Investigating Biomarkers for <i>USH2A</i> Retinopathy Using Multimodal Retinal Imaging
Pathogenic mutations in <i>USH2A</i> are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying p...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/8/4198 |
| Summary: | Pathogenic mutations in <i>USH2A</i> are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in <i>USH2A</i> retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed <i>USH2A</i>-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with <i>USH2A</i>-associated Usher syndrome type 2 (<i>n</i> = 14) or non-syndromic RP (<i>n</i> = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (<i>p</i> < 0.001). The IMPM border occurred just lateral to EZ loss (<i>p</i> < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 μm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (<i>p</i> < 0.001). As the strongest correlate of cone density (<i>p</i> < 0.001) and best-corrected visual acuity (<i>p</i> < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in <i>USH2A</i> retinopathy, rendering it a promising trial endpoint. |
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| ISSN: | 1661-6596 1422-0067 |