Usher syndrome (USH) is a rare genetic disorder characterized by progressive vision loss and sensorineural hearing loss (SNHL). Some cases also involve vestibular dysfunction. It was first reported by Albrecht von Graefe in 1858, and Scottish ophthalmologist Charles Usher clarified its hereditary nature 1).
In Japan, it is designated as one of the specified intractable diseases (110 diseases under the Intractable Disease Act) separately from RP. The prevalence in Japan is approximately 6.7 per 100,000 people, within the global estimated prevalence range of 4–17 per 100,000 1).
USH accounts for over 50% of cases with hereditary hearing and vision loss and is involved in 3–6% of congenital hearing loss 1). In the United States, the estimated incidence is about 1 in 23,000 people.
USH follows an autosomal recessive inheritance pattern, and its incidence is higher in populations with more consanguineous marriages 2). To date, 13 causative genes and 16 genetic loci have been identified.
Clinically, it is classified into three major subtypes, and more recently USH4 has been proposed 1).
| Type | Hearing loss characteristics | Vestibular function | Onset of RP |
|---|---|---|---|
| USH1 | Congenital, severe to profound | Absent | Around age 10 |
| USH2 | Congenital, mild to severe | Normal | After puberty |
| USH3 | Progressive | Variable | Variable |
Usher syndrome is recognized as one of the designated intractable diseases (110 diseases under the Intractable Disease Act) by the national government. It is designated as a disease concept independent of RP and is eligible for medical expense subsidies.
In Usher syndrome, hearing loss, vision loss, and balance disorders are the three main features. The age of onset and severity of symptoms vary greatly depending on the subtype.
Symptoms related to hearing loss
Symptoms related to vision
Symptoms related to balance disorders
Fundus findings due to RP are central.
Fundus Findings
Retinal vascular attenuation: Arteries become markedly narrow.
Bone spicule pigmentation: Bone spicule-shaped pigment deposits are seen in the mid-peripheral retina. This results from migration of retinal pigment epithelial cells into the neurosensory retina.
Pale optic disc: Waxy pallor indicating optic atrophy.
Cystoid macular edema (CME): Occurs in 8–60% of all cases and is an important cause of vision loss.
Electrophysiology and Imaging
Electroretinogram (ERG): Rod response amplitude decreases first, followed by cone response. Essential for functional diagnosis of RP.
Fundus autofluorescence (FAF): Patchy hypoautofluorescent areas reflect RPE atrophy.
Visual field testing: Begins with mid-peripheral visual field defects and progresses centripetally. Goldmann perimetry characteristically shows a “ring scotoma.”
OCT: Useful for evaluating macular edema and confirming thinning of the photoreceptor layer.
Carriers of Usher syndrome may develop retinitis pigmentosa sin pigmento (without pigment deposits). A case has been reported in a carrier of the USH1C gene who lacked bone-spicule pigmentation and had visual acuity reduced to approximately 0.1, indicating that RP-like phenotypes can occur in Usher carriers 2).
Usher syndrome may rarely be complicated by Fuchs heterochromic iridocyclitis (FHU) or congenital ectropion uveae. Among RP patients, the proportion reacting to retinal S-antigen is high (about 80%) in USH patients, suggesting an association between USH and FHU 5).
Additionally, a case of bilateral vasoproliferative tumor (VPT) of the retina has been reported in MYO7A-related USH. A 13-year-old female developed a devastating VPT and neovascular glaucoma in the left eye (OS), and approximately 3 years later, an asymptomatic VPT was found in the right eye (OD) 3). It is important not to attribute visual decline in RP patients solely to RP, but to actively search for complications such as VPT 3).
Cystoid macular edema occurs in 8–60% of USH patients and does not develop in all cases. Cystoid macular edema is an important cause of visual decline, and early detection through regular OCT examinations is recommended. For details, see the “Standard Treatment” section.
Usher syndrome is a genetic disorder with an autosomal recessive inheritance pattern; there are no environmental risk factors. If both parents are carriers, the probability of a child being affected is 25%.
To date, 13 causative genes have been identified.
USH1-related genes (6 types): MYO7A, USH1C, CDH23, PCDH15, USH1G (SANS), CIB2
Mutations in MYO7A account for approximately 50% of USH1 cases, making it the most frequent 1). USH1C mutations encode the harmonin protein, which is essential for mechanotransduction in cochlear hair cells 2). CDH23 mutations cause USH1 and have been reported to be associated with schizophrenia-like symptoms and bipolar disorder 4). USH1G mutations (SANS protein) are rare, accounting for 0–4% of USH1, but may present with severe phenotypes 6).
