Neurological Research and Practice (Jun 2024)

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

  • Max Braune,
  • Moritz Metelmann,
  • Jonathan de Fallois,
  • Christian Pfrepper,
  • Alonso Barrantes-Freer,
  • Grit Gesine Ruth Hiller,
  • Susette Unger,
  • Evelyn Seelow,
  • Jan Halbritter,
  • Johann Otto Pelz

DOI
https://doi.org/10.1186/s42466-024-00327-2
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 11

Abstract

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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.

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