NATURAL HISTORY, SEARCH FOR A MARKER AND THERAPY

这个项目的目标是定义自然历史，确定一个 诊断标志物，了解神经元功能障碍的机制，以及 在疾病发展的早期应用特定的疗法以改善 Rett综合征(RS)的神经功能状态基于RS的假设 是一种早期脑发育障碍，AIM 1重点识别 年轻患者和早期临床特征的描述。家族性 病例及其家系将被记录下来，以寻找基因 反常现象。目标1中确定的病例将是所有人的重要资源 项目。在目标2基因(S)的RS缺陷将寻找经典 细胞遗传学方法和代表性差异分析(RDA)。 AIM 2还将搜索具有UP-OR的蛋白质和表达的基因 在RS中下调，这可能是一个分子指纹 疾病。AIM 3旨在研究嗅觉感受器神经元(ONs) 来自RS女孩的嗅神经上皮活组织检查，以及 与来自正常和疾病对照组的Orns相比。一种细胞培养方法 将在早期提供对RS神经元的直接访问 疾病，并允许研究这种神经元缺陷的进化 无序。在AIM 4中，治疗性干预将试图防止 谷氨酸NMDA和AMPA受体增加的破坏性后果 受体拮抗剂的特定治疗引起神经元损伤， 右美沙芬和托吡酯。为了补偿那些重要的 胆碱乙酰转移酶水平的降低，用安慰剂治疗 乙酰胆碱酯酶抑制剂-盐酸多奈哌齐-改善 认知能力将接受测试。治疗的效果将由以下人员监测 临床和神经影像技术。仔细研究营养成分 吞咽困难在生长失败中的作用将在 治疗干预的光芒。使用生长因子或基因 当在动物身上确定疗效时，将考虑治疗 模特。

The goal of this project is to define the natural history, identify a diagnostic marker, understand the mechanism of neuronal dysfunction, and apply specific therapies early in the evolution of the disease to improve neurological status in Rett syndrome (RS). Based on the postulate that RS is a disorder of early brain growth, AIM 1 focuses on the identification of younger patients and delineation of early clinical features. Familial cases and their pedigrees will be documented in search of a genetic abnormality. Cases identified in Aim 1 will be a vital resource for all projects. In Aim 2 gene(s) defective in RS will be sought by classical cytogenetic approaches, and by representational difference analysis (RDA). Aim 2 will also search for proteins, and expressed genes that have up- or down regulated in RS, which may serve as a molecular fingerprint for the disease. Aim 3 is designed to study olfactory receptor neurons (ORNs) obtained from biopsies of olfactory neuroepithelium in RS girls, and compared to ORNs from normal and disease controls. A cell culture approach will provide direct access to RS neurons early in the course of the disease, and permit study of the evolution of neuronal defects in this disorder. In Aim 4 therapeutic interventions will attempt to prevent the devastating consequences of increased glutamate NMDA, and AMPA receptor induced neuronal injury by specific treatments with receptor antagonists, dextromethorphan and topiramate. To compensate for the significant reductions in choline acetyltransferase levels, treatment with an acetylcholine esterase inhibitor-donepezil hydrochloride- to improve cognition will be tested. Efficacy of treatment will be monitored by clinical and neuroimaging techniques. Careful study of the nutritional status, and the role of dysphagia in growth failure will be examined in the light of therapeutic interventions. Use of growth factors or gene therapy will be considered when efficacy is established in the animal model.