背景:视网膜血管病变伴脑白质脑病和全身表现(RVCL-S)是一种非常罕见的,由TREX1基因功能丧失变异引起的常染色体显性小血管病。最近,血管性血友病因子抗原(vWF-Ag)的血清水平升高表明了潜在的内皮病,微血管缺血被认为有助于RVCL-S的神经变性。这项研究的目的是进一步阐明RVCL-S中的内皮病。
方法:在两名基因证实的RVCL-S患者中重复测量vWF-Ag和ADAMTS-13活性。RVCL-S患者和自体脑的肾活检,肾,肝,与匹配的对照组相比,对一名RVCL-S患者的肺标本进行了免疫组织化学检查。此外,在自体视脑部标本中进行脑甲基化组分析,计算与对照组相比的差异甲基化位置.
结果:虽然vWF-Ag和活性强烈升高,RVCL-S中的ADAMTS-13活性较低,并且在整个疾病过程中进一步降低。自体脑标本显示脑小血管有血栓炎症的迹象,在RVCL-S的脑和肾小血管中vWF-Ag染色呈强阳性,而在对照组中仅发现轻度至中度的vWF-Ag染色。脑甲基化组分析在死亡的RVCL-S患者中产生115个差异甲基化的CpG(p<0.05),与没有脑病理学的8个对照相比。编码ADAMTS-13的低甲基化基因之一(p=0.00056)。
结论:这些发现表明RVCL-S患者的vWF-ADAMTS-13轴失衡,这可能最终导致肾脏和大脑小血管中vWF-Ag的积累。升高的vWF-Ag水平可以作为反映疾病活动的早期血清标志物。如果确认,未来的治疗方法可能旨在抑制vWF-Ag或增加ADAMTS-13活性。
BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene
TREX1. Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S.
METHODS: vWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls.
RESULTS: While vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs (p < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 (p = 0.00056).
CONCLUSIONS: These findings point to an imbalance of the vWF - ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.