Tracking Neurodegeneration in Early Wolfram Syndrome

Wolfram综合征是一种罕见的常染色体隐性遗传病，1938年临床定义为 儿童起病的胰岛素依赖型糖尿病、视神经萎缩、尿崩症和 耳聋。根据早期的描述，神经学特征被认为出现在疾病的较晚阶段 死亡发生在成年中期。重要的是，主要致病基因(WFS1)在 1998年。这一发现使研究人员能够确定WFS1基因编码wolframin蛋白， 它有助于保护细胞免受内质网(ER)应激介导的细胞凋亡，可能是通过 细胞内钙动态平衡。WFS1致病突变可导致细胞死亡或功能障碍 处于高内质网压力下的细胞，如产生胰岛素的胰腺β细胞，导致胰岛素依赖 糖尿病。此外，了解致病基因使我们能够通过患者的WFS1突变来识别他们 而不是一系列经典的症状，导致越来越多的人意识到WFS1相关的表型 (包括神经系统症状)比之前所了解的要多变得多。它的第一次迭代 格兰特(HD070855《追踪早期Wolfram综合征中的神经变性》)促成了这一转变 理解。在这段时间里，我们成功地建立了WFS的年度研究诊所，达到或超过了我们的 患者和对照的招募目标，验证了WFS的临床严重程度分级量表，描述了 出乎意料的是早期神经表型平衡、嗅觉识别和腹侧脑桥体积降低， 在传统的弥散张量成像(DTI)指标中发现的改变提示髓鞘过少是一种 WFS的弥漫性神经病理特征为选择两种原发疾病提供了依据 一项新资助的WFS(Barrett，PI)临床疗效研究的结果(视力和脑桥腹侧体积)。 我们的发现表明，未来有两条调查路线。首先，我们假设内质网压力- 相关功能障碍可抑制WFS神经发育过程中髓鞘的产生，如活动和 发育中的少突胶质细胞(大脑中产生髓鞘的细胞)比内质网应激更容易受到内质网压力的影响 成熟的人。然而，标准的DTI方法会混淆炎症过程(这也可以是 与内质网应激有关)，轴突和髓鞘完整性的指标，导致 潜在地混淆了测量结果。我们建议收集新的、有效的扩散序列 最先进的MRI扫描仪(西门子Prisma)和应用尖端分析方法测量白色 大脑和视神经的物质完整性，提高我们得出结论的能力 随着时间的推移，轴突和髓鞘的完整性。其次，需要更大和更多样化的样本来确定 WFS退变的预测因子。我们将把WU的关键变量与基线条件和安慰剂条件结合起来 来自英国的一项新的临床试验，迅速增加了我们的样本，并允许进行更复杂的分析。 这项工作的发现可能表明未来大脑特定干预的目标，确定结果衡量标准或 针对神经症状的临床试验的高危亚组，并将为其他 国际合作。这些数据还将极大地扩大我们对横截面和 WFS1突变相关疾病的纵向表型，而不是经典定义的Wolfram综合征。 这样的知识将对患者和家庭产生重大影响，因为它允许医生提供更多 准确的预测。最后，内质网应激介导的细胞凋亡的形式与更常见的 神经退行性、内分泌和神经发育疾病，可能受益于这些见解 在这里收获了。

Wolfram syndrome (WFS; OMIM #222300) is a rare autosomal recessive disease clinically defined in 1938 as the combination of childhood-onset insulin dependent diabetes, optic nerve atrophy, diabetes insipidus and deafness. Based on early descriptions, neurological features were thought to appear later in the disease with death occurring in middle adulthood. Importantly, the major causative gene (WFS1) was identified in 1998. This discovery allowed researchers to determine that the WFS1 gene encodes the protein wolframin, which helps protect cells from endoplasmic reticulum (ER) stress-mediated apoptosis, potentially via intracellular calcium homeostasis. Pathogenic mutations in WFS1 can result in death or dysfunction of cells that are under high ER stress, such as insulin-producing pancreatic β cells, causing insulin dependent diabetes. In addition, knowing the causative gene has allowed us to identify patients by their WFS1 mutation rather than the classic set of symptoms, leading to the increasing realization that the WFS1-related phenotype (including neurologic symptoms) is much more variable than previously understood. The first iteration of this grant (HD070855 “Tracking Neurodegeneration in Early Wolfram Syndrome”) contributed to this shift in understanding. In this time, we have built a successful annual research clinic for WFS, met or exceeded our recruitment goals for patients and controls, validated a clinical severity rating scale for WFS, described an unexpectedly early neurophenotype of reduced balance, smell identification and ventral pons volume, identified alterations in traditional diffusion tensor imaging (DTI) metrics that suggest hypomyelination as a pervasive neuropathological feature of WFS and provided justification for the selection of two primary outcomes (visual acuity and ventral pons volume) in a newly funded clinical efficacy study in WFS (Barrett, PI). Our findings suggest two lines of investigation going forward. First, we hypothesize that ER stress- related dysfunction could inhibit production of myelin during neurodevelopment in WFS, as active and developing oligodendrocytes (cells that produce myelin in the brain) are more vulnerable to ER stress than mature ones. However, standard DTI methods conflate inflammatory processes (which can also be associated with ER stress) in the extra-axonal space with metrics of axonal and myelin integrity, leading to potentially confounded measurements. We propose to collect novel, validated diffusion sequences on a new state of the art MRI scanner (Siemens Prisma) and apply cutting-edge analysis approaches to measure white matter integrity throughout the brain and in the optic nerve, improving our ability to draw conclusions about axonal and myelin integrity over time. Second, larger and more diverse samples are needed to determine the predictors of WFS degeneration. We will pool key variables from WU with baseline and placebo conditions from a new clinical trial in the UK, rapidly increasing our sample and allowing for more complex analyses. Findings from this work may indicate future targets for brain-specific intervention, identify outcome measures or high-risk subgroups for clinical trials targeting neurological symptoms and will lay the groundwork for additional international collaborations. These data will also greatly expand our understanding of the cross-sectional and longitudinal phenotype of WFS1-mutation related disorders, rather than classically defined Wolfram Syndrome. Such knowledge will have a significant impact on patients and families by allowing physicians to provide more accurate prognoses. Finally, forms of ER stress-mediated apoptosis have been implicated in more common neurodegenerative, endocrine and neurodevelopmental diseases, which may benefit from the insights gained here.