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Usher syndrome: for professionals


Overview

Prevalence
  • 4 – 17 in 100,000
Inheritance
  • Autosomal recessive
Genes involved (OMIM No.)Usher syndrome type 1Usher syndrome type 2Usher syndrome type 3
Symptoms
  • Nyctalopia
  • Peripheral visual field loss
  • Loss of central and colour vision in later life
Signs
  • Failed newborn hearing screen (Usher type 1 and 2)
  • Delayed speech development (Usher type 1)
  • Delayed motor development, independent walking age of >18 months (Usher type 1)
  • Difficulties with balance from birth (Usher type 1) or apparent later in life (Usher type 3)
  • Retinitis pigmentosa
Systemic features
  • Bilateral sensorineural hearing loss
  • Congenital, severe to profound (Usher type 1)
  • Congenital, mild to moderate in the low frequencies, and severe to profound in the high frequencies (Usher type 2)
  • Variable, progressive (Usher type 3)
  • Vestibular dysfunction (Usher type 1 and 3)
Key investigationsAuditory
  • Newborn hearing screen – otoacoustic emissions and automated auditory brainstem response
  • Pure tone audiometry
Ocular
  • Electrophysiology
  • Optical coherence tomography (OCT)
  • Fundus autofluorescence (FAF)
  • Kinetic perimetry
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal and deafness)
  • Whole exome sequencing
  • Whole genome sequencing
  • Targeted exome sequencing
ManagementAuditory
  • Cochlear implantation in Usher type 1 patients within first two years of life
  • Hearing aids fitting in Usher types 2 and 3 patients; cochlear implantation in later life if necessary
Ocular
  • Monitor visual field and visual acuity
  • Correcting associated refractive errors
  • Low vision aids
  • Monitor for cataracts and cystoid macular oedema
Therapies under research
  • Gene therapy (phase 1/2)
  • Antisense oligonucleotides (phase 1/2)
  • Stem cells (phase 1/2)
  • Nonsense suppression therapy (pre-clinical)
  • Non-viral gene therapy (pre-clinical)
  • Gene editing (pre-clinical)

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Clinical phenotype

Presenting features

Usher syndrome is a group of inherited disorders characterised by a combination of sensorineural hearing loss and retinitis pigmentosa (RP). It is categorised into three major clinical subtypes according to the severity and onset of hearing loss and whether vestibular dysfunction is present.[1] Atypical presentations have also been described.[2]

Usher type 1 patients exhibit severe to profound bilateral congenital sensorineural hearing loss, most frequently non-progressive, with vestibular areflexia.[3] In Usher type 2, the hearing loss is congenital and typically described as sloping, mild to moderate in the low frequencies, and severe to profound in the high frequencies.[4] Vestibular function is intact. In Usher type 3, hearing loss is of post-lingual onset and usually detected in the first decade of life. It is typically of a progressive nature, with audiograms showing high frequencies more affected or a U-shaped configuration. Vestibular abnormalities are present in approximately half of the patients.[5]

RP develops in all three Usher subtypes but with variable onset; Usher type 1 is most commonly pre-adolescent, with Usher 2 within the first two decades of life, and Usher 3 patients typically showing post-pubertal onset.[6,7] Typically, the first presenting symptom is night blindness (nyctalopia) with progressive visual field loss beginning in the mid-periphery caused by rod photoreceptor degeneration. It eventually progresses to central and colour vision loss over time resulting from cone photoreceptor degeneration.

Patients with Usher syndrome type 2 caused by USH2A have been found to show more visual field loss than patients with non-syndromic USH2A-related RP.[8]

Ocular features

The fundal findings of Usher syndrome may include:

  • Bone spicule pigmentation, retinal pigment epithelium atrophy or depigmentation
  • Optic disc pallor
  • Blood vessel attenuation
Multimodal imaging of a patient with biallelic USH2A variants. The fundal phenotype is of typical retinitis pigmentosa (A). There is a central ring of hyperautofluorescence on FAF imaging (B), demarcating the border between degenerated and preserved outer retinal layers (C)

Apart from the retinal changes, patients may develop cataracts as well which can lead to further visual deterioration.

