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 unpublished observations), when combined with reduced NAA in these regions by MR-spectroscopy, is of note.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.

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代表。列出的机构适用于该中心，这不一定是调查员的机构。 RETT综合征（RTT）是一种特征性发生在女性中的疾病。大多数患有RTT临床特征的患者（〜70％）已被确定为位于XQ28区域的MECP2基因中的突变。该基因参与抑制多个染色体上未知数基因的转录。最近，已经确定缺乏RTT经典特征的不同年龄段的男性在MECP2中具有突变，这是广泛的临床范围。除Kleinfelter综合征患者外，男性还具有基质性传播疾病。大多数女性是零星的病例，是由从头传播的从头突变发生的。 RTT患者的早期发育过程明显正常，随后是小头畸形，并在第一年结束时在获得认知和运动技能方面被捕。定型运动，癫痫发作，呼吸不规则，胃肠道和营养异常以及行为问题是频繁的临床伴随物。肌肉张力和运动的渐进异常与黑质Nigra Pars Compacta中的脑多巴胺和黑色素含量减少有关。在RTT中，事后脑组织在基底神经节中显示胆碱乙酰转移酶降低，这必须突显痴呆症。与年龄相关的NMDA/谷氨酸受体的过量与婴儿期和儿童期间指出的癫痫性脑病一致。据报道，成骨细胞中NMDA谷氨酸受体的存在值得考虑由于其过量而引起的毒性作用，从而导致骨质疏松症和RTT的骨折增加。值得一提的是，最近认识到背叶和岛岛的体积减少（Kaufmann等人未发表的观察结果），当通过MR谱镜检查中NAA减少时。脑电图表明，由中央颞区引起的尖峰，这些区域在睡眠中最大化，并且与MRI/MRS的发现一起可能表明，涉及岛状的睡眠中的发射活性是这些受试者突然意外死亡的可能原因。 在临床上，RTT中与年龄相关的体征和症状的均匀性表明了常见的致病机制。我们的研究旨在：1）确定尽管经典表型，在MECP2中有和没有突变的人常见的生物学因素，并确定自然史和表型变异性的基础，以便提供适当的预后和治疗选择。 2）通过对MRI扫描和扩散张量成像（DTI）的体积分析来确定具有选择性脆弱性的大脑区域，以与特定的神经系统缺陷以及突然意外死亡的基础相关。随着尾状和额叶区域的大脑体积减小，RTT DTI中的脑血流减少，将获得MR谱镜检查，以确定区域和途径的参与和促进性刚性，癫痫发作和行为差异的参与，并可能在将来改变治疗方法。 3）改善其他复杂症状，特别是严重的便秘，吞咽困难和未能推动的（尽管食物摄入良好），癫痫发作，行为问题以及呼吸和睡眠不规则。 4）我们还将遵循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）为了确定文献中报道的QTC间隔是否延长，我们将跟随心电图，以了解较大一系列患者的任何变化。我们将进行这些研究以遵循临床严重程度和过程，并与X灭活状态和基因型相关。我们预计会鉴定出治疗干预措施的新方向，以治愈/改善症状，并在婴儿早期治疗神经保护方向。将提交单独的方案进行治疗干预措施。