PATHOGENESIS OF RETT SYNDROME

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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。所列机构为中心机构，不一定为研究者机构。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（约70%）已被确定在位于Xq 28区域的MeCP 2基因中存在突变。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经典特征的不同年龄的男性已被鉴定为具有MeCP 2突变，导致广泛的临床谱。除了克兰费尔特综合征患者，男性都有母系传播的疾病。大多数女性为散发病例，发生于父系传播的新生突变。RTT患者有一个明显正常的早期发育过程，随后出现小头畸形，并在第一年结束时获得认知和运动技能。刻板动作、癫痫发作、呼吸紊乱、胃肠道和营养异常以及行为问题是常见的临床并发症。肌肉张力和运动的进行性异常与脑黑质黑质中多巴胺和黑色素含量的减少有关。在RTT中，死后脑组织显示基底神经节中胆碱乙酰转移酶减少，这一定加重了痴呆。与年龄相关的NMDA/谷氨酸受体过量与婴儿和儿童期的癫痫性脑病相一致。据报道，在成骨细胞中存在NMDA谷氨酸受体，这需要考虑由于其过量而导致的毒性作用，导致骨质疏松症和RTT中骨折增加。值得注意的是，最近认识到背顶叶和脑叶的体积减小（Kaufmann等人，未发表的观察结果），同时通过MR波谱分析减少了这些区域的NAA。EEG显示在睡眠中最大化的中央颞区产生的尖峰，以及MRI/MRS结果，可能表明睡眠中涉及小脑的发作活动是这些受试者突然意外死亡的可能原因。 临床上，RTT的年龄相关体征和症状的一致性表明共同的发病机制。我们的研究旨在：1）鉴定在MeCP 2中具有和不具有突变的那些人所共有的生物学因素，尽管具有经典表型，并确定自然史和表型变异性的基础，从而可以提供适当的预后和治疗选择。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脑区，以与特定的神经功能缺损相关，并为意外猝死提供依据。由于尾状核和额颞区沿着脑体积减小，同时RTT中脑血流减少，因此将获得DTI和MR波谱，以确定参与导致进行性强直、癫痫发作和行为异常的区域和途径，这些区域和途径可能在未来通过改进治疗而改变。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）、癫痫发作、行为问题以及呼吸和睡眠不规律。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)为了确定是否存在文献中报告的QTC间期延长，我们将跟踪更大系列患者的EKG变化。我们将进行这些研究，以跟踪临床严重程度和过程，并与X-失活状态和基因型相关。我们预计确定新的治疗干预措施，以治愈/改善症状，并在婴儿早期的神经保护的方向。将提交一份单独的治疗干预方案。

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.