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Usher syndrome: for patients


Overview

Usher syndrome is an inherited condition that involves both hearing loss and visual loss caused by retinitis pigmentosa (RP). A proportion of patients also experience difficulties with their balance. Usher syndrome is a rare condition that affects around 4 – 17 in 100,000 people worldwide.[1]

The condition is categorised into three subtypes depending on the severity of hearing loss and whether there are any difficulties with balancing. The three subtypes are:

  • Usher syndrome type 1— severe to profound hearing loss and difficulties with balance from birth
  • Usher syndrome type 2— moderate to severe hearing loss from birth and normal balance
  • Usher syndrome type 3 (very rare compared to types 1 and 2)— the severity of hearing loss is variable but affected children tend to be born with normal hearing but start deteriorating gradually by puberty; Around half of the patients also experience some degree of difficulties with balance

All Usher syndrome patients are affected by RP, a type of inherited retinal dystrophy that primarily affects the normal function of rod photoreceptor cells in the retina. It causes a gradual but permanent visual impairment in both eyes. Patients tend to notice difficulties seeing in dim light/at night (night blindness) initially along with “blind spots” in their peripheral vision, causing them to bump into things. Later on, they will notice issues with their central vision (things appearing blurry/not able to read) and colour vision as the cones start to degenerate as well.

The age of onset and the severity of visual symptoms among patients are highly variable, but symptoms of RP tend to begin earliest in Usher syndrome type 1, usually before the age of 10 years, while it is more variable in type 2, ranging from adolescence up to early 20s.

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The condition

Symptoms

1) Hearing loss

Patients affected by Usher syndrome experience hearing loss in both ears, which varies depending on the type:

  • Usher type 1: Severe to profound hearing loss from birth
  • Usher type 2: Mild to moderate hearing loss in the low frequencies, and severe to profound in the high frequencies, from birth
  • Usher type 3: Variable and progressive hearing loss; Onset is usually after speech development

Hearing loss is caused by abnormalities in cells in the inner ear that are responsible for detecting sound, known as hair cells. Children with Usher type 1 affected by profound hearing loss usually receive cochlear implants within the first two years of life, whereas patients with Usher types 2 and 3 tend to benefit from conventional hearing aids, although cochlear implantation may be recommended later in life.

2) Problems with balancing

In addition to hearing, the inner ear also has another system, known as the vestibular system, that helps the body to maintain balance by sending signals to a part of the brain that controls movement, called the cerebellum.

Patients with Usher type 1 and approximately half of the patients with Usher type 3 experience difficulties with balancing due to dysfunction of the vestibular system. Children affected by Usher type 1 will encounter balance problems from a young age, which can lead to delayed motor development. The first sign that parents may notice is usually when their child struggles to sit upright around 6 months of age. Affected children usually do not walk independently before the age of 18 months, but this can be addressed with support from occupational therapists and physiotherapists. Usher type 3 patients are typically affected by balancing difficulties later on in life. Patients experiencing balancing issues are advised to be cautious when underwater swimming due to the risk of disorientation.

3) Visual

Patients with RP experience the following initial symptoms related to rod photoreceptor degeneration:

  • Night blindness and difficulty to adapt to dark/dim environments (impaired dark adaptation)
  • Blind spots in the peripheral vision causing them to bump into things appearing at either side of their vision. Over time, these blind spots gradually enlarge and constrict inwards towards the centre of their vision, eventually leaving a small area of central vision to see out of, like seeing through a tunnel (tunnel vision)
A person driving a car with normal peripheral vision is able to see the girl in a red dress on the left. If the driver has a loss of peripheral vision, the same girl is not noticeable.
Peripheral vision loss
Seeing from the perspective of someone with tunnel vision. The person can see buildings from a small central area of his/her vision but the side vision around the central area is blurry.
Tunnel vision

As the disease progresses, the cone photoreceptors start to degenerate as well, causing the central vision to become blurry or the image sharpness (known as visual acuity) reduced. These symptoms gradually deteriorate over time, leading to difficulties in everyday activities such as reading or watching TV. During this stage, patients may also notice that they cannot distinguish colours as clearly as before.

The age of onset of RP varies between the three Usher subtypes. Visual symptoms usually start before age 10 in Usher type 1 while it is more variable among patients with Usher type 2, ranging from adolescence up to early 20s. Usher type 3 patients typically experience visual symptoms after puberty.[2,3] Disease progression also differs between the clinical types; Usher type 1 patients generally show a more severe visual decline with age than those with Usher type 2.[4,5] However, these factors are highly variable among patients, even those from within the same family.

