Clinical Guidance

Hearing loss. The hearing loss in Usher syndrome type I (USH1) is congenital (i.e., present at birth), bilateral, severe-to-profound sensorineural hearing impairment (SNHI). While congenital SNHI should be identified through universal hearing screening at birth, occasionally false negative screening or missed screening before discharge to home results in delayed diagnosis until speech delay is obvious. Affected individuals do not develop speech unless fitted with cochlear implants. Hearing aids are usually inadequate in individuals with USH1 because of the severity of the hearing loss. Alternatively, sign language and tactile signs (once visual loss occurs) are communication options for families who choose nonauditory communication. Imbalance.

Source: GeneReviews — "Usher Syndrome Type I"

Penetrance

Penetrance is complete in Usher syndrome type I.

Source: GeneReviews — "Usher Syndrome Type I"

Differential Diagnosis

Nonsyndromic hearing loss (NSHL). Often, a family with more than one affected sib is thought to have NSHL (see Hereditary Hearing Loss and Deafness Overview) until the oldest affected sib manifests signs of retinal degeneration (e.g., night blindness, dark adaptation impairment, contrast vision difficulties, visual acuity changes, and visual field narrowing) and is diagnosed with retinitis pigmentosa (RP). Subsequent visual evaluation often reveals the presymptomatic signs of RP in younger affected sibs. While the timing and extent of vestibulopathy related to Usher syndrome is not fully defined, vestibular symptoms in young children thought to have NSHL may also prompt visual evaluation and subsequent genetic testing. Coinheritance of NSHL and RP. Pathogenic variants associated with separate NSHL and RP (e.g., OTOA-NSHL and NR2E3-RP ) can be inherited independently by a single individual whose symptoms can then mimic those of Usher syndrome . Larger families lessen the statistical probability of this occurrence because at least one sib is likely to inherit one pathogenic variant without the other. NSHL and RP (or inherited retinal degeneration) are both relatively common, with frequencies of 1:1,000 and 1:3,000, respectively, and are both characterized by extreme genetic heterogeneity (to date, 110 genes have been associated with NSHL, 60 genes have been associated with RP, and 172 genes have been associated with inherited retinal degeneration) . See also Hereditary Hearing Loss and Deafness Overview and RetNet: Retinal Information Network. Hereditary disorders characterized by both sensorineural hearing impairment (SNHI) and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type I (USH1) are summarized in . Table 3. Genes of Interest in the Differential Diagnosis of Usher Syndrome Type I

Source: GeneReviews — "Usher Syndrome Type I"

Clinical Guidance

Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous. Persons with USH1 often become disoriented when submerged in water because they lack the sense of where "up" is; they should therefore exercise caution while swimming. Similarly, the vestibular dysfunction increases the risk of falls when walking on sloped or uneven surfaces. Progressive loss of peripheral vision may eventually impair the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.

Source: GeneReviews — "Usher Syndrome Type I"

Therapies Under Investigation

UshStat®

gene replacement of MYO7A – A Study to Determine the Long-Term Safety, Tolerability and Biological Activity of UshStat® in Patients with Usher Syndrome Type 1B. This is an interventional, Phase I/II clinical trial to evaluate the safety and activity of retinal gene therapy to treat RP in individuals with MYO7A-USH1. This trial is active but not recruiting. (See NCT02065011.) QR-421 antisense treatment – A Study to Evaluate Safety and Tolerability of QR-421a in Subjects with RP Due to Mutations in Exon 13 of the USH2A Gene (Stellar). This is an interventional, Phase I/II clinical trial to evaluate the safety of an antisense oligonucleotide (ASO) therapy to treat RP in individuals with USH2 due to specific USH2A pathogenic variants. (See NCT03780257.

Source: GeneReviews — "Usher Syndrome Type I"