Markers of Disease Progression in MECP2 Duplication Syndrome

 描述(申请人提供)：编码MeCP2(MECP2)的X连锁基因突变是女孩Rett综合征的原因。MeCP2重复综合征是一种X连锁的基因组疾病，占所有X连锁智力残疾(ID)病例的1-2%，主要发生在男孩身上。它的特点是反复呼吸道感染，婴儿低眼压，进行性神经功能下降，说话能力差或不能说话。数据表明，这种综合征有两种截然不同的临床途径。一种路径影响大约50%的人口，其特点是运动技能的急剧丧失(退化)，最终导致25岁之前死亡，原因是反复发生的下呼吸道感染的并发症，这表明可能存在免疫缺陷。相比之下，另一条道路更温和，包括那些保持里程碑和感染较少的人。还没有研究检查这两种替代疾病路径的基础，或者导致下降路径的促成因素。发病年龄在3-16岁之间。除了特定的临床 关于免疫标志物，我们最近发现，存在与退化有关的免疫标志物，可能是导致呼吸道感染高发的原因，包括产生细胞因子干扰素-γ的Th1细胞功能受损，以及疫苗效价较低。我们还发现，下丘脑-垂体-肾上腺(HPA)轴(应激的标志)活性降低与退行性有关。因此，这项申请提出了一项纵向研究，包括对3-12岁患有MECP2重复综合征的男性的临床、免疫和应激标志物进行三年一次的回归评估。具体目的是：1)确定呼吸道感染增加、认知能力下降、癫痫发作和社交退缩增加是否预测MECP2重复综合征的回归状态；2)确定Th1细胞干扰素-γ抑制和较低的流感疫苗效价是否预测回归状态；以及3)确定HPA轴活动不足是否预测回归状态。这项研究的完成将通过实施更好的年度疫苗指南和可能的免疫治疗指南立即影响临床实践。这也将为未来的治疗研究奠定基础，测试已知的改善TH1细胞功能的药物是否使临床病程正常化或改善，增强HPA轴的活动，从而改善生活质量。最后，完成我们的目标还将对持续与MeCP2过度表达相关的自身免疫性疾病具有更广泛的公共卫生意义，包括：狼疮、干燥综合征和类风湿性关节炎。

 DESCRIPTION (provided by applicant): Mutations in the X-linked gene that encodes MeCP2 (MECP2) are the cause of Rett Syndrome in girls. MECP2 duplication syndrome is an X-linked genomic disorder that accounts for 1-2% of all cases of X-linked intellectual disability (ID), primarily in boys. It is characterized by recurrent respiratory infections, infantile hypotonia, ID progressive neurological declines, and poor to absent speech. Data suggest that there are two distinct clinical paths in this syndrome. One path affects an estimated 50% of the population and is characterized by a dramatic loss of motor skills (regression) that eventually leads to death before the age of 25 resulting from complications of recurrent lower respiratory infections, suggesting possible immune deficits. In contrast, the other path is milder and includes individuals who maintain their milestones and have fewer infections. No study has examined the basis for these two alternative disease paths, or the contributing factors that lead toward a path of decline. The age of regression onset varies between 3-16 years. In addition to specific clinical markers, we have recently discovered that there are immune markers associated with regression that may account for the high frequency of respiratory infections, including impaired functioning of Th1 cells that make the cytokine interferon gamma (IFN-γ), and lower vaccine titers. We have also found that decreased activity of the hypothalamic-pituitary-adrenal (HPA) axis (a marker of stress) is associated with regression. This application therefore proposes a longitudinal study consisting of three annual evaluations of the clinical, immune, and stress markers of regression in males between the ages of 3-12 years with MECP2 duplication syndrome. The specific aims are: 1) To determine whether increased respiratory infections, lower cognition, seizures, and increased social withdrawal predict regression status in MECP2 duplication syndrome, 2) To determine whether suppression of IFN-γ from Th1 cells and lower influenza vaccine titers predicts regression status, and 3) To determine whether HPA axis hypoactivity predicts regression status. Completion of this study will immediately affect clinical practice through implementation of better guidelines for yearly vaccines, and guidelines for possible immune therapy. It will also lay the foundation for a future treatment study testing whether drugs known to improve functioning of TH1 cells normalize or improve clinical course, enhance HPA axis activity, and therefore improve quality of life. Finally, completion of our aims will also have broader public health significance for autoimmune disorders consistently associated with MeCP2 overexpression, including: lupus, Sjögren's syndrome, and rheumatoid arthritis.