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

项目摘要/摘要 尽管脆性X综合征(FXS)和脆性X预突变(FXPM)存在损害，但令人惊讶的是， 研究已经检查了这些损害的基础。一个潜在的因素是 损害是自主神经系统(ANS)功能障碍。生理唤醒提高，反映ANS 功能障碍，长期以来一直被认为是导致FXS学习障碍和非典型行为的原因。 虽然ANS功能障碍与FXS和FXPM的损害有关，但研究尚未检查 ANS功能障碍的存在、发病、发展轨迹或发展后果或如何 分子遗传因素是相关的。该项目通过以下具体措施解决了这些关键差距 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组(n=30名男性)和FXPM组(n=30名男性和15名男性)在6、9、12和24个月时进行纵向评估 女性)与典型对照组(n=45；30男性和15女性)进行对比；(2)确定分子遗传学 变异与FXS和FXPM中ANS功能障碍的发病和/或发展轨迹有关； 通过前瞻性纵向评估来表征行为和ANS对感官刺激的反应 6个月、9个月、12个月和24个月的FXS和FXPM；以及(4)记录ANS功能障碍的后果 婴儿期感觉处理障碍、适应技能、自闭症症状和社交能力， 同时，在FXS和FXPM为24个月。这项工作将大大扩展，产生巨大的影响。 关于症状进展的机制基础、生物学途径和时间的信息， 对于确定治疗目标和治疗时机至关重要，以降低FXS和FXPM的症状严重程度。我们的重点是 对婴儿期的干预是至关重要的，因为有证据表明，在生命早期提供干预可能会 多维加快发展，逐步完善发展轨迹。

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.