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A rare ciliopathy characterized by the association of a sensorineural hearing loss (HL) (usually congenital), a retinitis pigmentosa (RP) occurring in a second step with a night blindness and a progressive vision loss and in some cases vestibular dysfunction.
ORPHA:886Classification level: Disorder
- Retinitis pigmentosa-deafness syndrome
- Retinitis pigmentosa-hearing loss 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
Usher syndrome (USH) Prevalence is estimated at 1/30,000. It is far the most common cause of hereditary combined deafness-blindness.
Disease onset usually occurs during childhood. Three clinical entities have been defined according to hearing loss severity: 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, unassisted sitting and walking); type 2 (around 60% of cases), in which hearing loss is congenital, moderate or 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 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 in Usher syndromes 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.
So far, mutations in five genes (MYO7A, USH1C, CDH23, PCDH15, USH1G) have been implicated in USH type 1. Mutations in three genes (USH2A, ADGRV1 (=GPR98) 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, initially reported as a USH1 gene seems to be involved in non syndromic HL PDZD7 has been first reported as a modifier gene of retinal disease with USH2A and a contributor to digenic inheritance with ADGRV1 but is indeed involved in non syndromic HL.
Clinical diagnosis is based on findings of a bilateral sensorineural hearing loss (profound for type 1; moderate or severe with a predominant sensorineural high-frequency loss for type 2) 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 diagnoses include oculo-acoustic syndromes associated with peroxysomal genes alterations (Heimler syndrome with enamel dysplasia, including hypomorphic variants in PEX1, PEX6 and PEX26), with metabolic genetic inherited diseases (Refsum disease...), with moderate forms of Alstrom syndrome or mitochondrial DNA mutations (MIDD, Kearns-Sayre syndrome). Mutations in TUBB4B gene can cause an oculo-acoustic phenotype but with a dominant inheritance, Leber congenital amaurosis and early-onset HL. In some patients, a non syndromic form of HL can coexist with a non syndromic form of RP, which that means that HL and RP are not linked in these patients.
Prenatal diagnosis is feasible for families in which the disease-causing mutations have 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, 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 with 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, antisens oligonucleotide therapy (USH2A), neuroprotection and artificial vision systems.
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.