RETT SYNDROME NATURAL HISTORY CLINICAL PROTOCOL

RETT 综合征自然病史临床方案

基本信息

批准号：
8166675
负责人：
DANIEL G. GLAZE
金额：
$ 3.36万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8166675
关键词：
Age Alabama Apnea Apraxias Autonomic Dysfunction Autonomic nervous system Behavior Binding Binding Sites Brain Breathing Characteristics Clinical Clinical Investigator Clinical Protocols Complex Computer Retrieval of Information on Scientific Projects Database CpG dinucleotide Deceleration Development Disease Encephalopathies Enrollment Epidemiology Failure Female Functional disorder Funding Gait Gait abnormality Genes Genetic Transcription Genome Grant Growth Hand Hand functions Head Hyperventilation Individual Institution Learning Disabilities Life Limb structure Medicine Methyl-CpG-Binding Protein 2 Molecular Motor Movement Mutation Natural History Neurodevelopmental Disorder Participant Pattern Performance Phenotype Protein Family Reporting Research Research Personnel Resources Rett Syndrome Seizures Source Speech Symptoms Tissues Transcription Repressor/Corepressor United States National Institutes of Health Universities Wakefulness X Inactivation X-Linked Mental Retardation Xq28 base brain tissue college experience heart rate variability infancy male meetings member neuropathology neurophysiology nutrition prevent

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rett syndrome (RS) is a neurodevelopmental disorder that develops almost exclusively in females following apparently normal psychomotor development for the first six months of life. The characteristic features include loss of speech and purposeful hand use, occurrence of stereotypic hand movements, gait dyspraxia, and deceleration of head growth [1]. These individuals frequently develop severe motor problems including an abnormal gait or the loss of ability to ambulate. They may develop seizures, abnormal breathing consisting of periods of apnea and hyperventilation occurring only during wakefulness, symptoms suggesting autonomic nervous system dysfunction, and growth failure. Increases in occurrence of prolonged QTc (>0.45 secs) and abnormal heart rate variability consistent with clinical signs (e.g. cold, blue extremities) indicating autonomic dysfunction have been previously reported in Rett syndrome [2.3]. Recently, the gene for RS was discovered. Amir et al. [4] reported the presence of several mutations in MECP2 in individuals with RS. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2). MeCP2 is a member of a family of proteins known to bind specifically to methylated CpCs and to be capable of repressing transcription. Although MeCP2 is expressed in all tissues, it is more abundant inthe brain than any other tissue, and the brain may be more sensitive to abnormal MeCP2 than other tissues. The binding site of MeCP2 requires only a single methylated CpG dinucleotide to bind. It has been proposed that MeCP2 acts as a global transcriptional repressor that prevents unscheduled transcription throughout the genome and has been implicated as a key player in assembling transcriptional silencing complexes. Approximately 80% of females meeting the clinical criteria for Rett syndrome willhave a mutation in MECP2. Hence, we expect to enroll a higher number of participants from among those who have such mutations. Over the past twenty years, investigators in this network have acuqired significant experience concerning Rett Syndrome. We have an established consortium of clinical investigators at the University of Alabama at Birmingham and the Baylor College of Medicine in Houston, TX. Members of this consortium were among the first to provide extensive characterization of the clinical aspects of Rett Syndrome including growth, nutrition, neurophysiology, epidemiology including survival, motor performance, behavior, and the neuropathology of this disorder. Huda Zoghbi, a member of the Baylor team, directed the effort identifying mutations in the Xq28 gene MECP2, encoding methyl-CpG- binding protein 2 as the molecular basis for Rett syndrome. We now know that the phenotypic consequences of MECP2 mutations range in females from normal or mild learning disability to classic Rett syndrome, dependin on the pattern of X-chromosome inactivation. In males, MECP2 mutations also produce variable clinical consequences, ranging from fatal encephalopathy in infancy to X-linked mental retardation. The consortium''s ongoing phenotype- genotpe study has characterized the clinical characteristics of several hundred females from age one to 55 years with Rett syndrome and assessed the presence or absence of MECP2 mutations. More than 85% of participants with classic Rett syndrome have such mutations.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。雷特综合征 (RS) 是一种神经发育障碍，几乎只发生在女性出生后前六个月精神运动发育明显正常的女性中。其典型特征包括丧失言语和有目的的手部使用、出现刻板的手部动作、步态运动障碍和头部生长减慢[1]。这些人经常出现严重的运动问题，包括步态异常或丧失行走能力。他们可能会出现癫痫发作、呼吸异常（包括仅在清醒时发生的呼吸暂停和过度换气）、表明自主神经系统功能障碍的症状以及生长障碍。先前在 Rett 综合征中曾报道过，QTc 延长（>0.45 秒）和心率变异性异常的发生率增加，这与临床体征（例如四肢发冷、发青）一致，表明自主神经功能障碍[2.3]。最近，RS基因被发现。阿米尔等人。 [4]报道了 RS 个体中 MECP2 存在多种突变。 MECP2 编码甲基 CpG 结合蛋白 2 (MeCP2)。 MeCP2 是已知与甲基化 CpC 特异性结合并能够抑制转录的蛋白质家族的成员。尽管MeCP2在所有组织中表达，但它在大脑中比任何其他组织更丰富，并且大脑可能比其他组织对异常MeCP2更敏感。 MeCP2 的结合位点仅需要单个甲基化 CpG 二核苷酸即可结合。有人提出，MeCP2 作为一种全局转录抑制因子，可防止整个基因组中的非计划转录，并被认为是组装转录沉默复合物的关键参与者。大约 80% 符合 Rett 综合征临床标准的女性会有 MECP2 突变。因此，我们希望从具有此类突变的人中招募更多数量的参与者。在过去的二十年中，该网络的研究人员积累了有关雷特综合征的重要经验。我们在伯明翰阿拉巴马大学和德克萨斯州休斯顿贝勒医学院建立了一个由临床研究人员组成的联盟。该联盟的成员是最早提供雷特综合征临床方面广泛特征的成员之一，包括生长、营养、神经生理学、流行病学（包括生存、运动表现、行为和该疾病的神经病理学）。贝勒团队成员 Huda Zoghbi 领导了 Xq28 基因 MECP2 突变的鉴定工作，该基因编码甲基 CpG 结合蛋白 2，是雷特综合征的分子基础。我们现在知道，MECP2 突变对女性的表型影响范围从正常或轻度学习障碍到经典的 Rett 综合征，具体取决于 X 染色体失活的模式。在男性中，MECP2 突变还会产生不同的临床后果，从婴儿期致命性脑病到 X 连锁智力低下。该联盟正在进行的表型-基因型研究描述了数百名年龄从 1 岁到 55 岁患有 Rett 综合征的女性的临床特征，并评估了 MECP2 突变的存在或不存在。超过 85% 的经典雷特综合征参与者都有此类突变。