(Code 247691)

RVCL-S is a rare genetic disease with autosomal dominant transmission, caused by specific mutations in the TREX1 gene. It is a systemic disease affecting small vessels in many organs, primarily the retina and brain, but also the kidneys, liver, and intestines. Clinically, the first symptoms appear between the ages of 40 and 50. The disease may present with visual signs such as progressive loss of visual acuity due to retinal vasculopathy, variable neurological signs and symptoms including stroke, cognitive decline, migraine-like headaches, and seizures. Psychiatric conditions such as depression and anxiety may also be observed. Numerous systemic manifestations may be present, including Raynaud’s syndrome, anemia, and hepatic and renal involvement (Wilms et al., 2022). RVCL exposes young women to an increased risk of breast cancer (Chauvin SD, Nature Communications 2024). Finally, RVCL-S leads to premature death.

Retinal involvement is characterized by progressive capillary occlusion affecting the retinal periphery, complicated by neovascularization. It can lead to macular ischemia, macular edema, neovascular glaucoma, potentially resulting in blindness. Symptomatic treatment includes panretinal photocoagulation and intravitreal injections of anti-VEGF, but there is currently no treatment to prevent the progression of retinal capillary occlusions.

There is no specific treatment for RVCL-S. Immunosuppressive agents such as cyclophosphamide have been administered to some patients without benefit. Corticosteroids have temporarily reduced cerebral vasogenic edema, but had no effect on the underlying lesions. A recent study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody targeting P-selectin, approved for the prevention of sickle cell crises, with the aim of slowing retinal non-perfusion and preserving vision in patients with RVCL-S (Wang et al., 2024). Current therapeutic hopes rest on gene therapy and an oral treatment with small molecule drugs inhibiting the TREX1 protein.

References :

• https://www.orpha.net/en/disease/detail/247691
• Wilms AE, de Boer I, Terwindt GM. Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S): An update on basic science and clinical perspectives. Cereb Circ Cogn Behav. 2022 Feb 14;3:100046. doi: 10.1016/j.cccb.2022.100046. PMID: 36324396; PMCID: PMC9616387.
• Chauvin SD, Ando S, Holley JA, Sugie A, Zhao FR, Poddar S, Kato R, Miner CA, Nitta Y, Krishnamurthy SR, Saito R, Ning Y, Hatano Y, Kitahara S, Koide S, Stinson WA, Fu J, Surve N, Kumble L, Qian W, Polishchuk O, Andhey PS, Chiang C, Liu G, Colombeau L, Rodriguez R, Manel N, Kakita A, Artyomov MN, Schultz DC, Coates PT, Roberson EDO, Belkaid Y, Greenberg RA, Cherry S, Gack MU, Hardy T, Onodera O, Kato T, Miner JJ. Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans. Nat Commun. 2024 Jun 1;15(1):4696. doi: 10.1038/s41467-024-49066-7. PMID: 38824133; PMCID: PMC11144269.
• Wang WX, Spiegelman D, Rao PK, Rhee RL, Ford AL, Miner JJ, Apte RS. Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study. J Clin Invest. 2024 May 7;134(12):e180916. doi: 10.1172/JCI180916. PMID: 38950286; PMCID: PMC11178534.
• https://www.med.upenn.edu/rvcl