Usher syndrome: clinical features, molecular genetics and advancing therapeutics

Abstract

Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or without vestibular dysfunction. It is the most common cause of deaf-blindness worldwide with a prevalence of between 4 and 17 in 100 000. To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome. Variants in these genes can also cause non-syndromic RP and deafness. Genotype-phenotype correlations have been described for several of the Usher genes. Hearing loss is managed with hearing aids and cochlear implants, which has made a significant improvement in quality of life for patients. While there is currently no available approved treatment for the RP, various therapeutic strategies are in development or in clinical trials for Usher syndrome, including gene replacement, gene editing, antisense oligonucleotides and small molecule drugs.

Keywords: Usher syndrome; gene therapy; inherited retinal disease; inner ear; photoreceptor; retina; retinitis pigmentosa; sensorineural hearing loss; sensory hair cell.

Figure 1.

Audiograms of Usher syndrome type 1 and 2 patients. (a) Normal audiogram from a non-Usher individual. (b) Audiogram of a typical patient with Usher syndrome type 1 due to MYO7A mutation (homozygous c.4254del p.Asp1419fs) showing bilateral severe to profound sensorineural hearing loss (hearing loss in audiogram >95 dBHL). (c) Typical high frequency mild to severe sloping audiogram of an Usher syndrome type 2 patient (hearing loss in audiogram is 35–75 dBHL).

Figure 2.

Flowchart for investigation and treatment of bilateral profound sensorineural hearing loss. Source: Adapted from the British Association of Audiovestibular Physicians (BAAP) guidelines.

Figure 3.

Retinal imaging of a patient with MYO7A-related Usher syndrome type 1. Images taken from a 34-year-old male with homozygous nonsense variants in MYO7A; c.2914C > T, p.(Arg972*). Best corrected LogMAR visual acuity was 0.24 in the right eye and 0.28 in the left eye. (a) Widefield colour imaging of the right fundus showing patchy RPE atrophy along the arcades with bone spicule pigmentation in the mid-periphery and peripapillary atrophy with arteriolar attenuation. In the temporal periphery, extensive chorioretinal atrophic patches are noted in this patient. (b) Widefield autofluorescence imaging of the right fundus showing dense hypoautofluorescence corresponding to RPE atrophy around the arcades extending into the mid-periphery. A ring of hyperautofluorescence is seen at the macula with speckled loss centrally. (c) Spectral-domain optical coherence tomography (SD-OCT) of the right eye showing loss of retinal lamination, cystoid macular oedema with intraretinal cystic changes and extensive loss of the ellipsoid zone.

Figure 4.

Retinal imaging of a patient with USH2A-related Usher syndrome type 2. Images taken from a 58-year-old male with compound heterozygous variants in USH2A; c.2299delG, p.(Glu767Serfs*21) and c.100C > T, p.(Arg34*). Best corrected LogMAR visual acuity was 0.50 in the right eye and 0.30 in the left eye. (a) Widefield colour imaging of the right fundus showing scattered bone spicule pigmentation in the mid-periphery and areas of depigmentation with RPE atrophy. Preserved retinal island at the macula, arteriolar attenuation and a waxy pale disc. (b) Widefield autofluorescence imaging of the right fundus showing hyperfluorescence signal at the fovea with dense scalloped hypoautofluorescence around the macula, arcades and extending past the mid-periphery corresponding with RPE atrophy. (c) Spectral-domain optical coherence tomography (SD-OCT) of the right eye showing retinal thinning and a small residual ellipsoid zone.