Clinical, Genotypic and Imaging Characterization of the spectrum of ABCA4 Retinopathies

PURPOSE: To investigate the clinical and genotypic differences in the spectrum of ABCA4-associated retinopathies (ABCA4R). DESIGN: Observational, cross-sectional case series. PARTICIPANTS: Sixty-six patients (132 eyes) carrying biallelic ABCA4 variants. METHODS: Patients underwent visual acuity measurement and multimodal imaging. Clinical records were reviewed for age at onset, presenting symptoms, genetic variants, and electroretinogram (ERG). Each eye was assigned to a phenotype based on age at onset, imaging and ERG: cone dystrophy-bull's eye maculopathy (CD-BEM, 40 eyes), cone-rod dystrophy (CRD, 12 eyes), Stargardt disease (SD, 28 eyes), late-onset SD (LO-SD, 38 eyes), fundus flavimaculatus (FFM, 14 eyes). Images were analyzed for: peripapillary sparing, retinal pigment epithelium (RPE) atrophy (definitely decreased autofluorescence, DDAF), flecks patterns using autofluorescence; type of atrophy according to CAM reports, macular and choroidal thickness on optical coherence tomography (OCT); choriocapillaris flow deficits on OCT angiography. MAIN OUTCOME MEASURES: Primary outcome was to report the demographic, genotypic and imaging characteristics of the different ABCA4R phenotypes. Secondary objectives included the assessment of imaging biomarkers as outcome measures for clinical trials. RESULTS: Age at onset was lower in CRD (12±8 years) and higher in LO-SD patients (59±9 years) (all p<0.01). Central vision loss was a common presenting symptom in CD-BEM and SD, whereas LO-SD patients primarily complained of difficult dark adaptation. Missense variants were more frequent in CD-BEM, and splice site in CRD and LO-SD (p<0.05). Peripapillary sparing was absent in three eyes with LO-SD (8%). CD-BEM eyes typically had cORA alterations (98%), while CRD and SD eyes showed both cORA and cRORA (71-100%). LO-SD patients had larger areas of DDAF (100% cRORA) and of choriocapillaris flow deficits (all p<0.01). Repeatability of DDAF measurements was low for some phenotypes (CD-BEM and CRD) and atrophic areas <7.5 mm2. Resorbed flecks were significantly associated with CRD and LO-SD (p<0.01). CONCLUSIONS: This research provides a thorough evaluation of the spectrum of ABCA4R. Our findings suggest that certain phenotypes show preferential photoreceptor degeneration (e.g., CD-BEM), while others have substantial RPE and choriocapillaris alterations (e.g., LO-SD). We recommend that clinical trial endpoints take into consideration these imaging features to improve the interpretation of their results.