Usher Syndrome, Type Iiib

A number sign (#) is used with this entry because of evidence that Usher syndrome type IIIB (USH3B) is caused by homozygous mutation in the HARS gene (HARS1; 142810) on chromosome 5q31.

Description

Usher syndrome type III is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life (Karjalainen et al., 1985; Pakarinen et al., 1995).

For a discussion of genetic heterogeneity of type III Usher syndrome, see USH3A (276902).

Clinical Features

Puffenberger et al. (2012) studied Usher syndrome patients from Old Order Amish families in Pennsylvania. Growth and development were normal during infancy. Visual impairment became evident during early childhood with the emergence of fine horizontal nystagmus, light aversion, and optic pallor. Funduscopic changes included marked attenuation of retinal vessels, cellophane-like reflex that produces a 'bull's eye' macula, and diffuse pigmentary stippling of the peripheral retina, consistent with retinitis pigmentosa. Patients were typically blind by the second or third decade of life, but the pace of visual deterioration was highly variable. Although no auditory data were available from newborns, some auditory function was present during infancy and deteriorated during early childhood, with all evoked auditory waveforms being absent by age 5. Amplifiers or cochlear implants partially restored hearing. Patients had delayed gross motor development, hyperactive patellar tendon reflexes, mild truncal ataxia, and a wide-based gait, but upper limb coordination and reflexes, peripheral nerve function, strength, tone, and intelligence were normal. Puffenberger et al. (2012) stated that the condition was most consistent with the type III variant of Usher syndrome, characterized by progressive vision and hearing loss during early childhood.

Charles Bonnet Syndrome

Puffenberger et al. (2012) reported that the so-called 'Charles Bonnet syndrome,' involving decreased visual acuity and vivid visual hallucinations, occurred in some Usher syndrome patients from Old Order Amish families in Pennsylvania. The attacks, which were precipitated by infectious illnesses, began during early childhood and were sometimes accompanied by nonsensical speech, inappropriate laughter, repetitive eye blinking, or psychomotor agitation. In 1 case, acute psychosis merged into a deep catatonia that lasted several days. Hallucinations typically responded to antipsychotic medications and were sometimes associated with transient myopathy. Rarely, children died suddenly and unexpectedly during an illness, presumably from a cardiac event, but routine electrocardiogram and 24-hour Holter monitoring results were normal.

Mapping

In 2 patients with Usher syndrome type III from Old Order Amish families in Pennsylvania, Puffenberger et al. (2012) performed whole-exome sequencing and identified an 8.4-Mb region of homozygosity between SNPs rs2603014 and rs325229 on chromosome 5q.

Molecular Genetics

In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type III mapping to chromosome 5q, Puffenberger et al. (2012) identified homozygosity for a missense mutation in the HARS gene (Y454S; 142810.0001); the mutation was also found in homozygosity in an Old Order Amish patient from an unrelated deme in Ontario, Canada, with an identical phenotype. The variant was not found in dbSNP 129 or the 1000 Genomes Project; it was, however, detected in 7 of 406 Old Order Amish alleles, for a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)