Usher Syndrome

Usher syndrome is a rare genetic condition that affects both hearing and vision. It is the most common genetic cause of combined deafness and blindness. People with Usher syndrome are born with or develop hearing loss, and they also experience a gradual loss of vision caused by an eye disease called retinitis pigmentosa (RP). In some cases, the condition can also affect a person's balance. The severity of the symptoms and when they start can vary, which is why the syndrome is divided into three main types (Type I, Type II, and Type III). The vision loss in Usher syndrome happens because the light-sensing cells in the back of the eye (the retina) slowly break down over time. This usually starts with difficulty seeing in the dark or in dim light, known as night blindness. As the disease progresses, people lose their side (peripheral) vision, creating a "tunnel vision" effect, and eventually, it can affect their central, detailed vision as well. The hearing loss is caused by problems with the tiny hair cells in the inner ear that help transmit sound to the brain. While there is currently no cure for Usher syndrome, early diagnosis is very important. Treatments like hearing aids or cochlear implants can significantly help with hearing and speech development, especially in children. For vision, regular eye exams are needed to manage complications like cataracts or swelling in the retina. Researchers are actively studying new treatments, including gene therapy, which hold promise for slowing down or stopping the progression of the disease in the future. Families are encouraged to work with a team of specialists, including eye doctors, audiologists, and genetic counselors, to manage the condition and maintain the best possible quality of life.

Condition category: Syndromic IRD

Prevalence: 1 in 10,000 to 1 in 30,000

Inheritance patterns: Autosomal Recessive

Age of onset: Congenital to childhood (Type I and II), or first to fourth decades (Type III)

Clinical overview: Usher syndrome is a rare, autosomal recessive genetic disorder characterized by the dual sensory impairment of sensorineural hearing loss and progressive vision loss due to retinitis pigmentosa (RP). It is the most common condition that affects both hearing and vision, representing a significant cause of hereditary deaf-blindness. The syndrome is clinically and genetically heterogeneous, with mutations in at least 13 different genes identified to date. These genes encode proteins that are essential for the structural integrity and function of sensory hair cells in the inner ear and photoreceptor cells in the retina. The condition is classically divided into three major clinical subtypes (Type I, Type II, and Type III) based on the severity and progression of the hearing loss, the presence or absence of vestibular dysfunction, and the age of onset of the retinal degeneration. Type I is the most severe, featuring profound congenital deafness, absent vestibular function, and early-onset RP. Type II is characterized by moderate-to-severe congenital hearing loss, normal vestibular function, and later-onset RP. Type III involves progressive hearing loss, variable vestibular dysfunction, and variable onset of RP. The clinical significance of Usher syndrome lies in its profound impact on a patient's ability to communicate, navigate their environment, and maintain independence. Early diagnosis is crucial for implementing appropriate interventions, such as cochlear implants and specialized educational programs, to maximize developmental outcomes. The condition is cataloged under multiple OMIM entries, including 276900 (Type I), 276901 (Type II), and 276902 (Type III), among others, and is recognized by Orphanet number ORPHA:886.

Patient and family guide: Usher syndrome is a rare genetic condition that affects both hearing and vision. It is the most common genetic cause of combined deafness and blindness. People with Usher syndrome are born with or develop hearing loss, and they also experience a gradual loss of vision caused by an eye disease called retinitis pigmentosa (RP). In some cases, the condition can also affect a person's balance. The severity of the symptoms and when they start can vary, which is why the syndrome is divided into three main types (Type I, Type II, and Type III). The vision loss in Usher syndrome happens because the light-sensing cells in the back of the eye (the retina) slowly break down over time. This usually starts with difficulty seeing in the dark or in dim light, known as night blindness. As the disease progresses, people lose their side (peripheral) vision, creating a "tunnel vision" effect, and eventually, it can affect their central, detailed vision as well. The hearing loss is caused by problems with the tiny hair cells in the inner ear that help transmit sound to the brain. While there is currently no cure for Usher syndrome, early diagnosis is very important. Treatments like hearing aids or cochlear implants can significantly help with hearing and speech development, especially in children. For vision, regular eye exams are needed to manage complications like cataracts or swelling in the retina. Researchers are actively studying new treatments, including gene therapy, which hold promise for slowing down or stopping the progression of the disease in the future. Families are encouraged to work with a team of specialists, including eye doctors, audiologists, and genetic counselors, to manage the condition and maintain the best possible quality of life.