USH2-related genes (3 types): USH2A (usherin), ADGRV1 (GPR98), WHRN (whirlin)
USH2A is the most frequent and the main causative gene for USH2 1). The most common pathogenic variant is c.2299delG, especially in European populations 1). USH2A mutations can also cause non-syndromic RP, in which case they are often partial function-preserving mutations that cause only retinal degeneration while preserving hearing structure 1).
USH3-related genes (2 types): CLRN1 (clarin-1), HARS1
USH3 accounts for 2–4% of all cases and is the rarest; it is more common in Ashkenazi Jews and Finns (founder effect) 1).
USH4 (atypical type): ARSG (arylsulfatase G) gene mutations cause hearing loss and visual impairment starting around age 40. Retinal changes are characterized by ring-shaped atrophy around the macula, which differs from other USH subtypes 1,7).
Not necessarily. Some USH2A mutations (especially missense mutations that retain partial function) can cause non-syndromic RP without hearing loss. In contrast, loss-of-function mutations (truncations, severe splice mutations) are associated with the typical auditory and visual phenotype of USH2 1).
A definitive diagnosis of Usher syndrome requires integrated evaluation by multiple specialties.
Diagnostic criteria are based on genetic findings, symptom severity, progression pattern, age of onset, and presence of vestibular dysfunction 1). In recent years, the reliability of subtype differentiation based on vestibular phenotype differences has been questioned, and genetic testing is emphasized for confirmation 1).
Ophthalmic examination
Auditory and vestibular testing
Genetic testing
Genetic testing is the most definitive diagnostic tool 2). A panel test of 14 or more genes using next-generation sequencing (NGS) is recommended 6).
Cases illustrating the importance of definitive diagnosis using genetic testing include several reports of patients with congenital hearing loss, vision loss, and balance disorders clinically suspected of having USH, but exome analysis confirmed a different disease (e.g., Alström syndrome or TUBB4B mutation) 8). When hereditary hearing loss and visual impairment overlap, genes other than USH, such as ALMS1, TUBB4B, CEP78, ABHD12, and PRPS1, should also be considered in the differential diagnosis 8).
Currently, there is no curative treatment for Usher syndrome. The goal of management is to maximize residual sensory function and improve quality of life.
A case has been reported of a 4-year-old girl with a USH2A mutation whose hearing recovered and language/communication abilities improved after cochlear implant surgery. Early intervention (preferably before age 2) is recommended for congenital hearing loss9).
The combination of visual field constriction (tunnel vision) and night blindness in RP with vestibular dysfunction significantly increases the risk of accidents. Supervised sports activities that utilize somatosensory compensation are recommended. Fall prevention measures are important when visual field constriction progresses.
Cochlear implantation is worth considering for all types. In USH1, hearing aids have limited effectiveness, so cochlear implants are particularly important. In USH2 and USH3, hearing aids often work, but cochlear implants are also an option. Early intervention (before age 2) greatly contributes to language development 9).
Usher syndrome is classified as a ciliopathy, with dysfunction of protein complexes common to sensory cells of the inner ear and retina as the basis of pathology 1).
The stereocilia bundles of cochlear hair cells depend on the Usher protein network to maintain their structural integrity. USH gene mutations impair the following two major inner ear mechanisms.
USH1 and USH2 form different protein complexes. The USH2 complex (Usherin–ADGRV1–Whirlin) is required for stabilizing the ankle links of stereocilia, and its disruption impairs mechanoelectrical transduction 1).
At the junction between the inner and outer segments of photoreceptor cells, there is a periciliary membrane complex (PMC) that functions as a diffusion barrier controlling transport to the outer segment.
The USH2A gene spans approximately 800 kb and contains 72 exons. The encoded Usherin protein is a multi-domain transmembrane protein (including laminin EGF motifs, fibronectin type III repeats, and a pentaxin domain) that functions in both the cochlea and retina 1). Its mutations have a wide spectrum: truncation mutations cause the full USH2 phenotype, while missense mutations may present only with non-syndromic RP 1).
The Usher protein complex is positioned similarly to the BBSome as a multi-protein assembly essential for ciliary function, and its disruption leads to syndromic sensory degeneration 1).
The USH1G gene is located at 17q24-25 and encodes the SANS protein (a scaffold protein with ankyrin repeats and a SAM domain) 6). SANS is expressed in cochlear hair cells, vestibular organs, retina, cerebellum, and testis, and forms the USH1 complex in coordination with the USH1C protein (harmonin). USH1G mutations are rare (0–4%) but present with the severe phenotype typical of USH1 6).
