Limbic System Function in Carriers of the Fragile X Premutation

描述（由申请人提供）：本研究的目的是调查脆性X前突变成年男性的分子遗传和大脑异常之间的关系，这些异常是社会情感和认知功能的基础。脆性X前突变与X染色体上FMR 1基因中55至200个CGG重复扩增相关，是一种相对常见的遗传疾病，估计每813名男性中有1名，每250名女性中有1名。直到最近，人们还认为前突变携带者在临床上不受影响。然而，最近的证据表明，这些人中的一部分有明显的社会，情感和认知缺陷，甚至自闭症和智力迟钝。我们发现，有些人在晚年会继续发展一种新发现的进行性神经系统疾病，脆性X相关震颤共济失调综合征（FXTAS）。我们有证据表明，FXTAS，甚至在成年早期的心理障碍，与功能的毒性增益效应从突变前CGG重复范围内的FMR 1-mRNA升高。我们假设边缘功能障碍是具有前突变的年轻成年人社交情感和记忆缺陷的基础。在目前的研究中，我们将使用结构和功能MRI来确定是否有前突变的男性（年龄在18至45岁之间），与年龄和智商匹配的男性组相比，表现出边缘脑区域的异常脑形态和功能，重点是海马和杏仁核，以及与记忆和社会情感功能障碍相关的脑区域。我们还将研究与这些受试者的情绪障碍和社会认知和互惠相关的精神症状，并研究FMR 1基因功能的测量，包括mRNA的升高，是否与这些边缘脑区域的形态和功能相关。这项研究将导致更好地了解与FMR 1前突变相关的基因-大脑-行为关系。此外，从这项工作中产生的参与前突变的多个系统的知识将为未来更有针对性的精神药理学，行为学，也许还有遗传干预研究奠定基础。对相对同质的单基因条件（如脆性X前突变）的研究为理解更复杂疾病的分子遗传学、大脑和精神病学特征之间的联系提供了一个模型系统。

DESCRIPTION (provided by applicant): 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.