Study of Late-Onset Stargardt Type 1 Disease Characteristics, Genetics, and Progression

Purpose: Late-onset Stargardt disease is a subtype of Stargardt disease type 1 (STGD1), defined by an age of onset of 45 years or older. We describe the disease characteristics, underlying genetics, and disease progression of late-onset STGD1 and highlight the differences from geographic atrophy. Participants: Seventy-one patients with late-onset STGD1. Methods: Medical files were reviewed for clinical data including age at onset, initial symptoms, and bestcorrected visual acuity. A quantitative and qualitative assessment of retinal pigment epithelium (RPE) atrophy was performed on fundus autofluorescence images and OCT scans. Main Outcome Measures: Age at onset, genotype, visual acuity, atrophy growth rates, and loss of external limiting membrane, ellipsoid zone, and RPE. Results: Median age at onset was 55.0 years (range, 45-82 years). A combination of a mild and severe variant in ATP-binding cassette subfamily A member 4 (ABCA4) was the most common genotype (n 1/4 49 [69.0%]). The most frequent allele, c.5603A/T (p.Asn1868Ile), was present in 43 of 71 patients (60.6%). No combination of 2 severe variants was found. At first presentation, all patients have flecks. Foveal-sparing atrophy was present in 33.3% of eyes, whereas 21.1% had atrophy with foveal involvement. Extrafoveal atrophy was present in 38.9% of eyes, and no atrophy was evident in 6.7% of eyes. Time-to-event curves showed a median duration of 15.4 years (95% confidence interval, 11.1-19.6 years) from onset to foveal involvement. The median visual acuity decline was -0.03 Snellen decimal per year (interquartile range [IQR], -0.07 to 0.00 Snellen decimal; 0.03 logarithm of the minimum angle of resolution). Median atrophy growth was 0.590 mm2/year (IQR, 0.046-1.641 mm2/year) for definitely decreased autofluorescence and 0.650 mm2/year (IQR, 0.299-1.729 mm2/ year) for total decreased autofluorescence. Conclusions: Late-onset STGD1 is a subtype of STGD1 with most commonly 1 severe and 1 mild ABCA4 variant. The general patient presents with typical fundus flecks and retinal atrophy in a foveal-sparing pattern with preserved central vision. Misdiagnosis as age-related macular degeneration should be avoided to prevent futile invasive treatments with potential complications. In addition, correct diagnosis lends patients with late-onset STGD1 the opportunity to participate in potentially beneficial therapeutic trials for STGD1. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2024;131:87-97 (c) 2023 by the American Academy of Ophthalmology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).