RETT SYNDROME NATURAL HISTORY CLINICAL PROTOCOL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 Rett综合征（RS）是一种神经发育障碍，几乎只发生在出生后头六个月明显正常精神发育的女性中。 其特征包括言语和有目的的手部使用的丧失、刻板手部运动的发生、步态运动障碍和头部生长减速[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通气）、提示自主神经系统功能障碍的症状和生长障碍。 先前在Rett综合征中报告了与表明自主神经功能障碍的临床体征（例如四肢冰冷、发蓝）一致的延长和异常心率变异性的发生率增加[2.3]。 最近，RS的基因被发现。 Amir等人[4]报告了RS患者中MECP 2存在几种突变。 MECP 2编码甲基CpG结合蛋白2（MeCP 2）。 MeCP 2是已知特异性结合甲基化CpCs并能够抑制转录的蛋白质家族的成员。 虽然MeCP 2在所有组织中表达，但它在脑中比任何其他组织更丰富，并且脑可能比其他组织对异常MeCP 2更敏感。 MeCP 2的结合位点仅需要单个甲基化的CpG二核苷酸来结合。 已经提出MeCP 2作为一种全局转录抑制因子，防止整个基因组的非预定转录，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MECP 2突变。因此，我们希望从具有这种突变的人中招募更多的参与者。 在过去的二十年里，该网络中的研究人员已经获得了关于Rett综合征的重要经验。 我们在伯明翰的亚拉巴马大学和德克萨斯州休斯顿的贝勒医学院建立了一个临床研究者联盟。 该联盟的成员是第一批提供Rett综合征临床方面的广泛表征的成员，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指导了Xq 28基因MECP 2突变的鉴定工作，MECP 2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，MECP 2突变的表型后果在女性中的范围从正常或轻度学习障碍到经典的Rett综合征，取决于X染色体失活的模式。 在男性中，MECP 2突变也会产生不同的临床后果，从婴儿期的致命性脑病到X连锁精神发育迟滞。 该联盟正在进行的表型-基因组研究描述了数百名1至55岁Rett综合征女性的临床特征，并评估了MECP 2突变的存在与否。 超过85%的典型Rett综合征患者都存在此类突变。 由于雷特综合征是一种几乎只影响女性的疾病，因此这项纵向研究的大多数参与者都是女性。 所有族裔和种族群体都有资格参加研究。 我们Rett综合征诊所的种族和民族分布为70%白人，5%非洲裔美国人，21%西班牙裔，3%亚洲人和1%未知或未报告。 我们预计本研究的人种/种族分布将与Rett综合征诊所的人种/种族分布相似。 本研究的目的是在广泛的Rett综合征表型中建立表型-基因型相关性，包括纵向进展模式，即该队列中临床特征的自然史，包括生活质量和寿命评估。 这些数据对于正在进行的Rett综合征动物模型研究中预期的临床试验的开发和实施至关重要。 本研究不包括临床试验，但应为此类试验奠定基础。 任何未来的临床试验都将涉及额外的方案开发。

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.