Last updated:
5/9/2025
Years published: 2017, 2019, 2022, 2025
NORD gratefully acknowledges Jonathan J. Miner, MD, PhD, Associate Professor of Medicine, Drew Scoles, MD, PhD, Assistant Professor of Ophthalmology, and Samuel D. Chauvin, MD/PhD candidate, University of Pennsylvania Perelman School of Medicine, Taisuke Kato, PhD, Associate Professor, and Osamu Onodera, MD, PhD, Professor, Brain Research Institute, Niigata University, and David P. J. Hunt, MB BChir, PhD, Professor of Neuroinflammatory Medicine, University of Edinburgh, for the preparation of this report.
Summary
Retinal vasculopathy with cerebral leukoencephalopathy (pronounced: loo-ko-en-sef-uh-LAH-puh-thee) and systemic manifestations (RVCL or RVCL-S, previously called HERNS or CRV) is a rare genetic disease that damages small blood vessels, eventually leading to a severe illness in adulthood.
Symptoms of RVCL-S—including brain, eye, liver and kidney disease—typically become noticeable between ages 35 and 55, eventually resulting in neurological symptoms, strokes, eye disease leading to vision loss, memory problems and fatigue, followed by disability and premature death in all affected individuals. The brain and eye disease usually cause most symptoms, although multiple other organs are affected in RVCL-S. For example, chronic kidney disease of varying severity occurs in all people with RVCL-S and is associated with hypertension, although end-stage renal disease is very uncommon. Some people develop bone pain due to osteonecrosis and others may develop hypothyroidism or gastrointestinal bleeding. People with RVCL-S also appear to be at increased risk for injuries to large blood vessels, such as spontaneous aortic dissections or pseudoaneurysms with hemorrhage after femoral artery procedures.
RVCL-S is caused by variants in the TREX1 gene, which is the blueprint for the TREX1 protein, an enzyme that breaks down DNA when it leaks outside the cell’s nucleus. People with RVCL-S have a gene variant that makes a smaller than normal TREX1 protein, removing its anchor but maintaining its DNA-degrading activity. This allows a free-floating form of TREX1 to slip into the cell nucleus where it damages the cell’s DNA, ultimately causing organ damage that can mimic radiation injury in the brain. Females with RVCL-S also have heightened risk of early-onset breast cancer, another disease linked to DNA damage.
Recent research has focused on developing therapies for patients with RVCL-S.7 The development of novel therapies has been facilitated by research indicating how TREX1 variants damage cells to cause disease.6 This new understanding of RVCL-S is paving the way for custom, personalized therapies which are currently in development, offering hope to those living with this rare disease.
Introduction
In 1988, a team of doctors described a family with a mysterious illness, suffering from vision loss, memory problems and central nervous system issues (brain lesions) starting in middle age.1 Other families were subsequently identified2 and the disease was similarly rediscovered decades later by other physicians who referred to the disease by different names including HERNS3 and HVR.4 Today we understand that all of these researchers were describing the very same disease (RVCL or RVCL-S) which affects people of all races and nationalities and can be observed in any large population where genetic testing is routinely performed.
Major breakthroughs for RVCL-S include the following:
RVCL-S affects several organs and can result in a wide variety of symptoms depending on how organs are affected. Signs and symptoms typically emerge in mid-adulthood, often between ages 35 and 55. The disease attacks small blood vessels, causing progressive tissue damage as these vessels drop out over time, cutting off blood supply to vital areas.8 All people with RVCL-S eventually develop disease affecting the eyes, brain, liver and kidneys, progressively worsening as the damage accumulates. However, in some people the disease initially becomes apparent in the kidneys or the retina, while in other people the disease is first noticed in the brain or the liver. If treating physicians are attentive to multiple organs, damage affecting all of these sites (brain, retina, liver, kidney) is eventually detected as the disease progresses.
Vision loss is often the first sign of disease. People may notice floaters, blurry spots, or blind areas when retinal blood vessels leak or clog—a condition called retinal vasculopathy. This can lead to glaucoma, swelling, bleeding, or scarring in the back of the eye, sometimes causing permanent vision loss. To an ophthalmologist, the retinal disease appears highly similar to that of diabetic eye disease (diabetic retinopathy) or, in some people, occlusive vasculitis. It is therefore important for patients to undergo regular ophthalmological examinations. Prompt treatment can optimize visual outcomes.
People with RVCL-S universally develop brain lesions and atrophy due to cerebral small vessel disease and progressive brain injury. The term for this is “cerebral leukoencephalopathy” or white matter damage. Clinically, patients may have problems with headaches, memory, mood changes and confusion. Symptoms often start out mild and eventually become severe. Magnetic resonance imaging (MRI) of the brain can reveal “small vessel disease” in some patients, and large brain lesions or “pseudotumors” in others. Pseudotumors refer to a distinctive tumor-like swelling that on imaging can have the appearance of a brain tumor, but on biopsy shows inflammatory microvascular change. Swelling can occur around these pseudotumors which require glucocorticoid treatment. Patients with large pseudotumors sometimes develop seizures. Eventually, the brain lesions cause weakness in limbs, difficulty speaking, or even psychiatric disturbances like mood swings. Without a genetic test, patients are sometimes misdiagnosed as having multiple sclerosis, vasculitis (blood vessel inflammation), or suspected brain tumors.
