Braune Max, Metelmann Moritz, de Fallois Jonathan, Pfrepper Christian, Barrantes-Freer Alonso, Hiller Grit Gesine Ruth, Unger Susette, Seelow Evelyn, Halbritter Jan, Pelz Johann Otto
Paul-Flechsig-Institute for Neuropathology, University Hospital Leipzig, Leipzig, Germany.
Department of Neurology, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany.
Neurol Res Pract. 2024 Jun 20;6(1):32. doi: 10.1186/s42466-024-00327-2.
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.
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.
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).
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.
伴有脑白质脑病和全身表现的视网膜血管病变（RVCL-S）是一种由TREX1基因功能缺失变异引起的极其罕见的常染色体显性小血管疾病。最近，血管性血友病因子抗原（vWF-Ag）血清水平升高表明存在潜在的内皮病变，并且微血管缺血被认为是导致RVCL-S神经退行性变的原因。本研究的目的是进一步阐明RVCL-S中的内皮病变。
对两名基因确诊为RVCL-S的患者反复测量vWF-Ag和ADAMTS-13活性。对两名RVCL-S患者进行肾活检，并对一名RVCL-S患者的脑、肾、肝和肺的尸检标本与匹配的对照进行免疫组化检查。此外，对尸检脑标本进行脑甲基化组分析，计算与对照相比的差异甲基化位点。
虽然RVCL-S患者的vWF-Ag和活性显著升高，但ADAMTS-13活性较低，且在疾病过程中进一步降低。尸检脑标本显示脑小血管有血栓性炎症迹象，RVCL-S患者脑和肾小血管中的vWF-Ag染色呈强阳性，而对照中仅发现轻度至中度的vWF-Ag染色。与八名无脑部病变的对照相比，对已故RVCL-S患者进行的脑甲基化组分析产生了115个差异甲基化的CpG（p < 0.05）。其中一个低甲基化基因编码ADAMTS-13（p = 0.00056）。
这些发现表明RVCL-S患者中vWF - ADAMTS-13轴失衡，最终可能导致vWF-Ag在肾和脑小血管中积累。vWF-Ag水平升高可能作为反映疾病活动的早期血清标志物。如果得到证实，未来的治疗方法可能旨在抑制vWF-Ag或增加ADAMTS-13活性。