Symptoms and clinical features: The clinical presentation of Usher syndrome is characterized by the hallmark symptoms of sensorineural hearing loss and retinitis pigmentosa, with the timing and severity varying by subtype. In the early stages, particularly in Type I, infants present with profound congenital deafness and absent vestibular function, which manifests as delayed motor milestones (e.g., late sitting and walking). In Types II and III, hearing loss is moderate to severe, but motor development is typically normal. The earliest visual symptom across all types is nyctalopia (night blindness), which often begins in the first decade of life for Type I and the second decade for Types II and III, as rod photoreceptors begin to degenerate. During the intermediate stages, the retinal degeneration progresses to involve the peripheral visual field. Patients develop a mid-peripheral ring scotoma that gradually expands, leading to significant constriction of the visual field, commonly referred to as "tunnel vision." In Type III, hearing loss also progressively worsens during this stage, and vestibular dysfunction may become apparent. Patients may begin to experience difficulties with mobility and orientation, especially in low-light conditions, and may require the use of mobility aids. In the advanced stages of the disease, the degeneration extends to the cone photoreceptors in the macula, leading to a decline in central visual acuity and color vision. This typically occurs in early adulthood for Type I and later in adulthood for Types II and III. Many patients eventually progress to severe visual impairment or legal blindness. Complications such as early-onset cataracts and cystoid macular edema can further compromise vision in these later stages. The profound dual sensory loss in the advanced stages necessitates comprehensive supportive care and significant lifestyle adaptations.

Molecular pathology: The molecular pathology of Usher syndrome centers on the dysfunction of a specialized protein network essential for the development and maintenance of sensory cells in both the inner ear and the retina. In the inner ear, Usher proteins (such as myosin VIIa, harmonin, cadherin-23, protocadherin-15, and sans) interact to form the tip links and lateral links of stereocilia on hair cells. These links are crucial for the proper organization, structural integrity, and mechanotransduction of auditory signals. Mutations in these genes disrupt the formation and stability of the stereocilia bundles, leading to congenital or progressive sensorineural hearing loss and, in some cases, vestibular dysfunction. In the retina, the Usher protein network is localized to the periciliary membrane complex (PMC) at the connecting cilium of photoreceptor cells. This complex acts as a vital diffusion barrier and transport hub between the inner and outer segments of the photoreceptors. Proteins like usherin, ADGRV1, and whirlin are integral to the structural stability of the PMC. Mutations in these genes compromise the integrity of the connecting cilium, impairing the intracellular transport of essential molecules, such as opsins, to the outer segment. Additionally, the MYO7A gene encodes myosin VIIa, an actin-based motor protein that plays a critical role in the retinal pigment epithelium (RPE). Myosin VIIa is responsible for the transport of melanosomes and the proper localization of visual cycle proteins. Defects in MYO7A disrupt these transport mechanisms, impairing visual pigment regeneration and phagocytosis of shed photoreceptor outer segments. The combined structural and transport defects caused by Usher gene mutations ultimately lead to the progressive degeneration and apoptosis of photoreceptor cells, manifesting clinically as retinitis pigmentosa.

