RETT SYNDROME NATURAL HISTORY CLINICAL PROTOCOL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Rett综合征(RS)是一种神经发育障碍，几乎只发生在女性出生后6个月内明显正常的精神运动发育之后。特征特征包括语言丧失和有目的地使用手，出现刻板印象的手部动作，步态困难，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走能力。他们可能会出现癫痫发作，呼吸异常，包括呼吸暂停和过度换气，只有在清醒时才会发生，症状表明自主神经系统功能障碍，以及生长衰竭。与表明自主神经功能障碍的临床体征(如四肢发冷、发青)一致的延长和异常心率变异性的发生率增加，此前曾在Rett综合征中报道[2.3]。最近，RS基因被发现。Amir等人。[4]报道了在RS患者中存在MECP2的几个突变。MeCP2编码甲基CpG结合蛋白2(MeCP2)。MeCP2是已知能与甲基化的CP结合并能够抑制转录的蛋白质家族中的一员。虽然MeCP2在所有组织中都有表达，但它在大脑中的含量比任何其他组织都要丰富，而且大脑对MeCP2异常可能比其他组织更敏感。MeCP2的结合部位只需要一个甲基化的CpG二核苷酸就能结合。已有研究表明，MeCP2是一种全局性转录抑制因子，可以阻止整个基因组中的非计划转录，并且在转录沉默复合体的组装中起着关键作用。符合Rett综合征临床标准的女性中，大约80%会有MECP2突变。因此，我们预计将从那些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，这个网络的研究人员已经获得了关于Rett综合征的重要经验。我们在阿拉巴马大学伯明翰分校和德克萨斯州休斯敦的贝勒医学院建立了一个临床研究联盟。该联盟的成员是首批对Rett综合征的临床方面提供广泛描述的成员之一，这些方面包括生长、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)。贝勒团队成员胡达·佐格比(Huda Zoghbi)领导了这项工作，确定Xq28基因MECP2的突变，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，MECP2突变在女性中的表型后果从正常或轻度学习障碍到典型的Rett综合征，取决于X染色体失活的模式。在男性中，MECP2突变也会产生不同的临床后果，从婴儿时期的致命脑病到X连锁智力低下。S正在进行的表型-基因分型研究已经确定了数百名1至55岁的女性雷特综合征患者的临床特征，并评估了MECP2突变的存在或不存在。超过85%的典型Rett综合征患者都有这样的突变。由于Rett综合征是一种实际上只影响女性的疾病，这项纵向研究的大多数参与者将是女性。所有民族和种族都有资格参加学习。我们Rett综合征诊所的种族和民族分布是70%的高加索人，5%的美国人，21%的西班牙人，3%的亚洲人，1%的未知或未报告的人。我们预计，这项研究的种族/民族分布将类似于Rett综合征诊所的分布。这项研究的目的是在广泛的Rett综合征表型包括纵向进展模式，也就是整个队列中临床特征的自然历史，包括评估生活质量和寿命，建立一种小儿型-基因相关性。这些数据将对开发和进行临床试验至关重要，这些试验是通过正在进行的Rett综合征动物模型研究预期的。这项研究将不包括临床试验，但应该为此类试验奠定基础。未来的任何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.