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Overview

X-linked retinoschisis (XLRS) is a genetic disorder that causes vision loss and begins in early childhood—the disease is sometimes called “juvenile retinoschisis” due to its early onset. As with other X-linked disorders, such as choroideremia, the condition occurs almost exclusively in males. Most cases of the disease involve a mutation of the RS1 gene, which is located on the X chromosome, and since males generally have two different kinds of chromosomes (XY), a single mutation of RS1 will lead to the disease. Females have two of the same kind of chromosome (XX), and as a result a spare version of RS1 on the additional X chromosome. In women, then, both copies of the gene must be mutated for the disease to manifest, which is significantly less likely. According to the National Institutes of Health, X-linked retinoschisis affects approximately 1 in 5000 to 1 in 25,000 men globally.[1]

The RS1 gene is responsible for the production of a protein called retinoschisin, which plays an important role in the health and functionality of the retina, the light-sensitive tissue at the back of the eye. Without enough retinoschisin, small splits or tears appear in the macula or along the outer edges of the retina (“retinoschisis” translates to “splitting of the retina”), often forming a wheel or spoke-like pattern that can make the retina abnormally thick. If tears appear in the macula, the central portion of the retina, central and high-acuity vision are impaired. If tears appear along the edges of the retina, on the other hand, peripheral vision is affected. Approximately half of those with X-linked retinoschisis experience a loss of central vision, the other half a loss of peripheral vision.

A minority of individuals with the disease do not have a mutated RS1 gene; for them, the genetic cause of the disorder is unknown. Work is underway to determine what genetic factors are at play in these cases.

Symptoms

The symptoms of X-linked retinoschisis are usually noticed around the time a boy enters public school. In families where the disease is inherited, early genetic testing is often done to secure a diagnosis. If there is a mutation in the RS1 gene, genetic testing is able to pinpoint it with a high degree of accuracy—approximately 95% of the time. The most common symptoms are a general loss of vision and difficulty seeing fine detail, especially in cases where the macula is damaged. Peripheral vision may be obscured in cases where the retina’s outer edges are damaged. Some boys may also have nystagmus (rapid involuntary movements of the eye from side to side) and strabismus (eyes turned in or cross-eyed). As a result, the disease is sometimes incorrectly diagnosed as amblyopia (lazy eye).

For affected boys, vision loss tends to stabilize around adulthood and remains at the same level until mid-life (50s or 60s). The disease rarely leads to the complete loss of vision, but it does entail an increased likelihood for developing serious eye complications, including retinal detachment and bleeding into the vitreous body of the eye. Although women are considerably less likely to experience symptoms when they carry a mutated copy of the RS1 gene, some are at a higher risk of experiencing some vision loss, particularly a loss of peripheral vision, later in life.

Diagnosis

An ophthalmologist may suspect retinoschisis after a simple eye exam, especially if a wheel-like pattern of splits is visible in the macular. Several tests can clarify and confirm a diagnosis:

• ERG (electroretinography): this is a test that measures the electrical responses of the retina to light, evaluating responses of both rod and cone photoreceptors. Although both rods and cones may be affected in people with RP, the most marked changes early in the disease are in the rod cells; this characteristic pattern helps diagnose the condition. The ERG test involves staying in a darkened room for 30 minutes, with drops put into the eye or eyes being tested. A special contact lens or gold-foil electrode is then placed on the eye or lower eyelid, and the eye is exposed to flashes of light.
• OCT (optical coherence tomography): this is an imaging technique that involves taking digital images of the various layers of the retina. The process uses light rather than sound or radio waves, which is why the images are in high resolution.
• Visual field test: this exam is designed to detect, measure, and monitor blind spots in vision. It involves looking into a device that emits flashes of light, with the patient asked to indicate which flashes can be seen. The flashes that are not seen are recorded. This gives a measure of how much vision is affected.
• Genetic counselling: while not a test in the traditional diagnostic sense, genetic counselling is an important part of the diagnostic process. It can help determine the gene or genes that have been mutated, as well as the hereditary factors that are involved.

READ OUR GENETIC TESTING PRIMER

Existing Treatments

Currently, there is no treatment or cure for X-linked retinoschisis. However, a gene therapy for a rare form of RP was approved by the FDA at the end of 2017 and is now on the market in the United States. Called Luxturna, it has the potential to halt vision loss and even restore some sight in individuals with a biallelic mutation of their RPE65 gene (manifesting as either RP or Leber congenital amaurosis). Though X-linked retinoschisis results from a mutation of the X-linked RS1 gene, not RPE65, the approval and emergence of Luxturna shows that similar gene therapies could be used to treat other genetic disorders in the future, including X-linked retinoschisis.

