Usher syndrome (ORPHA:886)
A rare ciliopathy characterized by congenital or childhood onset sensorineural hearing loss (HL) and retinitis pigmentosa (RP) that occurs in a second step with a night blindness and a progressive vision loss and, in some cases, vestibular dysfunction.
Epidemiology
Prevalence of Usher syndrome (US) is estimated at 1/30,000. It is by far the most common cause of hereditary, combined deafness-blindness.
Clinical description
Sensorineural hearing loss is typically congenital and three clinical entities have been defined according to severity of hearing loss severity. Type 1 (around 40% of cases) is characterized by profound, nonprogressive congenital deafness, typically associated with vestibular areflexia that leads to delayed acquisitions (delayed head control, unassisted sitting and walking). Type 2 (around 60% of cases) is characterized by moderate or severe, congenital hearing loss that is slowly progressive and not associated with vestibular disorders. Type 3 (< 3% of cases, but more frequent in the Finnish and Ashkenazi Jewish populations) is characterized by rapidly progressive hearing loss that is often diagnosed during the first decade; vestibular disorders are associated with half of the cases. Retinitis pigmentosa appears later, mainly in the second or third decades, with characteristic night vision and progressive peripheral visual field impairment. Night blindness can be noted in early childhood. The only reported retinal phenotype is rod cone dystrophy. A central visual impairment can be caused by a macular edema. A cataract is frequently observed before the age of 50 years.
Etiology
So far, mutations in five genes (MYO7A, USH1C, CDH23, PCDH15, USH1G) have been implicated in USH type 1. Mutations in three genes (USH2A, ADGRV1 and WHRN) have been implicated in USH type 2. Mutations in a predominant gene (CLRN1) have been identified for USH type 3. Some genes are called into question: CIB2 and PDZD7 seem eventually to be involved in non syndromic HL.
Diagnostic methods
Clinical diagnosis is based on findings of a bilateral sensorineural hearing loss associated with a retinitis pigmentosa defined by a night blindness and a peripheral visual field impairment. Multimodal imaging with color, fundus autofluorescence frames (FAF), spectral domain-optical coherence tomography and full-field electroretinogram are required to confirm the diagnosis of rod cone dystrophy. Genetic testing is feasible now based on massively parallel sequencing (gene panels or exomes).
Differential diagnosis
Differential diagnoses include oculo-acoustic syndromes associated with peroxysomal gene alterations (Heimler syndrome with enamel dysplasia), metabolic genetic inherited diseases (Refsum disease), moderate forms of Alstrom syndrome, or mitochondrial DNA mutations (MIDD, Kearns-Sayre syndrome). Mutations in TUBB4B gene can cause a dominant inherited oculo-acoustic phenotype, Leber congenital amaurosis and early-onset HL. In some patients, HL can coexist independently of RP.
Antenatal diagnosis
Prenatal diagnosis is feasible for families in which the disease-causing mutations have already been identified.
Genetic counseling
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, occupational therapist, and all professionals implicated in adapted learning programs for patients with both hearing and visual deficits). Conventional hearing aids may be indicated for patients wit h moderate or severe hearing loss. Cochlear implants, (in most cases 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 the management of the rod cone dystrophy. A specific treatment with anhydrase carbonic inhibitor can be indicated in case of macular edema. Cataract surgery can be required. Current research is directed towards gene therapy, antisense oligonucleotide therapy (USH2A), neuroprotection and artificial vision systems.
Prognosis
The prognosis mainly depends on the progression of rod cone dystrophy: a severe visual impairment occurs between 50 and 70 years of age in most cases.

                            Last update: 
                            July 2020


                            - Expert reviewer(s): 
                            Dr Catherine BLANCHET  - Pr Isabelle MEUNIER  - Dr Anne-Françoise ROUX