TRACKING NEURODEGENERATION IN EARLY WOLFRAM SYNDROME

描述（由申请人提供）：Wolfram综合征（WFS）是一种罕见的常染色体隐性遗传病（77万分之一），临床症状见于幼儿期。它的特征是胰岛素依赖型糖尿病，随后是视神经萎缩、视力丧失、听力丧失、尿崩症和神经变性，导致中年死亡，通常是由于脑干萎缩引起的呼吸衰竭。目前还没有任何治疗方法可以减缓或阻止这种毁灭性的恶化。然而，人们对这些影响背后的机制知之甚少。致病基因（WFS1）是由我们的小组在1998年确定的，并描述了一些功能丧失突变。细胞和动物模型已经确定，WFS1编码内质网（ER）膜内嵌入蛋白wolframin，突变导致内质网钙稳态紊乱，驱动内质网应激介导的细胞凋亡。这个过程杀死产生胰岛素的胰腺细胞，导致糖尿病，并且被认为是WFS中惊人的神经变性的基础。WFS动物模型的研究工作正在朝着确定可行的干预措施的方向迅速进展。该疾病的神经学特征可能是临床试验中最可行的目标和监测，因为在患者被诊断为WFS时，胰腺中的¿-细胞已经发生损失。不幸的是，缺乏与WFS相关的神经退行性变模式的信息，特别是在疾病的早期阶段。因此，当前建议的目标是确定WFS早期神经退行性改变的模式。我们将对患有WFS的青少年进行横断面和纵向评估，通过量化的神经成像和行为测量来瞄准敏感的神经系统。此外，我们将建立WFS严重性评定量表（WFS统一评定量表或WFS统一评定量表）的效用

DESCRIPTION (provided by applicant): Wolfram syndrome (WFS) is a rare (1 in 770,000) autosomal recessive genetic disease with clinical signs apparent in early childhood. It is characterized by insulin-dependent diabetes, followed by optic nerve atrophy, vision loss, hearing loss, diabetes insipidus and neurodegeneration, resulting in death in middle adulthood, typically due to brainstem atrophy-induced respiratory failure. There currently are no treatments that slow or stop this devastating deterioration. However, much is known about the mechanisms underlying these effects. The causative gene (WFS1) was identified by our group in 1998, and a number of loss-of-function mutations have been described. Cell and animal models have determined that WFS1 encodes an endoplasmic reticulum (ER) membrane-embedded protein called wolframin and that mutations lead to disturbances of ER calcium homeostasis, driving ER stress-mediated apoptosis. This process kills insulin producing pancreatic ¿-cells, leading to diabetes, and is thought to underlie the striking neurodegeneration in WFS. Work in animal models of WFS is progressing rapidly towards the identification of viable interventions for this process. Neurological features of the disease may be the most feasible to target and monitor in clinical trials, due to the fact that ¿-cell loss in the pancreas has already occurred by the time patient is diagnosed with WFS. Unfortunately, there is a dearth of information on the pattern of neurodegeneration associated with WFS, particularly in the early stages of the disease. Thus, the goal of the current proposal is to determine the pattern of early neurodegenerative changes in WFS. We will perform cross-sectional and longitudinal assessments of youth with WFS, targeting sensitive neural systems with quantified neuroimaging and behavioral measures. In addition, we will establish the utility of a WFS severity rating scale (WFS Unified Rating Scale or WURS). Preliminary data support the feasibility of this approach and its potential to generate important new information about neurodevelopmental and neurodegenerative patterns in WFS. This work is necessary to position the field for future clinical trials to test interventions for WS neurodegeneration. Ultimately, a better understanding of the trajectory of neurodegeneration in WFS and the development of effective interventions may be relevant to other more common neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases in which ER stress has been implicated.