University Eye Hospital, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany.
Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen, Germany.
Invest Ophthalmol Vis Sci. 2022 May 2;63(5):9. doi: 10.1167/iovs.63.5.9.
Autosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype--phenotype correlation.
Forty-four patients (26 females; mean age ± SD, 43 ± 13 years) with a confirmed genetic diagnosis of PDE6A-associated arRP underwent comprehensive ophthalmological examinations including best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study charts, contrast sensitivity (CS) with Pelli-Robson charts at distances of 3 m and 1 m, and color vision testing using Roth 28-Hue and Panel D-15 saturated color cups.
The most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although the latter were younger at baseline. Annual decline rates in central retinal function were small.
We conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.
常染色体隐性视网膜色素变性（arRP）可由磷酸二酯酶 6A（PDE6A）基因突变引起。在此，我们描述了中央视网膜功能（即视力、对比敏感度和色觉）的疾病进展自然过程，并建立了详细的基因型-表型相关性。
44 名经基因确诊为 PDE6A 相关 arRP 的患者（26 名女性；平均年龄±标准差，43±13 岁）接受了全面的眼科检查，包括最佳矫正视力（BCVA）的早期糖尿病视网膜病变研究图表、3m 和 1m 距离的 Pelli-Robson 图表的对比敏感度（CS）和 Roth 28-Hue 和 Panel D-15 饱和色杯的色觉测试。
最常观察到的变异是 c.998+1G>A/p.?, c.304C>A/p.R102S 和 c.2053G>A/p.V685M。与 c.998+1G>A/p.？纯合子患者相比，c.304C>A/p.R102S 纯合子患者的中央视网膜功能更好，尽管前者的基线年龄更大。c.304C>A/p.R102S 纯合子患者和 c.304C>A/p.R102S 和 c.2053G>A/p.V685M 杂合子患者的中央视网膜功能相似，尽管后者的基线年龄更小。中央视网膜功能的年下降率较小。
我们得出结论，人类中不同 PDE6A 突变导致疾病的严重程度可能如下：c.2053G>A/p.V685M 纯合状态（最严重）>c.998+1G>A/p.? 纯合状态>c.304C>A/p.R102S 和 c.2053G>A/p.V685M 复合杂合状态>c.304C>A/p.R102S 纯合状态（最轻）。由于中央视网膜功能的年下降率较小，干预试验的治疗效果评估仍将具有挑战性。
