Tracking Neurodegeneration in Early Wolfram Syndrome

Wolfram综合征（WFS; OMIM #222300）是一种罕见的常染色体隐性遗传病，1938年临床定义为： 儿童期发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，神经学特征被认为是在疾病后期出现的 死亡发生在中年。重要的是，主要的致病基因（WFS 1）被确定在 1998.这一发现使研究人员能够确定WFS 1基因编码蛋白钨蛋白， 这有助于保护细胞免受内质网（ER）应激介导的凋亡，可能通过 细胞内钙稳态WFS 1的致病性突变可导致细胞死亡或功能障碍 在高ER应激下，如产生胰岛素的胰腺β细胞，引起胰岛素依赖性 糖尿病此外，了解致病基因使我们能够通过WFS 1突变来识别患者 而不是典型的症状，导致越来越多的人认识到，WFS 1相关的表型 （包括神经系统症状）比以前理解的要多变得多。第一次迭代 格兰特（HD 070855“跟踪早期Wolfram综合征的神经退行性变”）促成了这一转变， 认识在这段时间里，我们为WFS建立了一个成功的年度研究诊所，达到或超过了我们的 患者和对照组的招募目标，验证了WFS的临床严重程度评定量表，描述了一种 意想不到的早期神经表型减少的平衡，嗅觉识别和腹侧脑桥体积， 在传统的弥散张量成像（DTI）指标中发现了改变，提示髓鞘形成不足是一种 WFS的普遍神经病理学特征，并为选择两种主要的 一项新资助的WFS临床疗效研究的结果（视力和腹侧脑桥体积）（Barrett，PI）。 我们的调查结果表明，未来的调查有两条线。首先，我们假设ER压力- 相关功能障碍可抑制WFS神经发育过程中髓鞘的产生， 发育中的少突胶质细胞（在大脑中产生髓鞘的细胞）比其他细胞更容易受到ER应激的影响。 成熟的人然而，标准的DTI方法合并了炎症过程（其也可以是炎症性的）。 与ER应激相关），具有轴突和髓鞘完整性的指标，导致 可能混淆的测量。我们建议收集新的，验证的扩散序列上一个新的 最先进的MRI扫描仪（Siemens Prisma），并应用尖端分析方法测量白色 整个大脑和视神经的物质完整性，提高我们得出结论的能力， 轴突和髓磷脂的完整性。其次，需要更大和更多样化的样本来确定 WFS退化的预测因子。我们将汇总WU中的关键变量以及基线和安慰剂条件 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脑特异性干预的目标，确定结果措施或 针对神经系统症状的临床试验的高风险亚组，并将为额外的 国际合作。这些数据也将大大扩展我们对横截面和 WFS 1突变相关疾病的纵向表型，而不是经典定义的Wolfram综合征。 这些知识将对患者和家庭产生重大影响，使医生能够提供更多的信息， 准确的预测。最后，ER应激介导的细胞凋亡的形式已被牵连在更常见的 神经退行性疾病、内分泌疾病和神经发育疾病，这些疾病可能会受益于 在这里获得。

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.