Retinal thickness and visual acuity in early-onset Stargardt disease follow a non-linear progression curve: implications for clinical trials

We retrospectively evaluated early-onset, autosomal recessive Stargardt disease in younger siblings from affected sibships using longitudinal analysis of visual acuity and multimodal imaging. Between 2002 and 2022, two sibships (<i>n</i> = 4, <i>n</i> = 2) with molecularly-confirmed Stargardt disease had younger affected siblings with clinical data obtained prior to the onset of vision loss. Measurement of best-corrected visual acuity and acquisition of color fundus photographs, autofluorescence, SLO, and OCT imaging were performed as part of routine clinical care. Both sibships presented with early-onset vision loss between 5-9 years old. Fundus autofluorescence changes and a thickened external limiting membrane on OCT were the first biomarkers observed in the youngest siblings. Decline in visual acuity and total thickness in the fovea followed a distinct, three-phase course (initial, acute, slow/stable). The timing of the second (acute) phase of acuity loss differed by up to 5 years between siblings within a sibship. Loss of total retinal thickness in the fovea preceded the greatest drop in visual acuity. Clinical trials must account for interrelationship between structure and function and the heterogeneity among patients sharing the same genotype, which suggests the action of unidentified modifiers.

我们采用视力与多模态成像的纵向分析方法，回顾性评估了来自受累同胞家系的早发性常染色体隐性遗传性斯塔加德病（Stargardt disease）患者的同胞弟妹。2002年至2022年间，共纳入2个经分子学确诊的斯塔加德病受累同胞家系（分别含<i>n</i>=4、<i>n</i>=2名受试者），其患病的同胞弟妹均在视力丧失发病前获取了临床资料。最佳矫正视力（best-corrected visual acuity）检测，以及彩色眼底照片、眼底自体荧光（fundus autofluorescence）、扫描激光检眼镜（SLO）和光学相干断层扫描（OCT）成像的采集，均作为常规临床诊疗的一部分完成。两个家系的患者均在5~9岁时出现早发性视力丧失。眼底自体荧光改变与光学相干断层扫描下的外界限制膜增厚，是在最年幼的同胞弟妹中观察到的首批生物标志物。视力下降及黄斑中心凹总厚度变化遵循明确的三相病程模式（初始期、急性期、缓慢/稳定期）。同一受累家系内，同胞弟妹间视力丧失的第二（急性）阶段的出现时间最多可相差5年。黄斑中心凹视网膜总厚度丢失先于视力的大幅下降出现。临床试验必须兼顾结构与功能间的相互关联，以及携带同一基因型患者之间的异质性——这提示存在未明确的遗传修饰因子的作用。