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

Francesco Romano, Francesca Lamanna, Camiel J. F. Boon, Alessandro Siligato, Gagan Kalra, Aniruddha Agarwal, Chiara Medori, Matteo Bertelli, Marco Pellegrini, Alessandro Invernizzi, Giovanni Staurenghi, Anna Paola Salvetti

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Purpose: To investigate the clinical and genotypic differences in the spectrum of ABCA4-associated retinopathies (ABCA4Rs). 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), and fundus flavimaculatus (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 Classification of Atrophy Meeting reports, macular and choroidal thickness on OCT; and 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 patients with LO-SD (59 ± 9 years) (all P < 0.01). Central vision loss was a common presenting symptom in CD-BEM and SD, whereas patients with LO-SD 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 3 eyes with LO-SD (8%). Cone dystrophy-bull's-eye maculopathy eyes typically had complete outer retinal atrophy alterations (98%), whereas CRD and SD eyes showed both complete outer retinal atrophy and complete RPE and outer retinal atrophy (cRORA) (71%–100%). Patients with LO-SD 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), whereas others have substantial RPE and choriocapillaris alterations (e.g., LO-SD). We recommend that clinical trial end points take into consideration these imaging features to improve the interpretation of their results. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Original languageEnglish
Pages (from-to)509-519
Number of pages11
JournalOphthalmology Retina
Issue number5
Early online date2024
Publication statusPublished - May 2024


  • ABCA4 retinopathy
  • End points
  • Multimodal imaging
  • Phenotypes
  • Stargardt

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