A Retrospective Longitudinal Study of 458 Patients with Molecularly Confirmed ABCA4-Associated Retinal Disease

Abstract

Purpose : To investigate the natural history of ABCA4-associated retinal disease with regard to genotype, age at first vision loss, fundus appearance, OCT measurements, LogMar visual acuity and Goldmann visual field volume.

Methods : Samples from patients seen by the retina service at the University of Iowa between 1959 and 2022 and who were eventually suspected to have disease caused by mutations in ABCA4 were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed to identify the age at which the patient first experienced uncorrectable vision loss and to record the best corrected visual acuities for each visit. The latter were converted to LogMar for analysis. Goldmann visual fields were traced using a custom iPad-based tool and the volumes of the hill of vision were calculated. OCTs were segmented computationally. The pathogenic severity of the more common alleles was estimated by studying groups of patients that shared one allele.

Results : A total of 458 patients from 390 families had convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 400 patients and partial genotypes in 58. There were 1730 clinic visits among the members of this cohort (median 3, range 1-22 visits) with a median follow-up duration of 4 years (range 0-52 years). The median age of first vision loss was 16 years (range 4-77 years). The ten most common alleles in order of decreasing severity were: Ala1038Val/Leu541Pro, Pro1380Leu, Val256Val, IVS38-10, Arg1108Cys, IVS40+5, Gly1961Glu, Leu2027Phe, Gly863Ala, and Ala1038Val. Twenty genotypes, each composed of 2 of these 10 common alleles, were each present in 2 or more patients (65 patients total). Careful review of these patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a greater than 15 year difference in age of first vision loss.

Conclusions : ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before age 5 years to a very late onset (>60 years) RPE-based condition resembling pattern dystrophy or geographic atrophy. Reliable and objective sorting of ABCA4 patients into severity classes will be essential for successful clinical trials of treatments for this disease.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.