READ OUR STORY ABOUT THE APPROVAL OF LUXTURNA

Clinical Trials

With funding from FBC, a team of scientists led by Dr. Robert Molday at the University of British Columbia conducted crucial research into XLRS that paved the way for gene therapy trials that are currently underway.

Clinical trials are essential to the scientific process of developing new treatments: they test the viability and safety of experimental drugs and techniques, called “interventions,” on human beings. While there is no guarantee that enrolling in a clinical trial will provide any medical benefit, some patients do experience positive results after receiving experimental therapy.

READ OUR CLINICAL TRIALS GUIDE

The website clinicaltrials.gov is a centralized database of clinical trials that are offered globally. But as the disclaimer on the site’s home page states, there is no guarantee that a listed trial has been evaluated or approved—the National Institutes of Health runs the site but does not vet its content. This means that there could be bogus or dangerous trials listed that are preying on patients. It is essential that you discuss a clinical trial with your ophthalmologist before enrolling, and that you pay close attention to enrollment criteria.

If you are interested in exploring what is available on the site you can click on the button below, which will take you to clinicaltrials.gov and initiate a search for trials relevant for patients living with X-linked retinoschisis.

CLINICAL TRIALS FOR X-LINKED RETINOSCHISIS

Patient Registry

For individuals living with an inherited retinal disease (a disease caused by a genetic mutation), participation in a clinical trial could be a logical next step (for a description of clinical trials, see above). But in Canada, there is no centralized, guided mechanism for enrolling in a trial. With this in mind, Fighting Blindness Canada has developed a secure medical database of Canadian patients living with inherited retinal diseases. We call it the Patient Registry.

By enrolling in the Patient Registry, your information will become a part of this essential Canadian database that can be used to help connect you to a relevant clinical trial. The availability of relevant trials depends on a number of factors, so this tool provides no guarantees, but signing onto it will put you in a position to be connected to something appropriate. It is also a way of standing up and being counted: the more individuals enrolled in the Patient Registry, the better our chances of showing policymakers that there is a significant need for new treatments for inherited retinal diseases. The Patient Registry also helps to drive more sight-saving research!

You can begin the process of enrolling in the Patient Registry by clicking the button below.

PATIENT REGISTRY ENROLLMENT

Research Developments and Health Policy

Fighting Blindness Canada is committed to advancing the most promising sight-saving research, and has invested over $40 million into cutting-edge science and education since the organization was founded. Recognizing that science is tied to policy frameworks, FBC is also actively involved in health policy activities across Canada.

Many research groups are working to develop treatments and cures for XLRS. Experimental treatments can be divided into three broad categories:

• Protective Therapies
• Corrective Therapies
• Sight-Restoring Therapies

Protective therapies aim to stop (or at least slow) the damage caused by genetic mutations. These include treatments to stop the process of photoreceptor death (apoptosis), as well as cell-derived therapies that aim to help photoreceptors survive.

Corrective therapies aim to reverse the underlying genetic defect that causes vision loss. If these therapies are successful they might prevent a person who is treated when first diagnosed, from ever developing vision loss. Corrective therapies might also help slow the disease in people whose vision has already been affected, especially in the earlier stages. Gene therapies, which replace a non-functioning gene, are one type of corrective therapy. Several clinical trials of gene therapies for XLRS are underway.

Sight-restoring therapies are also a growing area of research success. These therapies are intended for people who have already lost all, or much, of their vision. Stem cell therapies aim to replace the retina’s lost photoreceptors. There are promising early results with stem cell trials involving other retinal degenerative diseases. Retinal prosthetics, such as the Argus II or “Bionic Eye,” use computer technology to generate vision. Fighting Blindness Canada helped to support the first Canadian trial of the Argus II and continues to work closely with health policy experts across Canada to ensure that patients who could benefit from the Argus II device have access to this innovative treatment. Drug and gene therapies are also being developed that may give non-photoreceptor nerve cells in the retina the capacity to sense light.

Thanks to our generous donors, we are funding ground-breaking research in these areas. Click on the button below to review the full list of FBC-funded projects:

FBC-FUNDED RESEARCH

Resources

Fighting Blindness Canada has developed additional resources that can be helpful in plotting an optimal path through vision care. Below is a link to our must-read resources, where you will find information on genetic testing, clinical trials, stem cell research, and more as well as a link to View Point (FBC’s virtual educational series).

MUST-READ RESOURCES

VIEW POINT: VIRTUAL EDUCATIONAL SERIES

Health Information Line

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References

[1] https://ghr.nlm.nih.gov/condition/x-linked-juvenile-retinoschisis#statistics

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Updated on August 23, 2018.