Natural History and Therapies

MeCP 2基因突变的患者（70-80%）和无突变的患者被认为具有Rett综合征的临床特征。虽然突变的位置可以部分地与表型相关，但它们不能提供重要的预后指导。我们将尝试描绘有助于表型变异性的各种突变的分子特征，因此，我们将把临床，胃肠道状态和神经影像学变化（MRI，MRS）与MeCP 2，其他甲基结合结构域蛋白和组蛋白乙酰化水平相关联，并在项目II中与嗅觉受体神经元的变化相关联。我们还将这些变化与那些具有表型但没有MeCP 2突变的变化进行比较。 以确定可能导致表型相似性的因素的共性。与Shemer博士（以色列）合作，我们将尝试在后一组中鉴定MeCP 2基因启动子区的突变。 在年轻RS受试者中，多巴胺能系统的表达增加导致我们用美沙芬治疗15岁以下的患者，以阻断NMDA/谷氨酸受体，从而防止兴奋性毒性并提供神经保护。为了进一步深入了解RS的神经生物学，我们将与项目IB一起进行SPECT和PET研究，以描述胆碱能和多巴胺能系统的异常，这将与项目IV中的小鼠模型研究一起提供未来的治疗策略。 从这个和其他项目之间的相互作用的数据将支持我们的假设，RS的表型是不同的MeCP 2突变对特定的神经元群体和他们的相互连接的活动依赖性突触可塑性的动态阶段的独特影响的结果。

Patients with (70-80%) and those without mutations in MeCP2 gene are recognized to have the clinical features of Rett Syndrome. Although location of mutations can in part be correlated with the phenotype, they do not provide essential prognostic guidelines. We will attempt to delineate the molecular profiles of the various mutations that contribute to phenotypic variability¿ We will therefore correlate the clinical, gastrointestinal status, and neuroimaging changes (MRI, MRS) to levels of MeCP2, other methyl-binding domain proteins, and histone acetylation in Project III, and with changes in olfactory receptor neurons in Project II. We will also compare these changes to those with the phenotype but without mutations in MeCP2 to determine commonality in factors that may contribute to phenotypic similarities. In collaboration with Dr. Shemer (Israel), we will attempt to identify mutations in the promoter region of the MeCP2 gene in this latter group. The increased expression of the glutamatergic system in younger RS subjects leads us to treat patients below 15 years of age with dextromethorphan to block NMDA/glutamate receptors so as to prevent excitotoxicity and provide neuroprotection. To gain additional insight into the neurobiology of RS, we will conduct SPECT and PET studies in conjunction with Project IB to delineate abnormalities in the cholinergic and glutamatergic systems that would provide future therapeutic strategies in conjunction with studies in murine models in Project IV. Data from interaction between this and other projects will support our hypothesis that the phenotype of RS is the result of the unique effects of different MeCP2 mutations on specific neuronal populations and their interconnections during the dynamic phase of activity-dependant synaptic plasticity.