What is RVCL? (also known as RVCL-S, CRV, or HERNS)

What does RVCL stand for?

• RVCL or RVCL-S stands for Retinal Vasculopathy with Cerebral Leukoencephalopathy (and Systemic manifestations), also known as retinal vasculopathy with cerebral leukodystrophy, cerebroretinal vasculopathy (CRV), or hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Other abbreviations also have been used, including CHARIOT and HVR.

• The name of the disease is explained as follows:

  • Retinal = relating to the retina or the portion of the eye that senses light and sends images to the brain

  • Vasculopathy = blood vessel disease

  • Cerebral = brain

  • Leukoencephalopathy = white matter disease

  • Systemic manifestations = an all-encompassing term reflecting the fact that patients with RVCL also develop kidney, liver, and sometimes also gastrointestinal, thyroid, and bone disease. Thus, RVCL is not just a disease of the brain and the eye.  It is truly a multi-system disease.

How is RVCL inherited?

RVCL is caused by mutations in a gene called TREX1, which is found on chromosome 3. RVCL is inherited in a autosomal dominant pattern, which means that about half of family members are affected.

Each affected individual has a 50% chance of passing the disease to each child. Every person has two copies of the TREX1 gene, one copy inherited from each parent.  Patients with RVCL have one normal copy of TREX1, and one mutated copy of TREX1. Only one copy of TREX1 is passed to the next generation, which is why there is a 50% chance of passing the disease to each child.

If you would like to find out about a procedure called pre-implantation genetic testing, you can read more about this on the "Finding a Cure" section of our web site.  Pre-implantation genetic testing is a procedure that allows couples to perform in vitro fertilization and then choose embryos without the TREX1 mutation for transfer to the uterus. If you have questions, you can contact us directly.

What is the TREX1 gene?

Each gene is the blueprint for a protein, and proteins are the machinery that make the human body work.  The TREX1 gene encodes the TREX1 protein. Normally, the TREX1 protein is attached to a membrane inside the cell. In patients with RVCL, one copy of TREX1 is abnormally shortened because of the mutation.  This causes the TREX1 protein to float freely in the cell, rather than being anchored to the membrane. Mislocalization of the TREX1 protein somehow causes cellular damage and disease. The exact mechanism remains to be defined, but therapies targeting the mutated TREX1 gene and protein are currently in development.

Diagnosis

RVCL is diagnosed based on a specific set of TREX1 gene mutations.

The mutations that cause RVCL are in a specific region of the TREX1 gene.  Other mutations in TREX1 can cause a other diseases, but all the mutations that cause RVCL are within a specifically defined region.

Unfortunately, many patients with RVCL are not genetically tested, and those patients can end up being diagnosed as having multiple sclerosis, brain tumors, lupus, or vasculitis.  Those diseases are much more common than RVCL. Since most physicians have not heard of RVCL, they often presume that patients with RVCL have one of these more common diseases. Genetic testing, which should only be performed under the direct guidance and support of expert physicians and genetic counselors, can be used to accurately diagnose RVCL.

We are hoping to raise awareness of RVCL so that more patients can receive the correct diagnosis. However, before genetic testing, it is important to consult with expert physicians and a genetic counselor with expertise in RVCL. Our team can help with this process.

Symptoms

Early symptoms

Most patients with RVCL are generally healthy until around age 40-50.  Occasionally, patients with RVCL develop symptoms earlier or later in life.  Early symptoms can include Raynaud’s syndrome (fingers changing color in the cold), blind spots, or small strokes. Many patients develop fatigue, partial loss of vision, or memory problems. Other patients develop kidney, thyroid, or liver abnormalities earlier in the course of disease.

Vasculopathy and organ damage in RVCL

One major process underlying RVCL is related to loss of small blood vessels. (Vasculopathy means “disease of the blood vessels.”) Loss of blood flow leads to progressive organ damage. Examples of organ damage in RVCL include chronic kidney disease, loss of blood flow to the retina leading to blindness or glaucoma, and strokes leading to neurological symptoms. Sometimes new symptoms can arise suddenly (e.g., glaucoma or strokes), but usually the disease is slowly progressive over the course of many years.

Impact of RVCL on the brain

Brain imaging typically shows disease of the white matter, including large brain lesions in about 1/3^rd of patients, and smaller brain lesions in about 2/3^rds of patients. Patients with RVCL also develop brain atrophy, which was recently characterized in a study by our colleague, Dr. Andria Ford of Washington University. Progressive brain injury caused by RVCL is usually associated with memory problems or other neurological symptoms like weakness, numbness, or stroke-like symptoms.

Physicians who monitor patients with RVCL typically perform eye exams with careful imaging of the retina, physical exams, cognitive testing, and brain imaging every 6 months, as well as blood work to monitor liver and kidney function every 3-6 months.

Treatment

We are committed to supporting patients and families with RVCL. We are conducting longitudinal studies as well as multiple clinical trials.  Currently, we have a clinical trial of Crizanlizumab for RVCL at University of Pennsylvania, and in collaboration with our colleagues at Washington University. 

Crizanlizumab  targets a protein called P-selectin, which captures blood cells and can contribute to blockages in small blood vessels.  Crizanlizumab is already FDA-approved for another disease associated with blockages in small blood vessels.  We are also developing novel therapies.  You can click here to read more about our search for a cure.

Please contact us if you would like to be connected with an expert physician.  Please do not include any confidential or protected health information in email messages.

In this interview with Rheumatology Advisor, Dr. Miner of Penn Medicine tells the story of RVCL, including the impact of rare disease research on patients and families. 

*Shared with permission from Rheum Advisor podcast.