NORD gratefully acknowledges M. Kathryn Liszewski, PhD, Assistant Professor of Medicine and John P. Atkinson, MD, Samuel Grant Professor of Medicine and Molecular Microbiology, Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, for preparing this report.
Summary
Retinal vasculopathy with cerebral leukoencephalopathy (pronounced: loooko-encefa-LA-pathee) and systemic manifestations (RVCL-S) is a rare genetic disease that causes progressive loss of tiny blood vessels, ultimately resulting in visual deterioration and a series of mini-strokes in the brain. The initial symptoms of visual disturbance often begin in middle age years (35 to 45 years of age). Usually there also are mild clinical changes seen in the liver and kidneys. There is a life expectancy of 5 to 10 years following onset of symptoms. The gene responsible for causing RVCL-S, called TREX1, codes for the protein of the same name whose two primary functions are to repair DNA and to control a specific kind of sugar machinery within cells. A mutation in the tail end of TREX1 produces a shortened version of the protein that mislocalizes inside cells and in middle age leads to development of RVCL-S. The disease is an autosomal dominant disorder, so one copy of an abnormal TREX1 gene leads to the disease even though the other copy is normal. Diagnosis can be conclusively established by genetic testing of the TREX1 gene. Because of its rarity, this disease is often misdiagnosed as a brain tumor, multiple sclerosis, vasculitis or disease of unknown origin. This may lead to unnecessary and often hazardous diagnostic procedures such as multiple biopsies of the brain. Currently, there is no established preventative therapy or treatment albeit a clinical trial with an experimental drug is in progress.
Introduction
In 1988, physicians at Washington University School of Medicine in Saint Louis, Missouri described a large family having a unique type of genetic disorder that particularly damaged parts of the brain including the eyes during adult middle years. They called this syndrome cerebroretinal vasculopathy (CRV) [1]. In particular, deterioration of small blood vessels (the microvasculature) in the retina (back of the eye) was the predominant cause of the vision loss. Additionally, brain magnetic resonance imaging (MRI) revealed the family suffered from mini-strokes in a part of the brain called the “white matter.” In this American-Caucasian family of Northern European extraction, eight afflicted patients spanning three generations were identified. An unrelated Ashkenazi-Jewish family with the same set of symptoms and pathologic findings was reported a year later [1,2]. Since then, approximately 28 other unrelated families have been identified with 14 (~ 50%) of these unrelated families having the same mutation (called V235Gfs*6) [3,4, and Liszewski M.K. and Atkinson, J.P., unpublished].
In 1997, Dr. Joanna Jen (currently at Mount Sinai Hospital, New York, NY) described a family of Chinese descent (Taiwan) that could trace similar disease symptoms back three generations [5]. She named the disease HERNS (hereditary endotheliopathy with retinopathy, nephropathy and stroke). In 1990 and 1998 Dutch researchers published a report of a family with a similar disease, but with a history of migraine headaches [6]. They called the disease HVR (hereditary vascular retinopathy).
In 2007, these researchers entered into a collaboration that conclusively proved through modern day genetics that CRV, HERNS and HVR are the same disease. The name was changed to RVCL [7]. All affected members of RVCL families had mutations in the tail end of the gene TREX1. Since then several additional scientific reports have described other cases with mutations that all localize to the tail region of TREX1 [4,8-10].
Note that there are a number of different diseases that are caused by mutations in other areas of TREX1 [9]. However, the mutations that cause RVCL originate only in the tail segment of TREX1.
TREX1 is an important protein in the body. It serves as both a DNA sensor and sugar sensor. As a DNA sensor it cleans up and digests DNA debris that is generated when tissue is damaged or cells die and regenerate. TREX1 is also important for eliminating DNA derived from viruses that invade and infect human cells.
In 2015, a second function of TREX1 protein, as a sugar sensor, was discovered [11]. In this case, it serves to oversee the ‘sugar polishing’ step (i.e., glycosylation) for newly made proteins. These special sugars (called glycans) are added to newly made proteins to help with the protein’s functions and stability. TREX1 gene mutations produce an altered form of TREX1 protein that interferes with this step and allow a build-up of glycans that likely harms blood vessels. These studies also identified an anthracycline antibiotic (Aclarubicin) that partially corrected this ‘sugar’ defect in both mouse disease models and in human RVCL patient cells. Studies are underway to better understand and expand on these remarkable discoveries. Additionally, a human clinical trial utilizing Aclarubicin is underway (see Investigational Therapies below).
In 2016, collaborators from around the world prepared a comprehensive report analyzing clinical features on 78 patients from 11 unrelated families and renamed the disease to RVCL-S [3].
In 2018, researchers focused on identifying and characterizing TREX1 protein in the brain [12]. They found that TREX1 was localized to a specialized subset of cells (called microglia) and that TREX1 levels increased in brain areas affected by loss of blood vessels. Future studies clarifying the relationship of TREX1, microglia and small blood vessels in the brain may not only provide new understandings of how RVCL-S develops but also suggest new treatment strategies.
Hallmark symptoms of RVCL-S usually begin in middle age (~35-45 years) with eye issues such as an increasing number of “floaters” and “blind spots.” The main pathologic process of RVCL-S is that small blood vessels prematurely drop out; that is, deteriorate and disappear [3]. This leads to mini-strokes (or “micro-infarcts”) in tissues. The loss of blood supply affects both the eye (retina) and the brain (white matter) since these organs serve key functions and are sensitive to even small disruptions in blood flow. As more vessels drop out, there is development of increased vision loss and larger brain infarcts (or tumor-like lesions), especially if the mini-strokes are clustered.
