PATHOGENESIS OF RETT SYNDROME

RETT 综合征的发病机制

• 批准号: 7378867
• 负责人: SAKKUBAI R NAIDU
• 金额: $ 1.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378867
• 关键词: PATHOGENESIS; RETT; SYNDROME

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 (RTT) is a disorder that characteristically occurs in females. A majority of patients (~70%) with clinical features of RTT have been identified to have mutations in the MeCP2 gene located in the Xq28 region. The gene is involved in repressing transcription of an unknown number of genes on multiple chromosomes. More recently, males of varying ages who lack classic features of RTT have been identified to have mutations in MeCP2, accounting for a wide clinical spectrum. Except for patients with Kleinfelter syndrome, males have matrilineally transmitted disease. The majority of females are sporadic cases, occurring from paternally transmitted de novo mutations. Patients with RTT have an apparently normal early developmental course followed by microcephaly, and arrest in acquisition of cognitive and motor skills by the end of the first year. Stereotyped movements, seizures, respiratory irregularities, gastrointestinal and nutrition abnormalities, as well as behavioral problems are frequent clinical concomitants. Progressive abnormalities in muscle tone and movement are associated with reduced brain dopamine and melanin content in the substantia nigra pars compacta. In RTT, postmortem brain tissue shows reduced choline acetyltransferase in basal ganglia, which must accentuate the dementia. An age-associated excess of NMDA/glutamate receptors coincide with the epileptic encephalopathy noted in infancy and childhood. The reported presence of NMDA glutamate receptors in osteoblasts warrants consideration of a toxic effect due to their excess, resulting in osteoporosis and increased fractures in RTT. Recent recognition of reductions in volume of the dorsal parietal lobe and insula (Kaufmann et al. unpublished observations), when combined with reduced NAA in these regions by MR-spectroscopy, is of note. EEG shows spikes arising from central temporal regions that maximize in sleep and, together with the MRI/MRS findings, may suggest that ictal activity in sleep involving the insula is a possible cause of sudden unexpected death in these subjects. Clinically, the uniformity of age-associated signs and symptoms in RTT suggest common pathogenetic mechanisms. Our study aims to: 1) identify biological factors common to those with and without mutations in MeCP2 despite classic phenotype, and determine basis for the natural history and phenotypic variability so that appropriate prognosis and treatment options can be provided. 2) identify brain regions that have selective vulnerability, by volumetric analyses of MRI scans and diffusion tensor imaging (DTI), to correlate with specific neurological deficits, and basis for sudden unexpected death. As brain volume is reduced in caudate and fronto-temporal regions along with reduced cerebral blood flow in RTT DTI and MR-spectroscopy will be obtained to determine involvement of regions and pathways contributing to progressive rigidity, seizures, and behavioral aberrations that may be altered with improved treatments in future. 3) ameliorate other complex symptoms, in particular, severe constipation, swallowing difficulties and failure-to-thrive (despite excellent food intake), seizures, behavior problems, and respiratory and sleep irregularities. 4) We will also follow the observed changes in serum lactate and organic acids to determine if mitochondrial function is impaired, so that appropriate therapy can be provided for this dysfunction if needed. 5) In order to determine if there is prolonged QTC interval as reported in the literature we will follow the EKG for any changes in a larger series of patients. We will conduct these investigations in order to follow the clinical severity and course, and correlate with X-inactivation status, and genotype. We anticipate identification of new directions for therapeutic interventions to cure/ameliorate symptoms, and for neuroprotection in early infancy. A separate protocol will be submitted for therapeutic interventions.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Rett综合征(RTT)是一种典型的女性疾病。大多数具有RTT临床特征的患者(~70%)已被证实存在位于Xq28区域的MeCP2基因突变。该基因参与抑制多条染色体上未知数量基因的转录。最近，缺乏RTT典型特征的不同年龄的男性被发现存在MeCP2突变，占临床范围的很广。除Kleinfelter综合征患者外，男性均为母系传播疾病。大多数女性是零星病例，发生于父系传播的从头基因突变。RTT患者有一个明显正常的早期发育过程，随后是小头畸形，在第一年结束时认知和运动技能的获得停止。千篇一律的运动、癫痫发作、呼吸异常、胃肠道和营养异常，以及行为问题是常见的临床伴随。肌肉张力和运动的进行性异常与大脑黑质致密部的多巴胺和黑色素含量减少有关。在RTT中，死后脑组织显示基底节胆碱乙酰转移酶降低，这肯定会加重痴呆。与年龄相关的NMDA/谷氨酸受体过量与婴儿期和儿童期的癫痫脑病相一致。已报道的成骨细胞中NMDA谷氨酸受体的存在值得考虑由于其过量而产生的毒性效应，导致骨质疏松和RTT中骨折的增加。最近认识到顶叶背侧和脑岛的体积减少(Kaufmann等人。未发表的观察结果)，当结合磁共振光谱学在这些区域减少的NAA时，是值得注意的。EEG显示中央颞区出现尖峰，睡眠时间最长，结合MRI/MRS的发现，可能表明睡眠中涉及脑岛的发作活动可能是这些受试者猝死的原因之一。临床上，RTT与年龄相关的体征和症状的一致性提示了共同的发病机制。本研究的目的是：1)确定典型表型的MeCP2基因突变患者和不突变患者共有的生物学因素，并确定其自然病史和表型变异的基础，以便提供适当的预后和治疗方案。2)通过MRI扫描和弥散张量成像(DTI)的体积分析，识别具有选择性易损性的大脑区域，以与特定的神经功能缺失相关，并为猝死奠定基础。随着RTT中尾状核和额颞区脑体积的减少以及脑血流量的减少，将进行DTI和MR波谱检查，以确定导致进行性强直、癫痫发作和行为异常的区域和路径，这些区域和路径可能会随着未来改进的治疗而改变。3)改善其他复杂症状，特别是严重便秘、吞咽困难和发育不良(尽管食物摄入量很好)、癫痫、行为问题以及呼吸和睡眠障碍。4)我们还将跟踪观察到的血清乳酸和有机酸的变化，以确定线粒体功能是否受损，以便在需要时为这种功能障碍提供适当的治疗。5)为了确定是否有文献报道的QTC间期延长，我们将在更大的患者系列中跟踪EKG的任何变化。我们将进行这些调查，以跟踪临床严重程度和病程，并与X-失活状态和基因相关。我们期待确定新的治疗干预措施的方向，以治愈/改善症状，并在婴儿早期进行神经保护。将提交一份单独的治疗干预方案。