In addition, some of the following eye conditions may be present as well that can cause further visual deterioration:

  • Cataracts
  • Swelling of the macula due to leakage of the retinal blood vessels (cystoid macular oedema); up to 50% of RP patients are affected by cystoid macular oedema.
The pupil appears white due to an opaque lens.
Cataract

Cause

Changes in at least 11 genes have been associated with Usher syndrome, out of which the MYO7A and USH2A genes are the most common causes, leading to Usher type 1 and type 2 respectively. These 11 genes provide instructions to make proteins vital to the healthy development and functioning of both the inner ear hair cells and retinal cells. A defect in any of these genes disrupt the smooth working of the inner ear and retina, leading to problems with hearing, balance and vision.

Usher syndromeAssociated genes
Type 1MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2
Type 2USH2A, ADGRV1, WHRN
Type 3CLRN, HARS1

 Genes associated with the different types of Usher syndrome

How is it diagnosed?

1) Hearing tests

Hearing loss in infants with Usher type 1 and type 2 is usually detected through the newborn hearing screen. In children of a suitable age and adults, hearing function is assessed using a test called pure tone audiometry that is conducted in the audiology clinic.

2) Eye examination

An ophthalmologist is able to diagnose RP based on the presenting symptoms, clinical examination and the results of numerous investigations that assess the structure and function of the retina. When examining the retina, the ophthalmologist will look for typical features of RP, one of which is the presence of dispersed dark spots towards the outside areas of the retina as a result of photoreceptor degeneration.

The retina of a patient with mutations in the USH2A gene, displaying typical characteristics of retinitis pigmentosa. There are multiple linear "bone-spicule" like dark deposits around the peripheral retina.
The retinal appearance of a patient with mutations in the USH2A gene. There are multiple linear “bone-spicule” like dark deposits around the peripheral retina. This is a fairly typical appearance of retinitis pigmentosa. The eye lashes are obstruction the bottom part of the image

Patients also tend to undergo the following tests as part of their assessment:

  • Colour vision testing
  • Visual field testing to reveal the extent of peripheral vision loss. There are different methods for testing this according to the age of the patient, but it can be performed from as young as 6 years of age, although the results become more accurate with increasing age and competency. Patients are asked to respond or press a button when they detect flashing lights and a map of their visual field is created.
  • Optical coherence tomography (OCT), a camera that allows detailed visualisation of all the retinal layers and reveal abnormalities in the retinal structure if present; it is useful for monitoring disease progression and detecting the presence of macular oedema.
  • Autofluorescence imaging (FAF) is another camera that can visualise and assess the health of the retina; it is a useful tool to monitor disease progression together with OCT.
  • Electroretinogram (ERG)–an electrodiagnostic test to assess the overall function of the photoreceptor cells, which will help the ophthalmologist in diagnosing RP; ERG is not routinely carried out in subsequent follow-up appointments nor used for monitoring.

Genetic testing can help confirm the diagnosis by identifying mutations in one of the genes associated with Usher syndrome.

How is it inherited?

1) Autosomal recessive (AR) inheritance

In AR inheritance, two faulty copies of a gene are required to cause disease. Both parents are usually unaffected carriers (who only carry one faulty copy of the gene) while the patient inherits two faulty gene copies (one faulty copy inherited from each parent). This means that every newborn has the following risks regardless of gender:

  • 25% chance of being affected by Usher syndrome
  • 25% chance of being unaffected and not a carrier
  • 50% chance of being a carrier with no symptoms
If the mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
Autosomal recessive inheritance

If you or your child is affected by Usher syndrome, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

1) Cochlear implantation and hearing aids

To treat the hearing loss in patients with Usher type 1, which is apparent from birth, the standard approach is to receive cochlear implants in both ears within the first two years of life, allowing them to achieve oral communication and the ability to understand speech without visual clues. Patients with Usher types 2 and 3 benefit from conventional hearing aids, although cochlear implantation may be recommended later in life if hearing deteriorates further.

