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Usher syndrome (US) is characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.
ORPHA:886Classification level: Disorder
- Retinitis pigmentosa-deafness syndrome
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal recessive
- Age of onset: Childhood, Infancy, Neonatal
- ICD-10: H35.5
- OMIM: 276900 276901 276902 276904 500004 601067 602083 602097 605472 606943 611383 612632 614504 614869 614990
- UMLS: C0271097
- MeSH: D052245
- GARD: 7843
- MedDRA: 10063396
Prevalence is estimated at 1/30,000. US is the most common cause of hereditary combined deafness-blindness.
Onset usually occurs during childhood. Three clinical entities have been defined: type 1 (around 40% of cases), in which hearing loss is congenital, profound, nonprogressive, and typically associated with vestibular areflexia leading to delayed acquisitions (delayed head control and unassisted sitting and walking); type 2 (around 60% of cases), in which hearing loss is prelingual, moderate/severe, slowly progressive, and not associated with vestibular disorders; type 3 (< 3% of cases, but more frequent in the Finnish and Ashkenazi Jewish populations), in which hearing loss is rapidly progressive, often diagnosed during the first decade and associated with vestibular disorders in half the cases. Retinitis pigmentosa, generally diagnosed after the deafness, first manifests by visual discomfort at low light levels, followed by a gradual vision loss leading to total blindness within a few decades.
So far, mutations in five genes (MYO7A, USH1C, CDH23, PCDH15, USH1G) and one locus (USH1E) have been implicated in US type 1. Mutations in three genes (USH2A, GPR98 and DFNB31) and one possible locus (15q) have been implicated in US type 2. Mutations in only one gene (CLRN1) have been identified for US type 3. Cases of digenic inheritance have been reported.
Clinical diagnosis is based on findings of bilateral sensorineural hearing loss (symmetric, congenital and profound for type 1, and moderate to severe with a predominant sensorineural high-frequency loss for type 2) associated with retinitis pigmentosa (pigment deposits on fundoscopy and a flat or diminished electroretinogram). Genetic testing is feasible with preliminary linkage analysis followed by molecular diagnosis based on genomic sequencing of candidate genes.
Differential diagnoses include oculo-acoustic syndromes associated with mitochondrial DNA mutations (MIDD, Kearns-Sayre syndrome), and, more rarely, Refsum disease and moderate forms of Alström syndrome (see these terms).
Prenatal diagnosis is feasible for families in which the disease-causing mutation has already been identified.
Transmission is autosomal recessive. Genetic counseling is straightforward but patients should be informed that heterozygous USH2A mutations are relatively frequent in the general population.
Management and treatment
Management requires a multidisciplinary team with experience in the management of combined deafness and blindness (ENT specialist, ophthalmologist, speech therapist, psychologist, hearing aid specialist, psychomotor development programs, and adapted learning programs for patients with both hearing and visual deficits). Conventional hearing aids may be indicated for patients with moderate to severe hearing loss. Cochlear implants, unilateral or bilateral, are now more frequently used for patients with profound congenital hearing loss. Both cochlear implants and hearing aids are more effective when implemented early. Lenses with specialized filters may be recommended for management of the retinopathy. Current research is directed towards gene therapy, neuroprotection and artificial vision systems.
The prognosis mainly depends on the progression of the visual loss: blindness occurs in almost all cases between 50 and 70 years of age.