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RVCL-S Research

At the LUMC a lot of research is performed into RVCL-S (Retinal Vasculopathy with Cerebral Leukoencephalopathie and Systemic manifestations). Our goal is to develop a treatment for this disorder. We perform fundamental research (= aimed at understanding the disease mechanism) and clinical research. We collaborate with different specialists in the LUMC and with other hospitals and research centers nationally and internationally.

Why do we perform research?

RVCL-S is a rare hereditary disorder that is caused by mutation in the TREX1 gene. In RVCL-S the small blood vessels are most affected. This leads to complaints caused by damage to several organs. Common complaints are (severe) visual impairment and neurological complaints. People suffering from RVCL-S have a decreased life expectancy.

There are many questions still open about how mutations in TREX1 lead to disease. We do not know why some patients develop symptoms at a relative young age, while other patients are older before they develop complaints. At this moment, there is no treatment that cures RVCL-S. All treatments are aimed at slowing down disease progression.

More research into RVCL-S is necessary to understand the disease mechanism. Our goal is to find a suitable treatment for the disorder.

In the LUMC different types of research into RVCL-S is being performed.

What type of research do we perform?

In het LUMC different types of research is being performed. We perform both fundamental (= research aimed at understanding disease mechanism) and clinical research.

Better understanding of the disease and its progression

In the LUMC we have been collecting information about the health status of RVCL-S patients since the 90’s. Soon we discovered that some patients pass away at a relatively young age, while some patients pass away around the age of 70 years. We are trying to find out where this difference comes from. Between 2014 and 2015 we performed a large study into the complaints of patients with RVCL-S (RVCL-ID study). Recently, a new study has been started with the aim to better understand the natural history of the disorder (see FORT below on this page).

Predictive biomarkers

We are trying to find biomarkers that can predict when disease onset occurs and when the disease will progress. Biomarkers are measures of a biological state that can be used to indicate the progression of a disorder, examples are signal molecules in blood or findings on images of the brain. Biomarkers will likely be used in the future to help test the efficacy of new treatments for RVCL-S. More knowledge about biomarkers can also help develop future therapies.

Identify disease mechanisms

Knowledge about disease mechanisms is indispensable for finding new treatments and for better monitoring of the disease. We use patient material (e.g. blood, cerebrospinal fluid, but also tissue samples), cell lines of patients and if necessary animal models. This type of research forms the basis of progress in the fight against the disorder.

We continually search for the practical application of this gained knowledge (translational knowledge). Multidisciplinary teams, with researchers working in laboratories and physicians work together on these research projects. This allows for a two way street: from patients to fundamental research and from fundamental research to patients. With this, we try to quickly translate our knowledge to clinical practice. This benefits the patients.


The RVCL-S research team in the LUMC has started a new study to understand the natural history of the disorder. The study, FOllowing RVCL-S to Treatment (so-called FORT study) has recently been started. Unfortunately, only participants living in the Netherlands are able to participate.

Do you want to know more about the FORT study?

Contact the researchers at the LUMC by the contact button or by sending an email to!

What we have accomplished so far

The LUMC is the national referral center for RVCL-S. A such, we have more then 25 years of experience in clinical care and research. The LUMC was one of the leading centers whose research led to the discovery of the disorder and we were one of the first groups to describe the clinical complaints that are caused by RVCL-S. Together with our international collaborators we discovered the gene (TREX1) in which mutations can cause RVCL-S. This step was essential for correctly diagnosing patients.

We played an important role in discovering the systemic manifestations of RVCL-S (commonly damage to the liver and kidney). We also found indications that a dysfunction in the endothelium (the inner layer of blood vessels) play an important role in RVCL-S. We found endothelium dysfunction in the vessels of both the arm and the brain. We also found elevated ‘endothelium markers’ in the blood of patients.

We are trying to find biomarkers that can predict when disease onset occurs. We already found that the retina of patients is thinner than in healthy participants. This also occurs in the early stages of disease, when the ophthalmological examination is still normal.  

Additionally, the LUMC has made it its mission to promote knowledge transmission about RVCL-S to physicians worldwide. We want to prevent that patients receive the wrong diagnoses. Therefore, we publish clinical guidelines that can assist physicians in recognizing and treating RVCL-S.

This is a drawing of a blood vessel. In RVCL-S, the endothelium appears to play an important role.


The RVCL-S research at the LUMC is partially funded by the Clayco Foundation, the International Retinal Research Foundation, Dioraphte and the Dutch Heart Association.

Would you also like to contribute to our research?

That is possible! Click here for more information.

International colaboration

The RVCL-S research team of the LUMC collaborates with physicians and researchers from across the world. Among our collaborators are Amsterdam University Medical Center, Clayco Foundation, Cleveland Clinic, Erasmus Medical Center, Liverpool Hospital, Ludwig-Maximilians Universität, Physics for Medicine Paris, University of California, University of Pennsylvania, University of Washington, and University of Sydney.