Given the increasing recognition of Usher syndrome among children, especially type 1, cochlear implants are now being fitted much earlier. Verbal communication tends to develop normally in these children. However, this may not be the case for many older patients, whom hearing loss was not detected earlier during their childhood due to limited awareness of Usher syndrome. Most of these patients use sign language to communicate instead. Among those who are severely visual impaired and not able to communicate with conventional sign language, hands-on signing is an alternative where both parties communicate by signing using each other’s hands.[6]

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2) Supportive visual measures

There is currently no approved treatment for RP associated with Usher syndrome at present but several clinical trials are ongoing. In the meantime, treatment is focused on alleviating symptoms and optimising remaining sight. These include:

  • Regular monitoring of visual function and prescribing glasses (if required) to optimise remaining vision
  • Referral to low vision services
  • Utilising visual aids and assistive technology to improve quality of life
  • Having a healthy diet consisting of fresh fruit and green leafy vegetables 
  • Using blue light screen protectors on mobile devices or computer screens*
  • Wearing hats/UV protected sunglasses and placing sunlight diffusers at the back window of cars to ease light sensitivity
  • Regular check-ups to monitor for other eye conditions frequently associated with RP such as cataracts and cystoid macular oedema

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

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3) Optimisation of development and educational support

Children with Usher syndrome are affected by hearing loss, progressive visual impairment and possibly balancing difficulties. As hearing and vision are equally important in normal childhood development and education, children affected by Usher syndrome should be referred to developmental paediatricians and advisory teaching services for children/adolescents with hearing loss and visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence.

Dual sensory clinics are now being established in some centres to improve the clinical experience of children with hearing and sight impairment. Patients are able to access the relevant specialists in one clinic visit, hence reducing the stress and burden associated with numerous, separate medical appointments. Such specialist clinics will promote faster and more accurate diagnosis through extensive genetic testing and detection of visual symptoms at an earlier stage.

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Current research in Usher syndrome

1) Gene therapy

Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins. A normal copy of the affected gene is “packaged” into a harmless virus which is then surgically injected into the retina (subretinal injection). This way, the affected retinal cells are maximally exposed to the viruses containing the normal gene.

The normal gene copy is packaged into a harmless virus, which is then injected below the retina through surgery. This allows maximum exposure of the photoreceptors to the injected therapy
Sub-retinal injection of gene therapy

The first gene therapy clinical trial for Usher syndrome evaluated the safety of subretinal injection of a treatment (UshStat) in patients with Usher type 1 caused by mutations in the MYO7A gene (NCT 01505062). This phase 1/2a trial was terminated prematurely as the trial sponsor decided to stop developing UshStat, and not because of safety concerns. A follow-on trial is ongoing to assess its long-term safety in patients who received UshStat (NCT 02065011).

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2) Antisense RNA oligonucleotides (AONs)

AONs are small molecules genetically engineered to correct a disease-causing genetic mutation. It is being investigated as a therapeutic option for specific changes in one of the most common Usher syndrome genes, USH2A.

The STELLAR trial (NCT 03780257) is studying an AON called QR-421a. It is injected intravitreally into patients with mutations in a particular region of the USH2A gene (exon 13). The most common mutations in USH2A causing Usher syndrome and isolated RP are both located in this region. So far, the interim analysis has shown promising results, so the treatments will continue to progress through testing. However, more extensive trials will be required and it will be a few years before this treatment could be generally available.

Injection of a drug into the clear jelly (vitreous) of the eye.
Intravitreal injection

3) Nonsense suppression therapy

Nonsense suppression therapy is a new drug-based treatment targeting conditions caused by nonsense mutations. A nonsense mutation introduces an abnormal “stop” signal into a gene that halts protein production prematurely, resulting in a protein which is too short and not functional. A drug called ataluren (Translarna™) modifies the affected cell to “ignore” these abnormal “stop” signals and produce normal full-length functioning protein.

About 20-30% of Usher syndrome patients have nonsense mutations. Ataluren and designer aminoglycosides (drugs traditionally used as antibiotics but have similar properties to Ataluren) have shown to generate full-length functional protein in animal and cell models of Usher syndrome.[7-9] However, it has not been studied in patients yet. If proven to be beneficial in clinical trials, ataluren could potentially offer a non-surgical alternative to gene therapy for Usher syndrome patients.

