Autonomic and Sensory Dysfunctions in FMR1 Conditions: Development, Mechanisms and Consequences

项目概要/摘要 尽管脆性X综合征（FXS）和脆性X前突变（FXpm）的损害， 研究已经研究了这些损害的基础。一个潜在的因素，有助于 损伤是自主神经系统（ANS）功能障碍。生理唤醒升高，反映ANS 功能障碍，长期以来一直被认为是导致FXS中的学习障碍和非典型行为的原因。 虽然ANS功能障碍与FXS和FXpm的损伤有关，但研究尚未检查 ANS功能障碍的存在、发作、发育轨迹或发育后果，或如何 与分子遗传因素有关。本项目通过以下具体措施解决这些关键差距 目的：（1）通过前瞻性研究，确定基线ANS功能障碍的发病和发展轨迹。 FXS（n=30只雄性）和FXpm（n = 30; 15只雄性和15只雄性）在6、9、12和24个月时的纵向评估 女性）与典型对照组（n=45; 30名男性和15名女性）进行对比;（2）确定分子遗传学如何 变异涉及FXS和FXpm中ANS功能障碍的发作和/或发育轨迹;（3） 通过前瞻性纵向评估表征对感觉刺激的行为和ANS反应， 在FXS和FXpm中6、9、12和24个月;以及（4）记录ANS功能障碍的后果， 婴儿期的感觉处理障碍，适应能力，ASD症状，和社会沟通， 在FXS和FXpm中同时和在24个月时。这项工作将产生巨大的影响， 关于机制基础、生物学途径和症状进展时间的信息， 对于确定治疗目标和时机以降低FXS和FXpm的症状严重程度至关重要。我们的重点 对婴儿期的干预至关重要，因为有证据表明，在生命早期提供的干预有可能 随着时间的推移，以多维度的方式加速发展并改善发展轨迹。

PROJECT SUMMARY/ABSTRACT Despite the impairment in fragile X syndrome (FXS) and the fragile X premutation (FXpm), surprisingly little research has examined the underpinnings of these impairments. One potential factor that contributes to impairment is autonomic nervous system (ANS) dysfunction. Elevated physiological arousal, reflecting ANS dysfunction, has long been implicated as contributing to learning impairments and atypical behavior in FXS. While ANS dysfunction has been linked to impairment in both FXS and FXpm, research has not examined the presence, onset, developmental trajectory, or developmental consequences of ANS dysfunction or how molecular-genetic factors are associated. This project addresses these critical gaps with the following specific aims: (1) Identify the onset and developmental trajectory of baseline ANS dysfunction through prospective longitudinal assessment at 6, 9, 12, and 24 months in FXS (n=30 males) and FXpm (n=30; 15 males and 15 females) contrasted to typical controls (n=45; 30 males and 15 females); (2) Determine how molecular-genetic variation relates to the onset and/or developmental trajectory of ANS dysfunction in FXS and FXpm; (3) Characterize behavioral and ANS reactivity to sensory stimuli through prospective longitudinal assessment at 6, 9, 12, and 24 months in FXS and FXpm; and (4) Document the consequences of ANS dysfunction across infancy on sensory processing impairments, adaptive skills, ASD symptoms, and social communication, concurrently and at 24 months in FXS and FXpm. This work will have tremendous impact by greatly expanding information on the mechanistic underpinnings, biological pathways, and timing of symptom progression, which is essential to identify targets and timing of treatment to reduce symptom severity in FXS and FXpm. Our focus on infancy is critical, as evidence has documented that intervention provided early in life has the potential to accelerate development and improve developmental trajectories over time in a multi-dimensional manner.