Usher Syndrome

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Overview

Usher syndrome is a genetic disorder characterized by the loss of both hearing and vision. It is the most common form of inherited deaf-blindness, accounting for approximately 50% of such cases and affecting somewhere between 4 to 17 out of every 100,000 individuals.[1] Named after Charles Usher, the Scottish ophthalmologist who first examined the disease’s pathology in detail, the syndrome results from a combination of retinitis pigmentosa (RP), which leads to gradual vision loss, and abnormalities in the inner ear, which lead to hearing loss. The inner ear abnormalities consist of damage to the sensory receptor cells—or “hair cells”—leading to what is referred to as “sensorineural” hearing loss. The structure of the inner ear, called the cochlea, is not able to detect sound and send the appropriate information to the brain.

Vision loss takes a similar form for patients with Usher syndrome: as in other forms of RP, the photoreceptor cells gradually die off and are no longer able to effectively send visual information to the brain. The rod photoreceptors typically die off first, resulting in a loss of the peripheral vision they are responsible for; this leads eventually to the loss of cone photoreceptors, which are responsible for central, high-acuity vision. The experience of vision loss for patients is often described as a progressively worsening form of tunnel vision.

The disease is subdivided into three types, with type 1 being the most severe and type 3 being least—a breakdown of symptoms associated with each type is provided below under “Symptoms and Diagnosis.” Mutations in at least six genes can lead to Usher syndrome type 1 (the most common being the genes MYO7A and CDH23); mutations in at least three genes can lead to type 2 (USH2A is the most common); and mutations in the CLRN1 gene leads to type 3.[2] In all cases, the mutations obstruct the production of proteins that are central to the development and function of cells that communicate information to the brain: in the case of hearing, hair cells, and in the case of sight, photoreceptors.

Content on this page was written by Dr. Chad Andrews and Dr. Mary Sunderland, and was most recently updated on August 23, 2018. An earlier version of the content was approved by Dr. Patrick Yang and Dr. Bill Stell.

Symptoms

There are three general types of Usher syndrome, each with varying degrees of severity in relation to hearing, vision, and balance:

TYPE 1

Hearing: Severe deafness in both ears from birth

Vision: Slow vision loss starts with loss of night vision usually in childhood

Balance: Balance problems from birth

TYPE 2

Hearing: Moderate to severe hearing loss from birth usually in higher frequencies

Vision: Slow vision loss starts with loss of night vision in late childhood or teens

Balance: No balance problems

TYPE 3

Hearing: No hearing loss at birth, but slow loss of hearing starting in childhood or teens

Vision: Timing and severity of vision loss vary, but most often night vision loss begins in teens

Balance: Minimal to no balance problems at birth, symptoms may get worse with age

Based on a table created by the US National Institute on Deafness and Other Communication Disorders (NIDCD).[3]

In general, parents of children with Usher syndrome often notice signs of limited hearing first, usually in the first few years of life. At this stage, vision loss is likely not apparent, though it may be possible to detect subtle changes with vision testing. When vision loss beings to be apparent, the first signs are the same as those in other forms of RP: first, the loss of night vision, followed by compromised peripheral vision and a gradual narrowing of one’s visual field.

Diagnosis

Early hearing loss can be detected and diagnosed with standard audiologic testing, which determines what frequencies of sound a child can hear, as well as how loud the sounds must be at these frequencies before they are audible. Children who are deaf or diagnosed with hearing loss can be screened for Usher syndrome in the following ways:

• ERG (electroretinography): this is a test that measures the electrical responses of the retina to light, evaluating responses of both rod and cone photoreceptors. 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.
• 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.
• 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.
• Balance tests: these can be used to measure a child’s balance and clarify the diagnosis.
• 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 CLINICAL TRIALS GUIDE

Existing Treatments and Standard of Care

Currently, there is no treatment or cure for Usher syndrome. 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 Usher syndrome results from a different set of mutations, none of which are RPE65, the approval and emergence of Luxturna shows that similar gene therapies could be used to treat other genetic disorders in the future, including Usher syndrome.

READ OUR STORY ABOUT THE APPROVAL OF LUXTURNA

Clinical Trials

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 an 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 Usher syndrome.

CLINICAL TRIALS FOR USHER SYNDROME

Patient Registry

For individuals living with an inherited retinal disease (a disease caused by a genetic mutation), such as Usher syndrome, 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 Usher syndrome. 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. Often protective therapies are not specific to one mutation, but may benefit people with different genetic forms of Usher syndrome. These include treatments to stop the process of photoreceptor death (apoptosis), as well as cell-derived therapies that aim to help photoreceptors survive.

Some protective therapies aim specifically to prevent the death of cone cells in Usher syndrome—and thus, the loss of central vision—in later stages of the disease.

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. The corrective therapies being developed now are specific to certain genetic forms of Usher syndrome.  Gene therapies, which replace a non-functioning gene, are one type of corrective therapy. Clinical trials of gene therapies and RNA therapies for several types of Usher syndrome are underway, and the results so far are encouraging.

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

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References

[1] https://www.nidcd.nih.gov/health/usher-syndrome

[2] https://ghr.nlm.nih.gov/condition/usher-syndrome#genes

[3] https://www.nidcd.nih.gov/health/usher-syndrome

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Updated on August 23, 2018