4) Non-viral gene therapy

The USH2A gene is the most common gene responsible for Usher syndrome. There is no effective treatment available. Viral gene therapy can only deliver genes of a limited size (>3 times smaller than USH2A), hence this is not a viable option. A non-viral gene delivery system, containing a human DNA element called scaffold/matrix attachment regions (S/MAR) to encase USH2A is being developed. S/MAR vectors have several benefits:

  • Capacity to hold large genes
  • Do not integrate into the patient’s DNA, thus reducing the risk of introducing cancer-related mutations
  • Do not have any viral components and therefore reducing any response from our own body’s immune system
  • Long-term gene expression (as long as 2 years has been noted in animal models)

Together this suggests that S/MAR vectors are safe and effective for gene delivery, and research is underway to assess this in the laboratory using human-derived retinal cells from an Usher syndrome patient with a USH2A mutation and zebrafish disease models. Non-viral S/MAR vectors may revolutionise the treatment of inherited retinal dystrophies by providing a safer and more applicable form of gene therapy.

5) CRISPR/Cas9 genome editing system

CRISPR/Cas9 (pronounced as “crisper”) stands for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. This system is a relatively new gene editing technique based on the immune system of bacteria.

It works like a pair of molecular “scissors”, where guided by specially designed markers, it can cut the abnormal section of a specific gene out and introduce the correct section. As a result, the affected cells will be able to produce the appropriate protein and function normally.

Research into CRISPR/Cas9 as a potential therapeutic option is mainly limited to cell models at the moment, where it has been shown to be able to correct the two most common mutations in the USH2A gene causing Usher syndrome type 2, although much work still has to be done before human trials can be considered.[10,11]

Related links

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Practical advice

Living with Usher syndrome

Patients are still able to lead independent lives through addressing the hearing loss, maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI), teachers for children with hearing loss (Teachers of the Deaf) and special educational needs co-ordinator (SENCO)
  • Utilising assistive technologies to improve quality of life and aid independence
  • Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

In addition, a referral to a dual sensory clinic (if available) such as the one in Great Ormond Street Hospital for Children in London can be very helpful as hearing, visual and vestibular issues can be addressed simultaneously by the relevant specialists in one clinic visit.

More information can be found in our “How to see a genetic eye specialist?” page.

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Further information and support

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A patient’s perspective

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References

  1.  Toms M, Pagarkar W, Moosajee M. Usher syndrome: clinical features, molecular genetics and advancing therapeutics. Ther Adv Ophthalmol. Jan-Dec 2020;12:2515841420952194
  2.  El-Amraoui A, Petit C. The retinal phenotype of Usher syndrome: Pathophysiological insights from animal models. Comptes Rendus Biologies. Mar 2014;337(3):167-177
  3.  Millan JM, Aller E, Jaijo T, Blanco-Kelly F, Gimenez-Pardo A, Ayuso C. An Update on the Genetics of Usher Syndrome. Journal of Ophthalmology. 2011 2011;417217
  4.  Testa F, Melillo P, Bonnet C, et al. CLINICAL PRESENTATION AND DISEASE COURSE OF USHER SYNDROME BECAUSE OF MUTATIONS IN MYO7A OR USH2A. Retina. Aug 2017;37(8):1581-1590
  5.  Blanco-Kelly F, Jaijo T, Aller E, et al. Clinical aspects of Usher syndrome and the USH2A gene in a cohort of 433 patients. JAMA Ophthalmol. Feb 2015;133(2):157-64
  6.  Skilton A, Boswell E, Prince K, Francome-Wood P, Moosajee M. Overcoming barriers to the involvement of deafblind people in conversations about research: recommendations from individuals with Usher syndrome. Res Involv Engagem. 2018;4:40
  7.  Goldmann T, Rebibo-Sabbah A, Overlack N, et al. Beneficial read-through of a USH1C nonsense mutation by designed aminoglycoside NB30 in the retina. Invest Ophthalmol Vis Sci. Dec 2010;51(12):6671-80
  8.  Goldmann T, Overlack N, Wolfrum U, Nagel-Wolfrum K. PTC124-mediated translational readthrough of a nonsense mutation causing Usher syndrome type 1C. Hum Gene Ther. May 2011;22(5):537-47
  9.  Goldmann T, Overlack N, Möller F, et al. A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol Med. Nov 2012;4(11):1186-99
  10.  Fuster-Garcia C, Garcia-Garcia G, Gonzalez-Romero E, et al. USH2A Gene Editing Using the CRISPR System. Molecular therapy Nucleic acids. Sep 15 2017;8:529-541
  11.  Sanjurjo-Soriano C, Erkilic N, Baux D, et al. Genome Editing in Patient iPSCs Corrects the Most Prevalent USH2A Mutations and Reveals Intriguing Mutant mRNA Expression Profiles. Molecular therapy Methods & clinical development. Jun 12 2020;17:156-173

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Updated on December 1, 2020

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