Profiles and Predictors of Pragmatic Language Impairments in the FMR1 Premutation

描述（由申请人提供）：新的基于人群的筛查表明，151名女性中有1名具有脆性X智力迟钝-1 （FMR1）基因的预突变等位基因（Seltzer, Baker, et al., 2012），这突出了FMR1预突变的临床表型研究作为一个重要的公共卫生优先事项。新出现的证据表明，具有FMR1前兆突变的个体在语用语言或语言的社交使用方面存在缺陷（Aziz等人，2003;Losh， Klusek等人，2012）。语用技能是有效沟通的关键，这方面的缺陷可能导致无效的社会交流和管理社会关系的困难（Bates, 1976）。本研究旨在进一步描述具有FMR1前兆突变的女性的语用语言表型，包括语用学和焦虑症之间可能存在的关联，在具有FMR1前兆突变的个体中，焦虑症的发生率较高（Bailey et al., 2008; Roberts et al., 2009）。一组患有自闭症谱系障碍（ASD）儿童的母亲将被纳入比较组，以了解不同表型的分离，并阐明可能归因于FMR1生化作用的实用特征范围。具体而言，本研究旨在：(1)确定具有FMR1前兆突变的母亲的语用语言特征与ASD儿童的母亲的语用语言特征的共同或不同的具体方面，并与对照组进行比较；(2)评估语用语言缺陷对个人和家庭结果的功能影响；(3)确定语用语言与焦虑之间的关系，以及具有FMR1前兆突变的母亲、ASD儿童的母亲和对照组母亲之间的关系。通过整合神经科学的科学进展，应用行为（标准化和实验）和生物标志物相结合的方法，本提案旨在阐明FMR1预突变中语用性损伤的本质、潜在机制和功能后果。这项研究将告知可能与FMR1的生化作用具体相关的特征范围，并对潜在的预防和治疗工作具有指导意义。这项研究将在南卡罗来纳大学优秀的培训环境中，在专家和跨学科的背景下实施

DESCRIPTION (provided by applicant): New population-based screening indicates that 1 in 151 women have premutation alleles on the Fragile X Mental Retardation-1 (FMR1) gene (Seltzer, Baker, et al., 2012), which highlights research on the clinical phenotype of the FMR1 premutation as a significant public health priority. Emerging evidence suggests that individuals with the FMR1 premutation show deficits in pragmatic language, or the social use of language (Aziz et al., 2003; Losh, Klusek, et al., 2012). Pragmatic language skills are critical for effectie communication, and deficits in this area may lead to ineffective social interchange and difficulty managing social relationships (Bates, 1976). This proposal aims to further delineate the pragmatic language phenotype of women with the FMR1 premutation, including the possible interface between pragmatics and anxiety disorders, which are seen at elevated rates among individuals with the FMR1 premutation (Bailey et al., 2008; Roberts et al., 2009). A comparison group of mothers of children with autism spectrum disorder (ASD) will be included in order to inform disassociation across phenotypes and shed light on the range of pragmatic features that may be attributed to the biochemical effects of FMR1. Specifically, this study aims to: (1) identif specific aspects of the pragmatic language profile of mothers with the FMR1 premutation that are shared or distinct from the profile of mothers of children with ASD, and compared to controls, (2) evaluate the functional impact of pragmatic language deficits on individual and family outcomes, and (3) determine the relationship between pragmatic language and anxiety, and how it differs among mothers with the FMR1 premutation, mothers of children with ASD, and control mothers. By integrating scientific advances in neuroscience to apply a combined behavioral (both standardized and experimental) and biomarker approach, this proposal aims to clarify the nature, underlying mechanisms and functional consequences of pragmatic impairments in the FMR1 premutation. This research will inform the range of features that may be specifically linked to the biochemical effects of FMR1, and has implications for potential prevention and treatment efforts. This research will be implemented within the excellent training environment at the University of South Carolina, within the context of an expert, interdisciplinary mentorship team that has a proven history of successful collaboration. The proposed training plan focuses on: (1) developing a comprehensive understanding of the impact of anxiety on language function, (2) attaining expertise in the use of physiological and neuroendocrine markers of stress, (3) training to use eyetracking methods to index language and related processes, (4) honing skills in pragmatic language assessment and theory, and (5) sharpening professional skills such as grant writing, research ethics, etc. The proposed research and training experiences will provide the fellow with the necessary skills to develop a programmatic line of research focused on identifying profiles and predictors of communication impairments in ASD and FMR1-associated conditions.