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：
7950620
负责人：
DANIEL G. GLAZE
金额：
$ 3.35万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7950620
关键词：
Affect Age Alabama American Animal Model Apnea Apraxias Asians Autonomic Dysfunction Autonomic nervous system Behavior Binding Binding Sites Brain Breathing Caucasians Caucasoid Race Characteristics Clinic Clinical Clinical Investigator Clinical Protocols Clinical Research Clinical Trials Complex Computer Retrieval of Information on Scientific Projects Database Conduct Clinical Trials CpG dinucleotide Data Deceleration Development Disease Encephalopathies Enrollment Epidemiology Failure Female Functional disorder Funding Future Gait Gait abnormality Genes Genetic Transcription Genome Genotype Grant Growth Hand Hand functions Head Hispanics Hyperventilation Individual Institution Learning Disabilities Life Limb structure Longevity Longitudinal Studies Medicine Methyl-CpG-Binding Protein 2 Molecular Motor Movement Mutation Natural History Neurodevelopmental Disorder Participant Pattern Performance Phenotype Protein Family Quality-of-Life Assessment Race Reporting Research Research Personnel Resources Rett Syndrome Seizures Source Speech Staging Symptoms Tissues Transcription Repressor/Corepressor United States National Institutes of Health Universities Wakefulness X Inactivation X-Linked Mental Retardation Xq28 base brain tissue cohort college experience heart rate variability infancy male meetings member neuropathology neurophysiology nutrition prevent protocol development racial and ethnic

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 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. Because Rett syndrome is a disorder that affects virtually only females, most participants in this longitudinal study will be females. all ethnic and racial groups will be eligible for study. The racial and ethnic distribution in our Rett Syndrome clinic is 70% Caucasian, 5% Afrom-American, 21% Hispanic, 3% Asian, and 1% Unknown or Unreported. We anticipate that the racial/ethnic distribution of this study will be similar to that of the Rett Syndrome Clinic. The purpose of this study is to establish a pehnotype-genotype correlation over a broad spectrum of Rett syndrome phenotpes including the longitudinal pattern of progression, that is the natural history of clinical features across this cohort including assessment of quality of life and longevity. These data will be essential to the development and conduct of clinical trials that are anticipated from ongoing studies in animal models for Rett syndrome. This study will not include clinical trials, but should set the stage for such trials. Any future clinical trials would involve additional protocol development.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此，可以在其他清晰的条目中表示。列出的机构是对于中心，这不一定是调查员的机构。 RETT综合征（RS）是一种神经发育障碍，在女性的前六个月显然正常的精神运动发展之后，在女性中几乎完全发展。特征的特征包括言语丧失和有目的的手用，刻板印象的手势，步态功能障碍以及头部生长减速[1]。这些人经常出现严重的运动问题，包括步态异常或失去行动能力。它们可能会出现癫痫发作，仅在清醒期间发生的呼吸暂停和过度换气，呼吸异常，表明自主神经系统功能障碍和生长失败的症状。长期和异常心率变异性的发生与临床体征（例如冷，蓝色肢体）一致，表明RETT综合征中已经报道了自主功能障碍[2.3]。最近，发现了RS的基因。 Amir等。 [4]报道了Rs个体中MECP2中存在几种突变。 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在所有组织中都表达，但它在大脑中比任何其他组织都更丰富，并且大脑对MECP2异常的敏感性比其他组织更敏感。 MECP2的结合位点仅需要单个甲基化的CpG二核苷酸才能结合。已经提出，MECP2充当全球转录阻遏物，可防止整个基因组中的外经转录，并被视为组装转录沉默复合物的关键参与者。符合RETT综合征临床标准的女性中约有80％将在MECP2中发生突变。因此，我们希望在患有这种突变的人中招募更多的参与者。在过去的二十年中，该网络中的调查人员在RETT综合征方面拥有丰富的经验。我们在阿拉巴马大学的伯明翰大学和德克萨斯州休斯敦的贝勒医学院拥有一个成立的临床研究人员。该财团的成员是最早提供RETT综合征临床方面的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，行为和这种疾病的神经病理学。贝勒团队的成员Huda Zoghbi指示识别XQ28基因MECP2突变的努力，编码甲基-CPG-结合蛋白2作为RETT综合征的分子基础。我们现在知道，女性从正常或轻度学习障碍到经典RETT综合征的MECP2突变的表型后果取决于X染色体失活的模式。在男性中，MECP2突变还会产生可变的临床后果，从婴儿期致命性脑病到X连锁的智力低下。该财团正在进行的表型研究表征了从1岁到55岁的RETT综合征的数百名女性的临床特征，并评估了MECP2突变的存在或不存在。超过85％的经典RETT综合征参与者具有这种突变。由于RETT综合征是一种几乎仅影响女性的疾病，因此这项纵向研究的大多数参与者都是女性。所有种族和种族群体都有资格进行学习。我们的RETT综合征诊所的种族和种族分配是70％的高加索人，5％的Afrom-American，21％的西班牙裔，3％的亚洲人和1％未知或未报告。我们预计这项研究的种族/族裔分布将与RETT综合征诊所相似。这项研究的目的是建立在广泛的RETT综合征表中，包括进展的纵向模式，这是该队列中临床特征的自然历史，包括评估生活质量和寿命。这些数据对于正在进行的RETT综合征研究中正在进行的研究中预期的临床试验的开发和进行至关重要。这项研究将不包括临床试验，而应为此类试验奠定基础。任何未来的临床试验都将涉及其他方案开发。