Imbalance of the von Willebrand Factor — ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)-Reference-Cited by-同舟云学术

Imbalance of the von Willebrand Factor — ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)

Published:2024-06-20 Issue:1 Volume:6 Page:
ISSN:2524-3489
Container-title:Neurological Research and Practice
language:en
Short-container-title:Neurol. Res. Pract.

Author:

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^ORCID

Abstract

Abstract 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.

Funder

DFG

Universitätsklinikum Leipzig

Publisher

Springer Science and Business Media LLC

Link

https://link.springer.com/content/pdf/10.1186/s42466-024-00327-2.pdf

Reference33 articles.

1. Stam, A. H., Kothari, P. H., Shaikh, A., Gschwendter, A., Jen, J. C., Hodgkinson, S., et al. (2016). Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain, 139, 2909–2922. https://doi.org/10.1093/brain/aww217.

2. de Boer, I., Pelzer, N., & Terwindt, G., et al. (2019). Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. In M. P. Adam, D. B. Everman, & G. M. Mirzaa (Eds.), GeneReviews®. Seattle (WA): University of Washington, Seattle. 1993–2022.

3. Pelzer, N., Hoogeveen, E. S., Haan, J., Bunnik, R., Poot, C. C., van Zwet, E. W., et al. (2019). Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: A monogenic small vessel disease. Journal of Internal Medicine, 285, 317–332. https://doi.org/10.1111/joim.12848.

4. Hoogeveen, E. S., Pelzer, N., de Boer, I., van Buchem, M. A., Terwindt, G. M., & Kruit, M. C. (2021). Neuroimaging findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and systemic manifestations. American Journal of Neuroradiology, 42, 1604–1609. https://doi.org/10.3174/ajnr.A7194.

5. Richards, A., van den Maagdenberg, A. M., Jen, J. C., Kavanagh, D., Bertram, P., Spitzer, D., et al. (2007). C-terminal truncations in human 3’-5’ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nature Genetics, 39, 1068–1070. https://doi.org/10.1038/ng2082.