Genetics: Usher syndrome is inherited in an autosomal recessive manner and exhibits significant genetic heterogeneity, with at least 13 genes and 16 loci identified across the three clinical subtypes. Usher syndrome Type I is caused by mutations in six known genes: MYO7A (USH1B), USH1C (harmonin), CDH23 (USH1D), PCDH15 (USH1F), USH1G (SANS), and CIB2 (USH1J). Mutations in MYO7A are the most common cause of Type I, accounting for up to half of the cases, followed by CDH23 and PCDH15. Usher syndrome Type II is associated with mutations in three genes: USH2A (usherin), ADGRV1 (GPR98/USH2C), and WHRN (DFNB31/USH2D). Mutations in the USH2A gene are the most frequent cause of Usher syndrome overall, responsible for up to 85% of Type II cases. Usher syndrome Type III is primarily caused by mutations in the CLRN1 (USH3A) gene, with mutations in PDZD7 also implicated in atypical or digenic forms of the disease. Genotype-phenotype correlations in Usher syndrome can be complex. While null or truncating mutations typically result in the classic, severe syndromic phenotypes, missense mutations in the same genes can lead to milder, atypical presentations or even nonsyndromic deafness (e.g., DFNB12 from CDH23 mutations) or nonsyndromic retinitis pigmentosa (e.g., from certain USH2A mutations). Digenic inheritance and the presence of modifier genes further contribute to the phenotypic variability observed among patients.

Diagnostic evaluation: Clinical diagnosis of Usher syndrome involves a comprehensive audiological, vestibular, and ophthalmological evaluation. Audiological testing includes pure tone audiometry and assessment of speech perception to determine the severity and progression of sensorineural hearing loss. Vestibular function is assessed using rotary chair testing, calorics, electronystagmography, and computerized posturography to differentiate between the subtypes, as Type I presents with absent vestibular function, Type II with normal function, and Type III with variable dysfunction. Ophthalmological workup is critical for identifying retinitis pigmentosa. Fundoscopy typically reveals characteristic signs such as intraretinal pigment migration (bone spicules), attenuated retinal vessels, and optic disc pallor. Visual field testing (Goldmann perimetry) is used to detect progressive peripheral visual field loss, which often begins as a ring scotoma. Full-field electroretinography (ERG) is essential for assessing retinal function, typically showing early loss of rod function followed by cone dysfunction, and changes can often be detected before overt fundoscopic signs appear. Spectral-domain optical coherence tomography (SD-OCT) is utilized to evaluate the structural integrity of the photoreceptor layers and to monitor for complications such as cystoid macular edema, which occurs in a significant portion of patients. Definitive diagnosis relies on genetic testing to identify pathogenic variants in known Usher syndrome genes. Single-gene sequencing (e.g., MYO7A for Type I) or multigene panels covering all known loci are standard approaches. If these fail, comprehensive genomic testing may be employed. Differential diagnosis includes other syndromic and nonsyndromic causes of hearing and vision loss, such as Alström syndrome, Bardet-Biedl syndrome, Refsum disease, and nonsyndromic retinitis pigmentosa or hearing loss. Careful clinical phenotyping combined with molecular diagnosis is necessary to distinguish Usher syndrome from these overlapping conditions.

Differential diagnosis: Differential diagnosis of Usher syndrome includes: (1) Nonsyndromic retinitis pigmentosa with coincidental hearing loss — no genetic linkage between the two conditions; separate genetic etiologies. (2) Refsum disease — RP with hearing loss plus elevated phytanic acid, polyneuropathy, cerebellar ataxia, and ichthyosis. (3) Cockayne syndrome — pigmentary retinopathy with hearing loss, dwarfism, photosensitivity, and progressive neurodegeneration. (4) Kearns-Sayre syndrome — pigmentary retinopathy with hearing loss, progressive external ophthalmoplegia, and cardiac conduction defects. (5) Alström syndrome — cone-rod dystrophy with hearing loss, obesity, cardiomyopathy, and insulin resistance. (6) CHARGE syndrome — coloboma, heart defects, choanal atresia, retardation, genital/ear anomalies. (7) Waardenburg syndrome — sensorineural hearing loss with pigmentary anomalies but no retinal dystrophy. (8) Mitochondrial disorders — variable hearing loss and retinal findings with systemic features.

