Nadine Pelzer1, Roel Bijkerk1, Marlies E J Reinders1, Anton Jan van Zonneveld1, Michel D Ferrari1, Arn M J M van den Maagdenberg1, Jeroen Eikenboom1, Gisela M Terwindt2. 1. From the Department of Neurology (N.P., M.D.F., A.M.J.M.v.d.M., G.M.T.), Department of Internal Medicine (Nephrology) (R.B., M.E.J.R., A.J.v.Z.), Einthoven Laboratory for Vascular and Regenerative Medicine (R.B., A.J.v.Z., J.E.), Department of Human Genetics (A.M.J.M.v.d.M.), and Department of Internal Medicine, Section Thrombosis and Hemostasis (J.E.), Leiden University Medical Center, the Netherlands. 2. From the Department of Neurology (N.P., M.D.F., A.M.J.M.v.d.M., G.M.T.), Department of Internal Medicine (Nephrology) (R.B., M.E.J.R., A.J.v.Z.), Einthoven Laboratory for Vascular and Regenerative Medicine (R.B., A.J.v.Z., J.E.), Department of Human Genetics (A.M.J.M.v.d.M.), and Department of Internal Medicine, Section Thrombosis and Hemostasis (J.E.), Leiden University Medical Center, the Netherlands. g.m.terwindt@lumc.nl.
Abstract
BACKGROUND AND PURPOSE: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease, caused by C-terminal truncating TREX1 mutations, that can be considered a model for stroke and vascular dementia. The pathophysiology of RVCL-S is largely unknown, but systemic endothelial involvement has been suggested, leading to pathology in the brain and other highly vascularized organs. Here, we investigated circulating endothelial markers to confirm endothelial involvement and identify biomarkers for disease activity. METHODS: We measured circulating levels of von Willebrand factor (VWF) antigen, VWF propeptide, and angiopoietin-2 in members of 3 Dutch RVCL-S families and matched unrelated healthy controls. Stratified analyses based on symptomatology and age were performed. RESULTS: We found elevated levels of VWF antigen, VWF propeptide, and angiopoietin-2 in TREX1 mutation carriers (n=31) compared with family members without a TREX1 mutation (n=33) and unrelated healthy controls (n=31; Kruskal-Wallis test P<0.001 for all comparisons). Effects were most pronounced in mutation carriers with clinical manifestations aged ≥40 years (Mann-Whitney U test P<0.001 for all comparisons). Compared with healthy controls, levels of VWF antigen (P=0.02) and angiopoietin-2 (P=0.04) were also elevated in mutation carriers aged <40 years. All 3 markers showed moderate correlations with markers of kidney and liver disease and inflammation (ie, systemic symptoms of RVCL-S). CONCLUSIONS: Our results confirm an important role of the endothelium in RVCL-S pathophysiology. VWF antigen, VWF propeptide, and angiopoietin-2 might serve as early biomarkers of disease activity. Our findings might also help to understand the pathophysiology of common neurovascular disorders, such as stroke.
BACKGROUND AND PURPOSE:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease, caused by C-terminal truncating TREX1 mutations, that can be considered a model for stroke and vascular dementia. The pathophysiology of RVCL-S is largely unknown, but systemic endothelial involvement has been suggested, leading to pathology in the brain and other highly vascularized organs. Here, we investigated circulating endothelial markers to confirm endothelial involvement and identify biomarkers for disease activity. METHODS: We measured circulating levels of von Willebrand factor (VWF) antigen, VWFpropeptide, and angiopoietin-2 in members of 3 Dutch RVCL-S families and matched unrelated healthy controls. Stratified analyses based on symptomatology and age were performed. RESULTS: We found elevated levels of VWF antigen, VWFpropeptide, and angiopoietin-2 in TREX1 mutation carriers (n=31) compared with family members without a TREX1 mutation (n=33) and unrelated healthy controls (n=31; Kruskal-Wallis test P<0.001 for all comparisons). Effects were most pronounced in mutation carriers with clinical manifestations aged ≥40 years (Mann-Whitney U test P<0.001 for all comparisons). Compared with healthy controls, levels of VWF antigen (P=0.02) and angiopoietin-2 (P=0.04) were also elevated in mutation carriers aged <40 years. All 3 markers showed moderate correlations with markers of kidney and liver disease and inflammation (ie, systemic symptoms of RVCL-S). CONCLUSIONS: Our results confirm an important role of the endothelium in RVCL-S pathophysiology. VWF antigen, VWFpropeptide, and angiopoietin-2 might serve as early biomarkers of disease activity. Our findings might also help to understand the pathophysiology of common neurovascular disorders, such as stroke.
Authors: Mays Al-Nofal; Irene de Boer; Seda Agirman; Anne E Wilms; Amir H Zamanipoor Najafabadi; Gisela M Terwindt; Irene C Notting Journal: Front Neurol Date: 2022-08-26 Impact factor: 4.086