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Genetics

At least 11 causative genes have been identified for Usher syndrome, encoding proteins with a diverse range of functions, including a number of scaffolding and cell adhesion proteins. Among these genes, MYO7A is the most common cause of Usher type 1 (>50% cases) and codes for an actin-binding motor protein, myosin VIIA. For Usher type 2, USH2A is the most frequent causative gene (~80% cases), encoding a large transmembrane protein called usherin.

Usher syndrome type 1

Usher syndrome type 2

Usher syndrome type 3

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

1) Electrophysiology

Full-field electroretinogram (ERG) can show reduction and delay in amplitudes (more prominent in rod-mediated responses than cones) in the early stages of disease. Later, the full-field ERG is often non-recordable.

2)  Fundus autofluorescence imaging (FAF)

FAF is performed to assess RPE integrity. A ring of hyperautofluorescence in the macula is often noted in patients with Usher syndrome-related RP.

3) Optical coherence tomography (OCT)

OCT can reveal loss of the outer retinal structure, initially sparing the fovea until late in the disease course. In addition, cystoid macular oedema can also be easily identified with OCT.

4) Kinetic perimetry

To establish baseline visual field and monitor disease progression.

Systemic

1) Hearing tests

Hearing loss in infants with Usher type 1 and type 2 is typically detected through the newborn hearing screen. These tests include otoacoustic emissions and automated auditory brainstem response. In children of a suitable age and adults, hearing function is assessed using pure tone audiometry.

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Diagnosis

Genetic testing should be undertaken to obtain a molecular diagnosis and direct future management.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (retinal and deafness)
  • Whole exome sequencing (WES)
  • Whole genome sequencing (WGS)
  • Targeted exome sequencing

Related links

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Management

1) Hearing loss management

  • For patients with Usher syndrome 1, the standard approach is to offer bilateral cochlear implants within the first two years of life, enabling the development of oral communication and open set speech perception.[3,9]
  • Patients with Usher syndrome 2 or 3 benefit from hearing aids, but cochlear implants may be required with progressive hearing loss.[10,11]

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.[12]

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2) Supportive ocular management

  • Correcting any refractive errors
  • Referral to low vision services
  • Monitoring for associated complications such as cataracts and cystoid macular oedema
  • Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
  • Encourage the use of assistive technology that may improve quality of life
  • UV protected sunglasses
  • Blue light screen protectors on mobile devices or computer screens*

*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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Optimisation of development

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 a multidisciplinary clinic in one 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.

Family management and counselling

Usher syndrome shows an autosomal recessive inheritance pattern. Parents who are both heterozygous carriers have a 50% chance of having offspring that are carriers and a 25% chance of having a child with Usher syndrome.

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

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Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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 in optimising patient management where both visual and audio-vestibular issues can be addressed simultaneously.

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Current research in Usher syndrome

1) Gene therapy

The first gene therapy trial for Usher syndrome evaluated sub-retinal injection of a recombinant equine infectious anaemia virus (EIAV)-based lentiviral vector for the delivery of MYO7A cDNA (UshStat) for treating patients with MYO7A-related Usher type 1 (NCT 01505062).[13] This phase 1/2a trial was terminated prematurely by the sponsor (Sanofi) after a review of its clinical development plans and priorities, 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).

2) Antisense RNA oligonucleotides (AONs)

AONs are small molecules that bind complementarily to their target messenger RNAs (mRNA) to block the transcription of a mutant allele or correcting splice defects at the pre-mRNA level.[14] A phase 1/2 clinical trial is currently ongoing for intravitreal injection of an AON candidate, QR-421a (ProQR), in patients with USH2A exon 13 variants (NCT 03780257). QR-421a has been designed to exclude the whole exon 13 in the USH2A mature mRNA transcript. Two of the most common USH2A mutations, c.2299delG p.(Glu767Serfs*21) and c.2276G>T p.(Cys759Phe), are located in exon 13 of this gene.

3) Nonsense suppression therapy

Nonsense suppression therapy is a new drug-based genetic treatment that can override the effect of nonsense mutations within the coding region of a gene. It promotes “read-through” of premature termination codons (PTC) during translation to continue protein production.

