Retinal vasculopathy with cerebral leukocencephalopathy and systemic manifestations (RVCL or RVCL-S, also previously known as retinal vasculopathy with cerebral leukodystrophy, RVCL; or cerebroretinal vasculopathy, CRV; or hereditary vascular retinopathy, HVR; or hereditary endotheliopathy, retinopathy, nephropathy, and stroke, HERNS) is an inherited condition resulting from a frameshift mutation in the C-terminal region of the TREX1 gene. This disease is associated witih DNA damage (chromosome damage) caused by a toxic mutant TREX1 protein, which causes organ damage mimicking radiation injury. RVCL affects small blood vessels, which disrupts blood flow to multiple organs including but not limited to the retina and the white matter of the central nervous system. Patients with RVCL develop vision loss, brain lesions, strokes, brain atrophy, and dementia. Other organ are also involved in many cases, including the kidney, liver, gastrointestinal tract, thyroid, and bone. Symptoms of RVCL commonly begin between ages 35 and 55, although sometimes disease onset occurs earlier or later. The overall prognosis is poor, and death can sometimes occur within 5 or 10 years of the first symptoms appearing, although some patients live more than 20 years after initial symptoms. Clinical trials are underway, as are efforts to develop personalized medicines for patients with RVCL. The Clayco Foundation supports research efforts to develop treatments and a gene therapy for RVCL, working closely with physician-scientists at multiple academic institutions including at the University of Pennsylvania and the University of Michigan.
Presentation For most patients, onset of disease is between ages 35 and 55. Earliest onset is usually not before age 35. Late onset is usually not after age 55. RVCL affects multiple organs. All patients develop brain and eye disease, leading to disability, vision loss, and premature death. All patients with RVCL develop kidney and liver disease, with elevated alkaline phosphatase. Some patients develop bone lesions (osteonecrosis) as well as hypothyroidism. Sometimes patients also develop gastrointestinal symptoms or bleeding. RVCL is associated with progressive deterioration in visual acuity due to multifocal microvascular disease, retinal neovascularization, and/or glaucoma. Retinal microvascular disease is noninflammatory and resembles that of diabetic retinopathy. This leads to partial or complete vision loss. Headaches due to multiple factors including brain lesions, edema, and papilledema. Mental confusion, loss of cognitive function, loss of memory, slowing of speech and hemiparesis due to brain lesions. Some patients have Jacksonian seizures or grand mal seizures. Progressive neurologic deterioration unresponsive to systemic immunosuppression including corticosteroid therapy and chemotherapeutic agents. Autopsy typically demonstrates discrete, often confluent, foci of coagulative necrosis in the cerebral white matter, with intermittent findings of fine calcium deposition within necrotic foci. Additionally, tissues exhibit vasculopathic changes involving both arteries and veins of medium and small caliber in the cerebral white matter. There is fibrinoid necrosis of vessel walls with extravasation of fibrinoid material into adjacent parenchyma present in both necrotic and non-necrotic tissue. Vessels can exhibit obliterative fibrosis in all the layers of vessel walls, as well as perivascular, adventitial fibrosis with limited intimal thickening. In rare cases, RVCL has been associated with severe disease involving other organs outside the brain and the eye (e.g., osteonecrosis requiring joint replacement, gastrointestinal ischemia leading to bowel resection, or liver failure requiring liver transplantation).
Clinical Associations Raynaud's phenomenon Anemia Hypertension Normocytic anemia Normochromic anemia Gastrointestinal bleeding or telangiectasias Elevated alkaline phosphatase Chronic kidney disease
Genetics RVCL is caused by mutations in the TREX1 gene. The official name of the TREX1 gene is "three prime repair exonuclease 1". The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes. Changes (mutations) to the TREX1 gene can result in a range of conditions, one of which is RVCL. The mutant TREX1 protein is produced and mislocalized. Haploinsufficiency of TREX1 does not explain the disease, since the parents of patients with Aicairdi-Goutieres syndrome, a disease characterized by insufficient TREX1 activity, are completely healthy with only one functional TREX1 allele. Different mutations in the TREX1 gene have also been identified in people with disorders involving the immune system. These disorders include a chronic inflammatory disease called Aicardi-Goutieres syndrome, as well as systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin. Those diseases, which are inflammatory, likely have a completely distinct mechanism compared with that of RVCL. The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644
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