Markers of Disease Progression in MECP2 Duplication Syndrome

MECP2 重复综合征疾病进展的标志物

基本信息

批准号：
9198265
负责人：
SARIKA U PETERS
金额：
$ 32.67万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-22 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198265
关键词：
Adolescence Affect Age Antibody titer measurement Attenuated Vaccines Autistic Disorder Autoimmune Diseases Autoimmune Process CCR6 gene CD4 Positive T Lymphocytes CXCR3 gene Cells Cessation of life Childhood Chorea Clinical Clinical Markers Clinical Paths Clinical assessments Cognition Data Development Disease Disease Marker Disease Progression Flow Cytometry Foundations Frequencies Future Genes Genomics Guidelines Hemagglutination Human Hydrocortisone Immune Immunologic Markers Immunotherapy Impairment Individual Infection Inflammation Intellectual functioning disability Interferon Type II Investigation Lead Link Longitudinal Studies Lower Respiratory Tract Infection Lupus Mediating Memory Methyl-CpG-Binding Protein 2 Motor Skills Muscle hypotonia Mutation Neurologic Outcome Patients Pattern Pharmaceutical Preparations Phenotype Population Prediabetes syndrome Prevention Protein Overexpression Public Health Quality of life Recurrence Respiratory Tract Infections Rett Syndrome Rheumatoid Arthritis Salivary Sampling Seizures Serum Sjogren&apos s Syndrome Speech Stress Syndrome Systemic Lupus Erythematosus T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Therapeutic Time Vaccines Withdrawal Work X-linked intellectual disability base biomarker identification boys chemokine chemokine receptor clinical practice clinical predictors cytokine emerging adult girls hypothalamic-pituitary-adrenal axis immune function improved improved functioning infancy inflammatory marker influenza virus vaccine insight male motor control overexpression predictive marker progression marker public health relevance research clinical testing respiratory response skills social

项目摘要

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.

描述（由申请人提供）：编码 MeCP2 (MECP2) 的 X 连锁基因突变是导致女孩雷特综合症的原因 MECP2 重复综合症是一种 X 连锁基因组疾病，占所有病例的 1-2%。 X 连锁智力障碍 (ID)，主要发生在男孩中，其特征是反复呼吸道感染、婴儿肌张力低下、ID 进行性神经功能衰退和言语能力差甚至缺席。该综合征有两种不同的临床路径，其中一种路径影响了估计 50% 的人口，其特点是运动技能急剧丧失（退化），最终导致 25 岁之前因复发性下呼吸道感染并发症而死亡，相比之下，另一种途径较为温和，包括保持其里程碑且感染较少的个体，没有研究检验这两种替代疾病途径的基础，或导致衰退途径的促成因素。退化开始的年龄因人而异3-16岁。标记物，我们最近发现一些与回归相关的免疫标记物可能导致呼吸道感染的高发，包括产生细胞因子干扰素γ (IFN-γ) 的 Th1 细胞功能受损，并且还发现疫苗滴度较低。下丘脑-垂体-肾上腺 (HPA) 轴（压力标记）活动的减少与退化相关，因此本申请提出了一项纵向研究，包括对男性退化的临床、免疫和压力标记的三个年度评估。年龄在 3-12 岁之间的 MECP2 重复综合征的具体目标是：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示着 MECP2 重复综合征的消退状态，2) 确定抑制是否会出现。 Th1 细胞中的 IFN-γ 和较低的流感疫苗滴度可预测消退状态，以及 3) 确定 HPA 轴功能减退是否可预测消退状态。完成本研究将通过实施更好的年度指南立即影响临床实践。它还将为未来的治疗研究奠定基础，测试药物是否可以改善 TH1 细胞的功能，使临床过程正常化或改善临床过程，增强 HPA 轴活性，从而提高生活质量。完成我们的目标还将对与 MeCP2 过度表达相关的自身免疫性疾病产生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。