When a USH patient with a MYO7A mutation also has a Calreticulin (CALR) gene mutation, it has been reported that impaired cardiomyocyte adhesion and mitochondrial dysfunction can lead to a specific type of dilated cardiomyopathy 10). In patient fibroblasts, ATP production capacity is reduced by approximately 20–30%, and galactose loading causes an additional 30% decrease 10). Disruption of cytoskeletal dynamics due to MYO7A mutation also contributes to abnormal mitochondrial distribution in the heart 10).
Yes, psychiatric symptoms (such as depression, anxiety, and schizophrenia-like symptoms) have been reported in 4–23% of USH patients 4). Three hypotheses have been proposed: (1) psychological stress due to sensory loss, (2) neurological abnormalities (e.g., cerebellar and cerebral atrophy), and (3) pleiotropic effects of USH-related genes (e.g., association between CDH23 mutations and schizophrenia) 4). Continuous mental health evaluation is important.
AAV gene therapy for MYO7A (USH1B) (AGTC-501/AAVC-081): Phase 1/2 trials using an AAV vector carrying the MYO7A gene are ongoing. Since the MYO7A coding sequence is approximately 6.7 kb, exceeding the standard AAV packaging capacity, split dual-vector strategies and large-capacity lentiviral vectors are being developed 1).
Antisense oligonucleotide (ASO) therapy: An ASO drug targeting the deep intronic mutation (c.7595-2144A>G) in exon 13 of USH2A is being developed. This is a targeted therapy for one of the most common pathogenic mutations in USH2A 1).
N-acetylcysteine (NAC): As an oral antioxidant, its effect on slowing retinal degeneration is being evaluated.
BF844: A small molecule targeting USH3-related CLRN1 mutations is in preclinical research 1).
Advances in genetic testing technology are making detailed genotypic diagnosis possible, including atypical types such as USH4. The development of molecular targeted therapies based on genotype is progressing rapidly, and gene therapy in particular is expected as a future treatment 1). Accurate genetic diagnosis at the current stage is significant in that it allows identification of individuals eligible for future gene-targeted therapies through early genetic diagnosis 8).
Morda D, Alibrandi S, Scimone C, et al. Decoding pediatric inherited retinal dystrophies: Bridging genetic complexity and clinical heterogeneity. Prog Retin Eye Res. 2025;109:101405. doi:10.1016/j.preteyeres.2025.101405.
Ayala Rodriguez SC, Ramirez Marquez E, Robles Bocanegra A, et al. Retinitis pigmentosa sine pigmento in a carrier of Usher syndrome. Cureus. 2023;15(4):e37719. doi:10.7759/cureus.37719
Pichi F, Rissotto F, Qadha KN, Smith SD, Khan AO. Bilateral vasoproliferative tumors in Usher syndrome. Case Rep Ophthalmol. 2025;16:261-266. doi:10.1159/000542415
Tesolin P, Santin A, Morgan A, et al. Which came first? When Usher syndrome type 1 couples with neuropsychiatric disorders. Audiol Res. 2023;13:989-995. doi:10.3390/audiolres13060086
Rezaei L, Ahmadyani R. A very rare association of Fuchs heterochromic uveitis and ectropion uvea in Usher syndrome. Adv Biomed Res. 2021;10:50. doi:10.4103/abr.abr_286_20
Galvez N, Lopez G, Tamayo ML. Identificación de una variante en el gen USH1G en una familia con el síndrome de Usher. Biomédica. 2025;45:528-534. doi:10.7705/biomedica.7498
Fowler N, El-Rashedy M, Chishti E, Vander Kooi CW, Maldonado R. Multimodal imaging and genetic findings in a case of ARSG-related atypical Usher syndrome. Ophthalmic Genet. 2021;42(3):338-343. doi:10.1080/13816810.2021.1891552
Medina G, Perry J, Oza A, Kenna M. Hiding in plain sight: genetic deaf-blindness is not always Usher syndrome. Cold Spring Harb Mol Case Stud. 2021;7:a006088. doi:10.1101/mcs.a006088
Wang H, Huo L, Wang Y, Sun W, Gu W. Usher syndrome type 2A complicated with glycogen storage disease type 3 due to paternal uniparental isodisomy of chromosome 1 in a sporadic patient. Mol Genet Genomic Med. 2021;9:e1779. doi:10.1002/mgg3.1779
Frustaci A, De Luca A, Galea N, et al. Novel dilated cardiomyopathy associated to Calreticulin and Myo7A gene mutation in Usher syndrome. ESC Heart Failure. 2021;8:2310-2315. doi:10.1002/ehf2.13260
