Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.
Int J Mol Sci. 2022 Apr 11;23(8):4198. doi: 10.3390/ijms23084198.
Pathogenic mutations in USH2A 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 USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-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 USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 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 (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint.
USH2A 中的致病突变是导致非综合征或与 Usher 综合征相关的色素性视网膜炎（RP）继发视力丧失的主要原因。随着越来越多的针对 RP 的临床试验的进行，我们试图评估临床视网膜成像中观察到的丧失模式下的光感受器形态，以指导 USH2A 视网膜病变中的替代终点选择。在这项前瞻性的横断面研究中，25 名经分子证实的 USH2A-RP 患者接受了眼底自发荧光（FAF）、谱域光学相干断层扫描（SD-OCT）和自适应光学扫描激光检眼镜（AOSLO）视网膜成像。分析包括测量 FAF 水平内（IR）和外（OR）高自发荧光环直径；SD-OCT 椭圆区（EZ）和外部限制膜（ELM）宽度，归一化 EZ 反射率；AOSLO 中心凹锥密度和完整的黄斑光感受器镶嵌（IMPM）直径。16 名患者（平均年龄 ± 标准差，36.0 ± 14.2 岁）的 32 只眼符合纳入标准，包括 14 只与 USH2A 相关的 Usher 综合征 2 型（n = 14）或非综合征性 RP（n = 2）。IR-EZ 和 OR-ELM 直径/宽度之间观察到空间对齐（p < 0.001）。IMPM 边界刚好位于 EZ 丢失的外侧（p < 0.001），尽管直到 ELM 破坏，才检测到更稀疏的完整光感受器内节。EZ 宽度和 IR 直径与锥密度呈双相关系，即在视网膜变性达到距黄斑中心凹约 1350 μm 之前，缓慢的锥丢失发生，此后锥密度的减少更为明显。归一化 EZ 反射率和锥密度呈显著相关性（p < 0.001）。作为锥密度的最强相关物（p < 0.001）和最佳矫正视力（p < 0.001），EZ 宽度是 USH2A 视网膜病变中结构和功能下降的最敏感生物标志物，因此是一种很有前途的试验终点。
