Usher syndrome is an autosomal recessive (AR) condition involving sensorineural hearing loss and retinitis pigmentosa (RP). It is the most frequent cause of deaf-blindness in humans. The approximate incidence of Usher syndrome is 1 to 6 per 100,000. It accounts for up to 6% of all childhood deafness and approximately 50% of all patient deaf-blindness. Penetrance is usually complete. Although hearing loss in children will be detected by either newborn hearing screening or later audiologic evaluation, most often due to delays or other abnormalities in speech, the diagnosis of Usher syndrome typically lags 5 to 10 years behind the identification of the hearing loss depending on the onset of its visual impairment.
There are three subtypes of Usher syndrome, differentiated by the presence of vestibular involvement, age of RP onset, and pace of disease progression. A diagnosis of Usher syndrome type I (USH1) is suspected when a patient presents with congenital profound bilateral sensorineural hearing loss, severe vestibular abnormalities (which may be clinically unapparent), and early-onset RP that typically progresses slowly. Affected patients develop abnormal speech. Vestibular areflexia is a defining feature of USH1. Because of this, children frequently walk later than usual. Older patients may experience balance issues. The remainder of the physical examination is usually normal.
Usher syndrome type II (USH2) is characterized by congenital bilateral sensorineural hearing loss that affects predominantly the higher frequencies, with normal vestibular function and adolescent-to-adult onset of RP. The most common Usher subtype is type 2, and the USH2A gene accounts for 75 to 80% of these cases. Usher syndrome type III (USH3) is characterized by postlingual progressive sensorineural hearing loss, later-onset RP, and variable impairment of vestibular function. In types 2 and 3, the progression of the RP is more apparent perhaps because of the later onset.
USH1 and USH2 proteins are organized into protein networks by the scaffold proteins harmonin, whirlin, and scaffold protein containing ankyrin repeats and SAM domain (SANS). USH protein networks have cytoskeletal functions as well as roles in transport processes and ciliary delivery in hair cells and photoreceptors. There are molecular links of not only USH to other ciliopathies, including nonsyndromic inner ear defects and isolated retinal dystrophies, but also to kidney diseases and syndromes like the Bardet–Biedl syndrome (BBS).
18.2 Molecular Genetics
Genes known to produce Usher syndrome when mutated are presented in ▶ Table 18.1.
USH1 subtype (proportion of cases)
USH1B (up to 60%)
USH1C (up to 15%)
USH1D (up to 20%)
USH1F (up to 10%)
USH1G (up to 5%)
USH2 subtype (proportion of cases)
USH2A (up to 75%)
USH2C (up to 20%)
USH2D (up to 10%)
USH3 subtype (proportion of cases)
aMutations can also cause autosomal dominant nonsyndromic hearing loss (DFNA11), through a dominant negative effect.
bA del(11)(p14–15) that includes USH1C is associated with hyperinsulinism, enteropathy, and deafness. Mutations can also cause autosomal recessive (AR) nonsyndromic hearing loss (DFNB18).
cMissense mutations can cause AR nonsyndromic hearing loss (DFNB12). This gene can also cause digenic recessive Usher with PCDH15.
dOne-third of patients have deletions or duplications. Missense mutations can cause nonsyndromic hearing loss (DFNB23).
eMutations may cause AR nonsyndromic hearing loss (DFNB48).
Although heterozygous carriers of gene mutations causing USH1 are asymptomatic, they may show slightly subnormal audiograms.