About 20-30% of Usher syndrome patients have nonsense mutations. Ataluren and designer aminoglycosides have shown to generate full-length functional protein in animal and cell models of Usher syndrome.[15-17] 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, reducing the risk of insertional mutagenesis
  • Do not have any viral components and therefore reduces any immune response
  • 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) Gene editing

One alternative approach to gene replacement is gene editing. In recent years, the CRISPR/Cas9 system has become highly popular for gene editing due to its efficiency and ease of use. This technique has been used for successful in vitro mutation repair in USH2A patient fibroblasts harbouring homozygous p.(Glu767Serfs*21) mutations[19], as well as patient-derived induced pluripotent stem cells (iPSCs) either homozygous for USH2A p.(Glu767Serfs*21) mutations or compound heterozygous for p.(Glu767Serfs*21) and p.(Cys759Phe).[20] Encouragingly, neither study reported off-target effects, which are unwanted mutations induced at DNA locations that show homology to the guide sequence.

CRISPR/Cas9-based editing shows huge promise for the treatment of inherited retinal dystrophies caused by a range of mutations, however ensuring the absence of off-target effects and a high level of editing efficiency in retinal cells will be essential for future investigations.

6) Cell-based therapy

Subretinal implantation of capsules containing human NT-501 cells that release ciliary neurotrophic factor (CNTF) has been trialled in patients with choroideremia and RP, including some with Usher type 2 and Usher type 3 (NCT 00447980 and NCT 01530659).

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Further information and support

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References

  1.  Cohen M, Bitner-Glindzicz M, Luxon L. The changing face of Usher syndrome: Clinical implications. Int J Audiol. Feb 2007;46(2):82-93
  2.  Nolen RM, Hufnagel RB, Friedman TB, et al. Atypical and ultra-rare Usher syndrome: a review. Ophthalmic Genet. Oct 2020;41(5):401-412
  3.  Pennings RJ, Damen GW, Snik AF, Hoefsloot L, Cremers CW, Mylanus EA. Audiologic performance and benefit of cochlear implantation in Usher syndrome type I. Laryngoscope. May 2006;116(5):717-22
  4.  Abadie C, Blanchet C, Baux D, et al. Audiological findings in 100 USH2 patients. Clin Genet. Nov 2012;82(5):433-8
  5.  Sadeghi M, Cohn ES, Kimberling WJ, Tranebjaerg L, Möller C. Audiological and vestibular features in affected subjects with USH3: a genotype/phenotype correlation. Int J Audiol. May 2005;44(5):307-16
  6.  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
  7.  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
  8.  Duncan JL, Liang W, Maguire MG, et al. Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity. Am J Ophthalmol. Nov 2020;219:87-100
  9.  Jatana KR, Thomas D, Weber L, Mets MB, Silverman JB, Young NM. Usher syndrome: characteristics and outcomes of pediatric cochlear implant recipients. Otol Neurotol. Apr 2013;34(3):484-9
  10.  Hartel BP, van Nierop JWI, Huinck WJ, et al. Cochlear Implantation in Patients With Usher Syndrome Type IIa Increases Performance and Quality of Life. Otol Neurotol. Jul 2017;38(6):e120-e127
  11.  Pietola L, Aarnisalo AA, Abdel-Rahman A, et al. Speech Recognition and Communication Outcomes With Cochlear Implantation in Usher Syndrome Type 3. Otol Neurotol. Jan 2012;33(1):38-41
  12.  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
  13.  Zallocchi M, Binley K, Lad Y, et al. EIAV-Based Retinal Gene Therapy in the shaker1 Mouse Model for Usher Syndrome Type 1B: Development of UshStat. PLoS One. Apr 4 2014;9(4)e94272
  14.  Collin RW, Garanto A. Applications of antisense oligonucleotides for the treatment of inherited retinal diseases. Curr Opin Ophthalmol. May 2017;28(3):260-266
  15.  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
  16.  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
  17.  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
  18.  Overlack N, Goldmann T, Wolfrum U, Nagel-Wolfrum K. Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination. Invest Ophthalmol Vis Sci. Jun 2012;53(7):4140-6
  19.  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
  20.  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 January 21, 2021

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