NEUROPHYSIOLOGICAL-MOLECULAR ASSOCIATION IN FXS INFANTS

脆性X综合征（FXS）是一种遗传性异常，在FMR-1基因上具有扩增DNA材料（大于230个CGG重复）的个体中引起轻度至中度智力迟钝。 一般人群中的患病率是有问题的，因为每250名女性中就有一名是FXS携带者。 本研究项目的目的是调查FXS对婴儿，幼儿和学龄前儿童早期神经认知发育的影响。 神经生理学，分子和行为的措施将整合在这项研究中，部分解释，生物行为功能障碍负责认知功能下降，在生命的前五年。 第一次，事件相关脑电位（ERP）将记录与FXS的婴儿和儿童。 FXS受试者的未受影响和突变前兄弟姐妹和无已知发育迟缓风险的（无关）受试者将作为对照组。 唐氏综合征（DS）受试者也将作为对照研究组。 该项目的研究将调查与注意力、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特定综合征的优势和劣势。 因此，研究结果将提供新的知识与FXS受试者（与DS受试者相比）的早期认知发展的基因型特异性神经组织。 此后，特定的ERP组分将与CGG重复区大小、FMRP（FMR-1基因蛋白）、甲基化百分比、mRNA以及女性中的X激活率相关。神经生理学，分子和行为的措施，通过分层线性模型的整合将评估FXS对人类神经认知发展的影响。在我们的项目结束时，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FXS特异性药物治疗和基因治疗的方法。 这项研究的结果将提供一个时间过程中的神经病理学由于FMRP的缺陷在早期发展，因此，提供了一个更精确的目标，在FMRP蛋白替代的理想年龄应适用于FXS儿童。

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.