Plasma neurofilament light chain as a potential disease monitoring biomarker in Wolfram syndrome

Wolfram综合征（OMIM #222300）是一种罕见的常染色体隐性遗传疾病，最常见的特征是 儿童期胰岛素依赖型糖尿病、视神经萎缩、感音神经性听力损失和糖尿病 尿崩症症状出现在幼儿期，并随着时间的推移而增加，最终导致失明， 耳聋、共济失调和其他显著的神经系统症状。纵向分析有 证明了特定的临床（例如视力，色觉）和衍生的神经影像学变量（例如， 丘脑和腹侧脑桥体积）随时间恶化。这些措施目前正在被用于一项持续的 临床疗效试验（ClinicalTrials.gov标识符：NCT 03717909）。但是，它们也是昂贵的，时间- 消耗并需要专门的现场设备和专业知识。相比之下，基于生物流体的 神经变性将更便宜，更容易标准化和可重复，因此对 正在进行和未来的临床试验，旨在减缓或停止神经系统进展。新兴的生物流体标记物 神经变性、神经丝轻链（NfL）和胶质细胞酸性蛋白（GFAP）对 但在神经退行性疾病中是非特异性的。Wolfram患者血浆中的NfL水平更高 综合征相比，控制，而GFAP还没有在这种疾病的研究。我们需要了解如果 Wolfram中的NfL升高与潜在的混杂因素无关，包括糖尿病状态和年龄， 水平随时间变化，以及这些变化是否跟踪神经症状的进展。临床 使用相同的测定法在相同的血液样品中测量NfL和可能的GFAP的验证是一种有效的方法。 建议在干预研究中使用NfL和/或GFAP的重要前提， 动物模型中的神经病理学验证研究。这项建议的重点是这些必要的后续步骤 如果成功的话，将为使用NfL和/或GFAP监测神经变性提供一个强大的平台。 Wolfram综合征

Wolfram syndrome (OMIM #222300) is a rare autosomal recessive disorder, characterized most frequently by childhood-onset insulin dependent diabetes, optic nerve atrophy, sensorineural hearing loss, and diabetes insipidus. Symptoms appear in early childhood and increase over time, ultimately resulting in blindness, deafness, ataxia and other significant neurologic symptoms by early adulthood. Longitudinal analyses have demonstrated that specific clinical (e.g. visual acuity, color vision) and derived neuroimaging variables (e.g. thalamic & ventral pons volumes) deteriorate over time. These measures are now being used in an ongoing clinical efficacy trial (ClinicalTrials.gov Identifier: NCT03717909). However, they are also costly, time- consuming and require specialized on-site equipment and expertise. In contrast, a biofluid-based measure of neurodegeneration would be cheaper, more easily standardized and repeatable, and thus extremely useful for ongoing and future clinical trials designed to slow or halt neurologic progression. Emerging biofluid markers of neurodegeneration, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), appear sensitive but non-specific in neurodegenerative diseases. NfL levels are greater in plasma of individuals with Wolfram syndrome compared to controls while GFAP has not been studied in this disease. We need to understand if NfL is elevated in Wolfram independent of potential confounders including diabetic status and age, whether its levels change over time and whether these changes track the progression of neurologic symptoms. Clinical validation of NfL, and possibly GFAP, measured in the same blood sample using the same assay, is an important precursor to proposing the use of NfL and/or GFAP in intervention studies or conducting neuropathological validation studies in animal models. This proposal is focused on these necessary next steps and, if successful, will provide a strong platform for using NfL and/or GFAP to monitor neurodegeneration in Wolfram syndrome.