NEUROPHYSIOLOGICAL-MOLECULAR ASSOCIATION IN FXS INFANTS

脆性X染色体综合征（FXS）是一种遗传性异常，在FMR-1基因上DNA物质扩增（超过230个CGG重复）的个体中导致轻度至中度智力迟钝。在普通人群中的流行是有问题的，因为每250名女性中就有一人携带FXS。本研究项目旨在探讨FXS对婴幼儿和学龄前儿童早期神经认知发展的影响。本研究将结合神经生理学、分子和行为测量来部分解释在生命的前五年认知功能下降的生物行为功能障碍。首次记录FXS婴儿和儿童的事件相关脑电位（ERPs）。未受影响和突变前的FXS受试者的兄弟姐妹和没有已知发育迟缓风险的（无关的）受试者将作为对照组。唐氏综合症（DS）患者也将作为对照研究组。该项目的研究将调查与注意、期望、刺激编码、顺序信息处理、视觉识别记忆和社会凝视相关的综合征特异性优势和劣势。因此，研究结果将为FXS受试者（与DS受试者相比）早期认知发展的基因型特异性神经组织提供新的知识。因此，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）X激活率相关。通过层次线性模型整合神经生理、分子和行为测量，评估FXS对人类神经认知发展的影响。在我们的项目结束时，在我们的研究中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评价后续药物治疗和FXS特异性基因治疗的手段。本研究的结果将提供早期发育过程中由于FMRP缺乏而导致神经病理学发病的时间过程，从而为FXS患儿应用FMRP蛋白替代的理想年龄提供更精确的目标。

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.