Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates

BACKGROUND. Outcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4-associated (ABCA4-associated) retinopathy. We aimed to quantify ellipsoid zone (EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4- associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age. METHODS. We analyzed 132 eyes from 66 patients (of 67 enrolled) with molecularly confirmed ABCA4-associated retinopathy from a prospective natural history study with a median [IQR] follow-up of 4.2 years [3.1, 5.1]. Longitudinal spectral-domain optical coherence tomography volume scans (37 B-scans, 30 degrees x 15 degrees) were segmented using a deep learning (DL) approach. For genotype phenotype analysis, a model of ABCA4 variants was applied with the age of criterion EZ-loss (6.25 mm(2)) as the dependent variable. RESULTS. Patients exhibited an average (square-root-transformed) EZ-loss progression rate of [95% CI] 0.09 mm/y [0.06, 0.11]. Outer nuclear layer (ONL) thinning extended beyond the area of EZ-loss. The average distance from the EZ-loss boundary to normalization of ONL thickness (to +/- 2 z score units) was 3.20 degrees [2.53, 3.87]. Inner segment (IS) and outer segment (OS) thinning was less pronounced, with an average distance from the EZ-loss boundary to layer thickness normalization of 1.20 degrees [0.91, 1.48] for the IS and 0.60 degrees [0.49, 0.72] for the OS. An additive model of allele severity explained 52.7% of variability in the age of criterion EZ-loss. CONCLUSION. Patients with ABCA4-associated retinopathy exhibited significant alterations of photoreceptors outside of EZ-loss. DL-based analysis of photoreceptor laminae may help monitor disease progression and estimate the severity of ABCA4 variants.