Beyond the eyes and brain, RVCL-S also causes more generalized symptoms such as severe fatigue.8 Chronic kidney disease can contribute to swelling, high blood pressure, and sometimes gout. Liver disease rarely causes symptoms in people with RVCL-S but still requires monitoring. Many people with RVCL-S develop bone pain due to osteonecrosis—dead bone tissue. Some develop hypothyroidism (low thyroid function), Raynaud’s syndrome (blue, white and red discoloration of fingers), or intestinal bleeding due to abnormal blood vessels known as “arteriovenous malformations” (AVMs). Some people with RVCL-S have had aortic dissections and others have had pseudoaneurysms of the femoral artery after catheterization procedures, leading to hemorrhage and even death. This might be a consequence of disease affecting the blood vessel wall of large arteries. Females with RVCL-S also have a higher risk of early-onset breast cancer in their 20s or 30s.6 Therefore, some clinicians may suggest yearly breast MRIs for cancer screening adult females with RVCL-S.
RVCL-S is caused by specific variants in the TREX1 gene, which normally makes a protein (TREX1) that acts like a molecular housekeeper to clean up stray DNA in the wrong part of a cell. In RVCL-S, this variant cuts the gene’s instructions short, producing a shorter TREX1 protein that still functions, but in the wrong part of the cell.
Normally, the TREX1 protein stays in a specific part of the cell called the cytoplasm, which is like the main room where it can do its housekeeping job effectively. TREX1 breaks down abnormal DNA that has leaked into the cytoplasm where DNA should not be found. The shortened TREX1 protein drifts into the nucleus—the cell’s control center where DNA is stored, and damages the chromosomes, leading to organ damage. TREX1 being in the wrong place is the key to understanding RVCL-S. The protein is still active but in the wrong part of the cell.
Whether a TREX1 variant causes disease depends on the location of the change within the gene and type of TREX1 variant.9 Not all variants in TREX1 cause RVCL-S. Some variants in TREX1 cause no disease at all and other variants cause completely different diseases. Therefore, any person with a TREX1 variant should undergo consultation with an expert to help them determine whether their variant is meaningful or not.
RVCL-S follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Rarely, TREX1 variants can arise after conception in only a small portion of the embryo’s cells during early development—a phenomenon called mosaicism. Although infrequent, this is another way RVCL-S can appear unexpectedly in families.
RVCL-S affects both males and females of all races and nationalities. People with RVCL-S have been identified in many countries across the world—anywhere that genetic testing is routinely performed.
RVCL-S should be considered in middle-aged patients presenting with retinal microvascular abnormalities, cerebral pseudotumors, brain atrophy, or even smaller white matter lesions, including MRI evidence of small vessel disease of the brain. Since RVCL-S has an autosomal dominant inheritance pattern, a careful family history should be taken and considered. However, some people have de novo variants and are therefore the first in their family to be diagnosed. In many patients, brain MRIs reveals either large brain lesions such as pseudotumors, or other large white matter or periventricular lesions, often mistaken for multiple sclerosis or malignancy. In other patients, smaller brain lesions are predominant, often mistaken for age-related small vessel disease of the brain. On ophthalmological exam, retinal vasculopathy mimics diabetic eye disease.
Definitive diagnosis requires genetic testing of the TREX1 gene, with C-terminal frameshift or premature stop codons in a specific region being diagnostic for the disease.
Genetic counseling or consultation with a physician expert in RVCL-S is strongly recommended prior to testing to ensure that patients and families understand the potential diagnosis and its impact.
Treatment
Currently, there are no FDA-approved medications for the treatment of RVCL-S. However, when patients develop brain swelling (edema) or large brain lesions, very short-duration courses of glucocorticoids are sometimes prescribed to reduce brain swelling. This is typically prescribed only for a few weeks or months. Additionally, statin medications and anticoagulants are sometimes prescribed to help prevent stroke in patients with RVCL-S. Consultation with an expert physician in treating RVCL-S is recommended for all patients.
MRI scans do not expose patients to radiation and may be safer than CT scans for patients with RVCL-S. However, in the case of an emergency, CT scans are still important for rapidly obtaining key imaging data.
Monitoring and preventative care for RVCL includes:
Personalized medicines for RVCL-S are currently in pre-clinical development. Under the direction of RVCL-S experts at the University of Pennsylvania (Penn) and chemists at the University of Michigan, small molecule drugs are being developed to block the harmful activity of the abnormal TREX1 protein that causes RVCL-S. The goal is to begin clinical trials soon for these small molecule drugs. The RVCL research team at Penn has also developed gene therapies that fix the RVCL-S-causing TREX1 variant in mice, transforming the gene variant back into the normal version.7 Researchers in Scotland have also identified DNA damage in endothelial cells that line the blood vessel wall,10 making this cell type an important target for therapeutic intervention. However, it may still take years before gene therapies are ready for testing in humans. Small molecule drugs for the treatment of RVCL are anticipated to be ready for clinical trials in the very near future.
About a decade ago, a phase 1 clinical trial of aclarubicin was conducted in patients with RVCL-S. Those results were never formally reported in a medical journal. Aclarubicin is a chemotherapeutic agent that would be expected to cause DNA damage. Subsequent research revealed that chemotherapeutic agents cause excess DNA damage and injury in models of RVCL-S.6 Analysis of a single person’s imaging indicated significant disease progression while on aclarubicin.6 Since RVCL-S is associated with DNA damage, chemotherapeutic agents are not recommended for the treatment of RVCL-S.
A previous phase 2 clinical trial of crizanlizumab—a drug that keeps blood vessels open in sickle cell disease—failed to prevent progression of brain disease in people with RVCL-S.11 Although some suggested that crizanlizumab may hold promise, the drug’s effect on retinal disease was also unclear for several reasons. For example, some patients dropped out of the trial because of disease progression or died from RVCL-S despite having received the medication.11
For more information about RVCL-S and current research studies, please contact the RVCL Research Centers:
RVCL Research Center at the University of Pennsylvania Perelman School of Medicine in Philadelphia: https://www.med.upenn.edu/rvcl/
Jonathan Miner, MD, PhD: [email protected]
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
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