Natural history: The natural history of Usher syndrome varies significantly depending on the clinical subtype. In Usher syndrome Type I, patients are born with profound sensorineural hearing loss and absent vestibular function, which typically leads to delayed motor milestones, such as walking independently only after 18 months of age. The onset of retinitis pigmentosa occurs early, often within the first decade of life, presenting initially as night blindness (nyctalopia). Visual field loss progresses steadily, leading to severe visual impairment or legal blindness by early adulthood. Usher syndrome Type II is characterized by congenital, moderate-to-severe hearing loss that is generally non-progressive, and normal vestibular function, allowing for normal motor development. The onset of retinitis pigmentosa in Type II typically occurs later than in Type I, usually during the second decade of life (adolescence). Visual acuity is often preserved longer, sometimes into the third or fourth decades, although peripheral vision progressively constricts. Usher syndrome Type III presents with progressive hearing loss that typically becomes evident in the first decade of life and worsens over time. Vestibular function is variable, with some patients developing progressive dysfunction. The onset of retinitis pigmentosa in Type III is also variable, generally beginning in the second to fourth decades of life. The rate of visual decline in Type III can be unpredictable, but it ultimately leads to significant visual impairment similar to the other subtypes.

Management and treatment research: ### Current management and supportive care There is currently no cure for Usher syndrome. Care focuses on preserving remaining vision and hearing, supporting communication and independence, and treating complications of retinal degeneration. Management should be individualized because hearing loss, balance difficulties, and retinal disease vary among Usher types and among individuals. - **Hearing and communication:** Hearing aids may help people with usable hearing. Cochlear implants can provide access to sound for many people with severe to profound hearing loss, including children with Usher syndrome type 1. Audiology care, speech and language services, sign language, captioning, and assistive listening technology can support communication. - **Balance and mobility:** Vestibular, or inner-ear balance, problems are especially common in Usher syndrome type 1. Physical therapy, occupational therapy, and orientation and mobility training can help with balance, fall prevention, and independent travel. - **Eye care:** Regular care with an ophthalmologist experienced in inherited retinal diseases can monitor retinitis pigmentosa and address complications such as cataracts or cystoid macular edema, a fluid-related swelling in the central retina. Cataract surgery and carbonic anhydrase inhibitors may be considered for selected people with macular edema. - **Low-vision rehabilitation:** Low-vision specialists can recommend magnifiers, electronic reading devices, lighting and contrast strategies, mobility tools, and school or workplace accommodations. - **Genetic testing and counseling:** Genetic testing can identify the responsible gene, clarify the Usher subtype, inform family planning, and help determine eligibility for gene-specific research. Vitamin A and other nutritional supplements are not routinely recommended as treatments for Usher syndrome because benefits are uncertain and some supplements may pose risks. ### Approved therapies There are no FDA-approved treatments that stop or reverse the retinal degeneration of Usher syndrome. Hearing devices, cochlear implants, rehabilitation services, low-vision support, and treatment of eye complications remain central to care. ### Investigational therapies #### RNA therapy for USH2A-related disease - **Ultevursen** is an antisense oligonucleotide, an RNA-based medicine designed to alter how genetic instructions are processed. It is being studied for retinitis pigmentosa caused by disease-causing changes in **exon 13 of the USH2A gene**. Given by injection into the eye, it is designed to skip exon 13 and allow production of a shorter usherin protein. A Phase 2 study is active but not recruiting (NCT06627179). A long-term safety study is not yet recruiting (NCT07796646). #### Gene therapy for Usher syndrome type 1B - **AAVantgarde MYO7A** is a dual-vector gene therapy for **MYO7A-related Usher syndrome type 1B**. Because the MYO7A gene is too large for one standard adeno-associated virus (AAV) vector, the treatment uses two AAV vectors to deliver the gene sequence to photoreceptor cells. A Phase 1/2 study is recruiting (NCT06591793). #### Neuroprotective and small-molecule approaches - **N-acetylcysteine amide (NACA)** is an oral antioxidant designed to reduce oxidative damage to photoreceptors. A Phase 1/2 study in Usher syndrome has been completed (NCT04355689). - **BF844** is a small molecule studied for **Usher syndrome type 3**. It is intended to stabilize altered clarin-1 protein and prevent its degradation. Its Phase 1 study has been completed (NCT05882006). - **NPI-001** is being evaluated in two Phase 3 trials for preservation of photoreceptors in retinitis pigmentosa associated with Usher syndrome. These trials are not yet recruiting (NCT07710196 and NCT07290530). #### Cell-based approaches - **OpCT-001** uses photoreceptor precursor cells made from induced pluripotent stem cells (iPSCs), which are cells reprogrammed to become retinal cells. The cells are delivered beneath the retina with the goal of replacing degenerated photoreceptors. A Phase 1/2 study in adults with primary photoreceptor disease is recruiting (NCT06789445). - **jCell** uses human retinal progenitor cells injected into the eye. These cells are intended to release factors that may support surviving photoreceptors. A Phase 2 study has been completed (NCT03073733). ### Clinical trial participation Clinical trials may be an option for some people with Usher syndrome, particularly when genetic testing identifies a relevant gene or mutation. Eligibility can depend on the Usher subtype, genetic result, age, amount of remaining retinal function, and other health factors. Some studies track disease progression rather than test a treatment. For example, an USH2A-related retinal degeneration natural-history study is active but not recruiting (NCT03146078). An inherited retinal degenerative disease registry is recruiting (NCT02435940). Participation may involve additional visits and testing and does not guarantee benefit. A retinal specialist, audiologist, or genetic counselor can help determine whether a study may be relevant.