Most recent publications

  • A.E. Wilms, I. de Boer, N. Pelzer, S.G.J.G. in’t Veld, H.A.M. Middelkoop, C.E. Teunissen, G.M. Terwindt. NFL and GFAP in (pre)symptomatic RVCL‑S carriers: a monogenic cerebral small vessel disease. J Neurol, 2024.
    M. Al-Nofal, I. de Boer, S. Agirman, A.E. Wilms, A.H. Zamanipoor Najafabadi, G.M. Terwindt, I.C. Notting. Optical coherence tomography angiography biomarkers of microvascular alterations in RVCL-S. Frontiers in Neurology, 13, 2022.
  • A.E. Wilms, I. de Boer, G.M. Terwindt. Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S): An update on basic science and clinical perspectives. Cerebral Circulation - Cognition and Behavior, Volume 3, 2022, 100046.
  • E.S. Hoogeveen, N. Pelzer, E. Ghariq, M.J. van Osch, A. Dahan, G.M. Terwindt, M.C. Kruit. Cerebrovascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. J Cereb Blood Flow Metab. 2021; 41(4):831-840.
  • E.S. Hoogeveen, N. Pelzer, I. de Boer, M.A. van Buchem, G.M. Terwindt, M.C. Kruit. Neuroimaging Findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. AJNR Am J Neuroradiol. 2021;42(9):1604-1609.
  • I. de Boer, S.R. Steenmeijer, N. Pelzer, M. Al-Nofal, G. Dijkman, I.C. Notting, G.M. Terwindt. Spectral Domain Optical Coherence Tomography in Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations: A Monogenic Small Vessel Disease. J Neuroophthalmol. 2021; epub ahead of print.
  • I. de Boer, G.M. Terwindt. Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2020.
  • I.A. Mulder, E. Rubio-Beltran, K. Ibrahimi, O. Dzyubachyk, A. Khmelinskii, M. Hoehn, G.M. Terwindt, M.J.H. Wermer, A. Maassen van den Brink, A.M.J.M. van den Maagdenberg. Increased Mortality and Vascular Phenotype in a Knock-In Mouse Model of Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations. Stroke. 2020;51(1):300-307.
  • I. de Boer et al. Phenotypic variability in a Mexican Mestizo family with RVCL-S and a TREX1 mutation: early manifestations. Rev Invest Clin. 2019;71:141-142.
  • N. Pelzer, E.S. Hoggeveen, J. Haan, R. Bunnik, C.C. Poot, E.W. van Zwet, A. Inderson, A.J. Fogteloo, M.E.J. Reinders, H.A.M. Middelkoop, M.C. Kruit, A.M.J.M. van den Maagdenberg, M.D. Ferrari, G.M. Terwindt. Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease. J Intern Med. 2019;285(3):317-332.
  • I. de Boer, A.M.J.M. van den Maagdenberg, G.M. Terwindt. TREX1 Mutation Causing Autosomal Dominant Thrombotic Microangiopathy and CKD Is in Fact a Case of RVCL-S Presenting With Renal Features. Am J Kidney Dis. 2019;73:893. 
  • I. de Boer, N. Pelzer, G.M. Terwindt. Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations. In: GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2021. 2019 Sep 19.
  • I. de Boer, A.H. Stam, L. Buntinx, R. Zielman, I. van der Steen, A.M.J.M. van den Maagdenberg, E.J.P. de Koning, M.D. Ferrari, J.N. de Hoon, G.M. Terwindt. RVCL-S and CADASIL display distinct impaired vascular function. Neurology. 2018;91(10):e956-e963.
  • N. Pelzer, R. Bijkerk, M.E.J. Reinders, A.J. van Zonneveld, M.D. Ferrari, A.M.J.M. van den Maagdenberg, J. Eikenboom, G.M. Terwindt. Circulating Endothelial Markers in Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations. Stroke. 2017;48(12):3301-3307.
  • T.A. Hardy, S. Young, J.S. Sy, A.F. Colley, G.M. Terwindt, M.D. Ferrari, M.W. Hayes, S. Hodgkinson. Tumefactive lesions in retinal vasculopathy with cerebral leucoencephalopathy and systemic manifestations (RVCL-S): a role for neuroinflammation? J Neurol Neurosurg Psychiatry. 2018;89:434-435.
  • Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, Hardy TA, Hayes M, Kempster PA, Kotschet KE, Bajema IM, van Duinen SG, Maat-Schieman ML, de Jong PT, de Smet MD, de Wolff-Rouendaal D, Dijkman G, Pelzer N, Kolar GR, Schmidt RE, Lacey J, Joseph D, Fintak DR, Grand MG, Brunt EM, Liapis H, Hajj-Ali RA, Kruit MC, van Buchem MA, Dichgans M, Frants RR, van den Maagdenberg AM, Haan J, Baloh RW, Atkinson JP, Terwindt GM, Ferrari MD. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain. 2016;139(11):2909-2922.
  • de Vries B, Steup-Beekman G, Haan J, Bollen E, Luyendijk J, Frants R, Terwindt G, van Buchem M, Huizinga T, van den Maagdenberg A, Ferrari M. TREX1 Gene Variant in Neuropsychiatric Systemic Lupus Erythematosus. Ann Rheum Dis. 2010;69(10):1886-7.
  • A Richards, AMJM van den Maagdenberg, JC Jen, D Kavanagh, P Bertram, D Spitzer, MK Liszewski, M Barilla-Labarca, GM Terwindt, Y Kasai, M McLellan, M Gilbert Grand, KRJ Vanmolkot, B de Vries, J Wan, MJ Kane, H Mamsa, R Schäfer, AH Stam, J Haan, PTVM de Jong, CW Storimans, MJ van Schooneveld, JA Oosterhuis, A Gschwendter, M Dichgans, KE Kotschet, S Hodgkinson, TA Hardy, MaB Delatycki, RA Hajj-Ali, PH Kothari, SF Nelson, RR Frants, RW Baloh, MD Ferrari, JP Atkinson. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39(9):1068-70.