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QTC（> 0.45秒）的发生率和心率变异性异常，与临床体征（例如冷，蓝色肢体）一致，表明RETT综合征已报道过自主功能障碍[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。该财团的持续表型 - Genotpe研究表征了Rett综合征从一岁到55岁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。