutation, associated with a CGG repeat expansion of 55 to 200 in the FMR1 gene on the X chromosome, is a relatively common genetic condition, present in an estimated 1 per 813 men and 1 per 250 women. Until recently, it was believed that carriers of the premutation were clinically unaffected. Recent evidence, however shows that a proportion of these individuals have significant social, emotional, and cognitive deficits, and even autism and mental retardation. We have found that some will go on to develop in their later years a newly discovered, progressive neurological disorder, fragile X associated tremor ataxia syndrome (FXTAS). We have evidence that FXTAS, and even psychological disturbance in earlier adulthood, is related to a toxic gain of function effect from elevated FMR1-mRNA in the premutation CGG repeat range. We hypothesize that limbic dysfunction underlies social-emotional and memory deficits in young adult individuals with the premutation. In the current study, we will use structural and functional MRI to determine whether men with the premutation (ages 18 to 45 years), in comparison to an age and IQmatched group of men, demonstrate abnormal brain morphology and function in limbic brain regions, focusing on the hippocampus and amygdala, and related brain regions associated with memory and socialemotional dysfunction. We will also examine psychiatric symptoms related to mood disorder and social cognition and reciprocity in these subjects, and examine whether measures of FMR1 gene function, including elevated mRNA, are associated with the morphology and function of these limbic brain regions. This research will lead to a better understanding of gene-brain-behavior relations associated with the FMR1 premutation. In addition, the knowledge of multiple systems of involvement in the premutation generated from this work will lay the groundwork for more targeted psychopharmacological, behavioral, and perhaps genetic intervention studies in the future. The study of a relatively homogeneous single gene condition such as the fragile X premutation provides a model system for understanding links between molecular genetic, brain, and psychiatric features of more complex disorders. ? ? ? ?
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