Another study found systemic manifestations of the disease as well [3]. In a report detailing 11 unrelated families, five different mutations in the tail of the TREX1 gene were identified. Disease-related findings were similar across all mutations and families including visual loss, brain disease producing stroke-like symptoms, mental impairment, migraine, psychiatric disturbances and seizures. Additional systemic features included mild liver and kidney disease, anemia, high blood pressure, and, less commonly, mild Raynaud’s phenomenon and intestinal bleeding. These features likely arise primarily because small blood vessels progressively deteriorate in the organs (e.g., liver, kidney, skin, intestine).
Because RVCL-S is so rare and only recently recognized, it is often misdiagnosed as a severe type of multiple sclerosis, diabetic retinopathy, brain tumor, or vasculitis (inflammation of blood vessels).
However, the correct diagnosis can be definitively made to conclusively establish if the patient has the disease by genetic testing for mutations in the TREX1 gene on a small blood sample. However, prior to obtaining genetic testing, we highly recommend discussing with a genetic counselor who is familiar with RVCL-S.
Studies are being conducted at the RVCL Research Center at Washington University School of Medicine that follow disease progression. These are open to individuals of age 21 or over who have been genetically tested and shown to have a RVCL-S mutation.
A mutation in the TREX1 gene causes RVCL-S. The abnormal gene results in production of a truncated form of TREX1 protein.
Normal TREX1 protein is located inside cells in a network of ‘sacks’ or membranes called the endoplasmic reticulum (ER). The ER is attached to the nucleus of each cell and serves important roles in manufacturing and releasing proteins needed by the body. In RVCL-S, one copy of the TREX1 gene is normal, but one is mutated. These TREX1 mutations occur in the last one-fourth (i.e., the tail end) of the gene. This region codes for a part of the protein that is important for keeping it localized to the ER compartment. Mutations in this area allow the protein to drift out of the ER and mislocalize throughout the cell. In an unknown way, mislocalized TREX1 protein particularly affects and ultimately damages the lining of blood vessels and thereby disrupts brain and eye function.
RVCL-S is an autosomal dominant genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Autosomal refers to the gene being a non-sex chromosome. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, a dominant disorder could be due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
RVCL-S affects males and females with equivalent frequency and commonly begins in middle age (35-45 years). It is commonly first noticed as eye symptoms (increased ‘floaters’ or ‘blind spots’). Patients have been identified in a number of countries including the USA, Taiwan, Japan, the Netherlands, Germany, Switzerland, France, Mexico, Italy, Spain, Turkey and Australia. It has not been identified in Africans.
RVCL-S should be considered when a middle-aged individual has retinal and microvascular abnormalities and who has a family history of similar symptoms. The definitive work up is genetic testing for mutations in the TREX1 gene from a small blood sample. Mutations, especially in the tail region, conclusively establish if the patient has the disease. Additional testing may include a retinal exam and a brain MRI.
Treatment
There currently is no approved treatment for RVCL-S. Sometimes substantial brain edema may lead to a larger lesion and cause pressure on other parts of the brain. This edema has been reduced by steroid treatment. Additionally, the use of statins may be indicated upon consultation with a physician familiar with RVCL-S.
A clinical trial utilizing Aclarubicin infusion is in progress at Washington University School of Medicine in St. Louis, MO, USA. For more information about the clinical trial being conducted see https://clinicaltrials.gov/ct2/show/NCT02723448
For more specifics or to become part of the trial, contact:
Madonna Bogacki 314-362-8391 (mbogacki@wustl.edu)
Kathy Liszewski 314-362-0157 (kliszews@wustl.edu)
For more information about RVCL-S and research studies being conducted, contact the RVCL Research Center at Washington University School of Medicine in St. Louis:
https://rvcl-research.wustl.edu
M. Kathryn Liszewski kliszews@wustl.edu
John P. Atkinson, MD j.p.atkinson@wustl.edu
Jonathan J. Miner, MD jonathan.miner@wustl.edu
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: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
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/
JOURNAL ARTICLES
1. Grand MG, Kaine J, Fulling K, et al. Cerebroretinal vasculopathy: A new hereditary syndrome. Ophthalmology.1988;95:649-653.
2. Gutmann DH, Fischbeck KH, Sergott RC. Hereditary retinal vasculopathy with cerebral white matter lesions. Am J Med Genet.1989;34:217-220.
3. Stam AH, Kothari PH, Shaikh A, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain.2016;139:2909-2922.
4. Kolar GR, Kothari PH, Khanlou N, Jen JC, Schmidt RE, Vinters HV. Neuropathology and genetics of cerebroretinal vasculopathies. Brain Pathol. 2014;24(5):510-518.
5. Jen J, Cohen AH, Yue Q, et al. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology. 1997;49:1322-1330.
6. Terwindt GM, Haan J, Ophoff RA, et al. Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, mig
raine and Raynaud’s phenomenon. Brain. 1998;121 ( Pt 2):303-316.
7. Richards A, van den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nature Genetics. 2007;39(9):1068-1070.
8. Kavanagh D, Spitzer D, Kothari PH, et al. New roles for the major human 3′-5′ exonuclease TREX1 in human disease. Cell Cycle. 2008;7(12):1718-1725.
9. Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015;35(3):235-243.
10. Winkler DT, Lyrer P, Probst A, et al. Hereditary Systemic Angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy. J Neurol. 2008;255(1):77-88.
11. Hasan M, Fermaintt CS, Gao N, et al. Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation. Immunity.2015;43:463-474.
12. Kothari, PH, Kolar GR, Jen JC,Hajj-Ali R; Bertram P, Schmidt RE, Atkinson JP. TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia. Brain Pathology. 2018;28:806-821.
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