Clinical features

Depending on the severity and progression of the hearing impairment, and the age of onset of RP that develops in all types of Usher syndrome, three clinical subtypes are distinguished and designated as types 1, 2, and 3 (Table 2).

Usher syndrome type 1

Usher syndrome type 1 is the most severe form of the disease that is characterized by congenital, bilateral, severe-to-profound sensorineural hearing impairment (Table 2). As patients are typically profoundly deaf from birth, they do not develop speech, unless fitted with a cochlear implant. In some cases the hearing loss becomes profound and severe within the first year of life. Vestibular areflexia affecting the balance is present and results in retarded motor development. Children begin sitting independently later than usual and typically walk later, at age approximately 24 months. Older children experience frequent accidental injuries due to impaired balance or have difficulty with activities and sports requiring balance. Progressive vision loss caused by RP becomes apparent in childhood, almost always by age around 10 years. However, in children older than 4 years who present with association of bilateral hearing impairment and vestibular deficit, the electroretinogram (ERG) may reveal vision abnormalities and serve as a helpful tool for early diagnosis of Usher syndrome. The visual deficit manifests with difficulty seeing at night and progressively constricted visual fields (for detailed information, see the Chapter on retinitis pigmentosa). At age of 30-40 years, patients with USH1 usually have visual field of 5-10 degrees or less. However, "typical" patients with USH1 usually do not become completely blind. Cataracts and macular edema may develop later in life. Histopathologic features of USH type 1 include degeneration of the organ of Corti and cochlear nerve, decrease in cochlear ganglion cell number, and sometimes degeneration of the inferior vestibular nerve.

Further subdivision of Usher syndrome type 1 is based on genetic criteria and some clinical variations, e.g. some USH1 patients exhibit less severe dysfunction of the vestibular system. Usher syndrome type 1 includes the following genetic forms: USH1B, USH1C, USH1D, USH1E, USH1F, USH1G, USH1H (Table 1).

Usher syndrome type 2

Usher syndrome type 2 is the most common subtype and, in general, is less severe (Table 2). It is characterized by congenital bilateral sensorineural hearing loss that predominantly affects high tones (mild-to-moderate in the low frequencies and severe-to-profound in the higher frequencies). Speech perception may decrease over time and the hearing loss may be perceived as progressing, with characteristic 'sloping' audiogram. The degree of hearing loss varies significantly within and among the affected families. Subtle variations within the hearing phenotype of USH type 2 have been reported, mostly regarding the rate of hearing impairment. The latter is considered as stationary and non-progressive, or at least progressing with a much slower rate than that reported for USH type 3. Most of the children with USH type 2 have good oral communication skills. The onset of RP can be during or after puberty, with typical manifestations of night blindness and constricted visual fields (tunnel vision), and eventually decreased central visual acuity. The rate and degree of vision loss vary within and among families but usually tends to progress more slowly than in type 1. Unlike other forms of Usher syndrome, vestibular function is normal and children walk at the normal age of 10 to 14 months. Tooth enamel defects have been reported in some children with USH type 2 (and in single cases of USH type 1).

Usher syndrome type 2 includes the following genetic forms: USH2A (accounting for over 80% of all USH type 2 cases), USH2C, USH2D (Table 1).

Usher syndrome type 3

Unlike the other forms of Usher syndrome, in USH type 3 the hearing and the vestibular function at birth are normal (or near-normal) (Table 2). Hearing loss typically begins during the first two decades of life, after the development of speech, and worsens over time (progressive hearing impairment). By middle age, most affected individuals are profoundly deaf. The onset of RP may vary, but in most cases occurs in late childhood to early adulthood. By mid adulthood, these patients are usually blind. Vestibular function may deteriorate with time and balance may be affected in about half of USH type 3 patients.

Additional features

In some cases, vision is further impaired by cataracts (reported in some USH1 patients), macular edema or central macular atrophy. Several studies indicate that Usher syndrome can also be associated with reduced odor identification (reported in some USH1 and USH2 patients), lower sperm motility, pigmentary glaucoma, mental deficiency, cerebral atrophy and ataxia.

Table 2: Clinical manifestations of Usher syndrome