Diagnosis and Predictive Value of the Ocular Manifestations of Fabry Disease

项目摘要 溶酶体贮积病是由病理性蓄积引起的全身性代谢紊乱 包括眼睛在内的各种细胞和器官中的副产品。法布里病是最常见的 X连锁GLA基因突变导致的溶酶体胆积症 α-半乳糖苷酶A（α-Gal A）。鞘糖脂逐渐积累，导致 肾衰竭、心功能障碍、脑血管疾病、 胃肠道症状和慢性疼痛。患者还患有特异性轮状角膜， 通常在诊断时出现。其他症状包括白内障，结膜和视网膜 弯曲和扩张的程度。重要的是，在以下情况之间存在直接相关性： 伴有角膜轮状的法布里病的某些眼部表现和疾病严重程度通常导致 初步诊断。与其他器官系统疾病相比，眼部检查结果的出现时间并不准确 由于患者群体的异质性，描述和难以在人类中研究。鼠标 模型已用于酶替代疗法（ERT）的开发，但受到以下限制： 事实上，它们并不重现眼部表型。使用深色琼脂糖α-Gal A敲除动物 模型与患者中观察到的角膜、晶状体和视网膜血管变化，我们试图评估 基因敲除大鼠和人类的眼痛和视网膜表型，以前没有在一项研究中评估过。 这种罕见疾病的队列中。我们独特的方法整合了 动物模型，提供了研究大型受控人群的机会，而人类研究 确定病理学的临床意义。我们建议这样做的具体目标如下： 1)评价法布里病α-Gal A KO大鼠模型中眼部病理学的程度和时间进程 以及早期ERT对晚期ERT的影响，以及2）评估患有法布里病的人类受试者的眼部疾病， 在α-Gal A KO中观察到的具有临床意义的疾病之前的疼痛和亚临床眼部变化 大鼠这项工作有望对我们理解溶酶体储存产生重大影响 通过使用再现眼部症状的动物模型来阐明疾病的时间过程， 与全身症状相关的法布里病的眼部病理学。这些发现将有助于 确定ERT启动的最佳时机和新疗法的疗效，同时提供 对其他溶酶体或代谢性疾病的眼部病理学的机械见解。

PROJECT SUMMARY Lysosomal storage diseases are systemic metabolic disorders caused by pathologic accumulation of byproducts in various cells and organs, including the eye. Fabry disease is the most common lysosomal storage disease and results from a mutation of the X-linked GLA gene causing a deficiency of the enzyme α-galactosidase A (α-Gal A). Glycosphingolipids progressively accumulate, resulting in a shorter and poorer quality of life from renal failure, cardiac dysfunction, cerebrovascular disease, gastrointestinal symptoms, and chronic pain. Patients also have pathognomonic cornea verticillata that is usually present at the time of diagnosis. Other symptoms include cataract, conjunctival and retinal tortuosity, and aneurysmal dilation. Importantly, a direct correlation exists between the prevalence of certain ocular findings and disease severity in Fabry disease with cornea verticillata often leading to the initial diagnosis. The timing of the ocular findings relative to other organ system disease is not well described and difficult to study in humans because of heterogeneity in the patient population. Mouse models have been used in the development of enzyme replacement therapy (ERT), but are limited by the fact that they do not recapitulate ocular phenotypes. Using a Dark Agouti α-Gal A knockout animal model with the corneal, lenticular, and retinal vascular changes seen in patients, we seek to evaluate both knockout rats and humans for an ocular pain and retinal phenotypes not previously evaluated in a in a cohort for this rare disease. Our unique approach integrates the complementary strengths of an animal model, giving the opportunity to study a large controlled population, while human studies determine the clinical significance of pathology. We propose to do this with the following specific aims: 1) evaluate the extent and time course of ocular pathology in a α-Gal A KO rat model of Fabry disease and the effect of early versus later ERT and 2) evaluate human subjects with Fabry Disease for ocular pain and subclinical ocular changes that precede clinically significant disease observed in α-Gal A KO rats. This work is expected to have a significant impact on our understanding lysosomal storage diseases by using an animal model that recapitulates eye symptoms to elucidate the time course of ocular pathology of Fabry disease in relation to systemic symptoms. These findings will aid in the determination of optimal timing of ERT initiation and the efficacy of new therapies, while providing mechanistic insight into the ocular pathology of other lysosomal or metabolic diseases.