Outlook: The prognosis for individuals with Usher syndrome involves a progressive decline in visual function, ultimately leading to severe visual impairment or legal blindness in most cases. The rate of progression varies by subtype, with Type I generally having the earliest onset and most rapid progression of visual field loss, while Types II and III may retain central visual acuity into later adulthood. Hearing loss is profound and congenital in Type I, moderate-to-severe and stable in Type II, and progressive in Type III. Quality of life is significantly impacted by the dual sensory loss, requiring substantial adaptations for communication, mobility, and daily living. However, early interventions, such as cochlear implantation for hearing loss and specialized educational and orientation/mobility training, can greatly improve developmental outcomes and independence. While the retinal degeneration is currently incurable, ongoing clinical trials in gene and RNA therapies offer hope for future treatments that may stabilize or restore vision.

Epidemiology: Usher syndrome is a rare genetic disorder with an estimated prevalence of approximately 3 to 6.2 cases per 100,000 individuals worldwide. It is the most common cause of hereditary combined deafness-blindness, accounting for about 50% of such cases. Among individuals with congenital deafness, Usher syndrome is responsible for 3% to 10% of cases, and it accounts for up to 18% of all retinitis pigmentosa cases. The prevalence and distribution of the three clinical subtypes vary significantly among different populations due to founder effects. Type I is particularly prevalent among individuals of Ashkenazi Jewish and French Acadian descent. Type II is the most common form globally, comprising up to 85% of all Usher syndrome cases. Type III is the rarest overall, accounting for only about 2% of cases worldwide, but it is notably more frequent in the Finnish population and among Ashkenazi Jews.

Selected references: 1. Yan D, Liu XZ. Genetics and pathological mechanisms of Usher syndrome. J Hum Genet. 2010;55(6):327-335. PMID: 20379205 2. Koenekoop RK, Arriaga MA, Trzupek EA, et al. Usher Syndrome Type I. 1999 Dec 10 [Updated 2020 Dec 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301442 3. Koenekoop R, Arriaga M, Trzupek E, et al. Usher Syndrome Type II. 1999 Dec 10 [Updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301515 4. Delmaghani S, El-Amraoui A. The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification. Hum Genet. 2022;141(4):709-735. PMID: 35353227 5. Toms M, Burgoyne T, Patel A, et al. Usher syndrome: clinical features, molecular genetics and advancing therapeutics. Ther Adv Ophthalmol. 2020;12:2515841420952194. PMID: 32974552 6. Castiglione A, Möller C. Usher Syndrome. Audiol Res. 2022;12(1):42-65. PMID: 35076461 7. Leong YC, Li Z, Chen S. Molecular pathology of Usher 1B patient-derived retinal organoids at single-cell resolution. Stem Cell Reports. 2022;17(11):2426-2441. PMID: 36240769 8. Fuster-García C, García-Bohórquez B, Pelayo-García L, et al. Expanding the Genetic Landscape of Usher-Like Phenotypes. Invest Ophthalmol Vis Sci. 2019;60(10):3556-3566. PMID: 31419302