NEUROPHYSIOLOGICAL-MOLECULAR ASSOCIATION IN FXS INFANTS

脆性X综合征(FXS)是一种遗传性异常，在FMR-1基因上有扩增的DNA物质(超过230个CGG重复)的个体中，导致轻到中度智力低下。普通人群中的流行率是有问题的，因为每250名女性中就有一人是FXS携带者。本研究的目的是探讨FXS对婴幼儿和学龄前儿童早期神经认知发育的影响。这项研究将整合神经生理学、分子和行为测量，以部分解释导致生命头五年认知功能下降的生物行为障碍。将首次记录患有FXS的婴儿和儿童的事件相关脑电位(ERPs)。FXS受试者和(无血缘关系)受试者的未受影响和预突变的兄弟姐妹将作为对照组。患有唐氏综合症(DS)的受试者也将作为对照研究组。该项目中的研究将调查与注意力、预期、刺激编码、顺序信息处理、视觉识别记忆和社会凝视相关的特定症状的优势和劣势。因此，结果将提供有关FXS受试者(与DS受试者相比)早期认知发展的基因特异性神经组织的新知识。此后，特定的ERP成分将与CGG重复区域大小、FMRP(FMR-1基因蛋白)、甲基化百分比、mRNA以及在女性中的X激活率相关。通过分层线性建模将神经生理、分子和行为测量相结合，将评估FXS对人类神经认知发育的影响。在我们的项目结束时，我们研究范围内制定的措施将为评估早期干预的有效性提供新的方法。结果测量同样将提供批评后续药物治疗和特定于FXS的基因治疗的手段。这项研究的结果将提供由于早期发育过程中FMRP缺陷而导致的神经病理的发病时间进程，并相应地为FXS儿童应用FMRP蛋白替代的理想年龄提供更准确的靶点。

Fragile X syndrome (FXS) is an inherited abnormality responsible for mild to moderate mental retardation among individuals with expanded DNA material (greater than 230 CGG repeats) on the FMR-1 gene. Prevalence in the general population is problematic since one in 250 females are carriers of FXS. The purpose of this research project is to investigate the impact of FXS on early neurocognitive development among infants, toddlers and preschoolers. Neurophysiological, molecular and behavioral measures will be integrated in this study to explain, in part, biobehavioral dysfunction responsible for the decline in cognitive functioning during the first five years of life. For the first time, event-related brain potentials (ERPs) will be recorded from infants and children with FXS. Unaffected and premutation siblings of subjects with FXS and (unrelated) subjects without known risk of developmental delay will serve as comparison groups. Subjects with Down syndrome (DS) will likewise serve as a contrast study group. Studies within this project will investigate syndrome-specific strengths and weaknesses related to attention, expectancy, stimulus encoding, sequential information processing, visual recognition memory and social gaze. Results will therefore provide new knowledge concerning genotypic-specific neural organization of early cognitive development among subjects with FXS (as compared to subjects with DS). Specific ERP components will thereafter be correlated to CGG repeat region size, FMRP (FMR-1 gene protein), percent methylation, mRNA and, among females, the X activation ratio. The integration of neurophysiological, molecular and behavioral measures through Hierarchical Linear Modeling will assess the impact of FXS upon human neurocognitive development. At the conclusion of our projects, measures developed within our studies will provide new methodologies in the assessment of the effectiveness of early intervention. Outcome measures will likewise provide the means to critique subsequent pharmacotherapy and gene therapy specific to FXS. Results of this study will provide a time course of onset of neuropathology due to deficiencies of FMRP during early development and, accordingly, provide a more precise target of the ideal age at which FMRP protein replacement should be applied among children with FXS.