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.