Different Phenotypes Represent Advancing Stages of ABCA4-Associated Retinopathy: A Longitudinal Study of 212 Chinese Families From a Tertiary Center

Abstract

Purpose: To evaluate the nature and association of different phenotypes associated with ABCA4 mutations in Chinese.

Methods: All patients were recruited from our pediatric and genetic eye clinic. Detailed ocular phenotypes were characterized. The disease course was evaluated by long-term follow-up observation, with a focus on fundus changes. Cox regression was used to identify the factors associated with disease progression.

Results: A systematic review of genetic and clinical data for 228 patients and follow-up data for 42 patients indicated specific features in patients with two ABCA4 variants. Of 185 patients with available fundus images, 107 (57.8%) showed focal lesions restricted to the central macula without flecks. Among these 107 patients, 30 patients (28.0%) initially presented with relatively preserved visual acuity and inconspicuous performance on routine fundus screening. A pigmentary change in the posterior pole was observed in 22 of 185 patients (11.9%), and this change mimicked retinitis pigmentosa in 10 cases (45.5%). Follow-up visits and sibling comparisons demonstrated disease progression from cone-rod dystrophy, Stargardt disease, to retinitis pigmentosa. An earlier age of onset was associated with a more rapid decrease in visual acuity (P = 0.03). Patients with two truncation variants had an earlier age of onset.

Conclusion: Phenotypic variation in ABCA4-associated retinopathy may represent sequential changes in a single disease: early-stage Stargardt disease may resemble cone-rod dystrophy, whereas the presence of diffuse pigmentation in the late stage may mimic retinitis pigmentosa. Recognizing the natural progression of fundus changes, especially those visualized by wide-field fundus autofluorescence, is valuable for diagnostics and therapeutic decision-making.

Figure 1.

Fundus photography, FAF images and OCT results showing the early stage of ABCA4-associated retinopathy (Stage I). (A) Patient 21567-II2 was the sister of patient 21567-II1 (B) and did not show reduced central vision. Color fundus photography showed inconspicuous changes and relatively preserved visual acuity. Small-scale bull's-eye–like macular degeneration was observed on FAF imaging, and increased hyperreflectivity in the external limiting membrane and outer nuclear layer was found on OCT examination. (B–F) Various degrees of irregular pigment mottling were observed on fundus photography, decreased autofluorescence in the macular region surrounded by an increased autofluorescence parafoveal ring was found on FAF imaging, and macular atrophy was seen on OCT scans. The increased autofluorescence parafoveal ring became larger as the disease duration increased. The disease duration is shown in parentheses.

Figure 2.

Fundus photography and FAF images showing the typical (Stage II) and atypical (Stage III) fundus presentation of ABCA4-associated retinopathy. (A–D) Specific yellowish flecks extending from central to vascular arcades, macular dystrophy on fundus photography, and corresponding hyper-autofluorescence or hypo-autofluorescence flecks on FAF (Stage II). (E–H) Flecks were partly resorbed, and choroid atrophy was detected in the macula region on color fundus photography. A heterogenous background with an enlarged area of hypo-autofluorescence was observed on the FAF image (Stage III). The disease duration is shown in parentheses.

Figure 3.

Wide-field fundus images of different fundus stages among patients with ABCA4-associated retinopathy. (A) Normal control. (B) Typical bull's-eye macular degeneration on FAF image (Stage I). (C) Hypo-autofluorescence change at the macular region with hyper-autofluorescence flecks scatter at the vascular arcades (Stage II). (D, G) Expanded retinal degeneration area observed at the posterior pole, showing an enlarged hypo-autofluorescence area on the FAF image. Hyper-autofluorescence and hypo-autofluorescence flecks could be found at the periphery (Stage III). (E, H) Pigmentary foci on the macular area and many hypo-autofluorescence flecks could be found at the periphery on FAF images (Stage IV). (F, I) Pigment deposits were extended from the macular area to the periphery in the advanced stage (Stage IV).

Figure 4.

Fundus changes in the progression of ABCA4-associated retinopathy in our study. (A, B) Confined macular degeneration (Stage I) was observed in patient 13247-II1 at the first visit. A specific “beaten-bronze” macular appearance with a few bone spicule pigments scattered at the vascular dome (Stage IV) was found during the follow-up examination. (C, D) One sibling with the same biallelic ABCA4 variants, confirmed by co-segregation. The younger patient 6721-II2 showed specific macular dystrophy with inconspicuous flecks (Stage II) and her sister 6721-II-1 had nummular or bone spicule pigments deposited at the macular area (Stage IV). (E, F) Another follow-up sibling with the same ABCA4 variants. The younger patient 4303-II3 showed a specific “beaten-bronze” macular appearance plus choroid atrophy (Stage III), whereas his brother 4303-II1 had pigmentary changes at the posterior pole (Stage IV). (G, H) The long-term follow-up data for patient 2508-II1 showed typical enlarged macular degeneration (Stage III) that progressed to the advanced stage (Stage IV). The disease duration is shown in parentheses.

Figure 5.

Schematic diagram of the progressive nature of ABCA4-associated retinopathy. The disease duration was calculated as the difference between the age of presentation and the age of onset. As the disease duration increased, the fundus changed from early typical bull's-eye macular degeneration (Stage I) to advanced pigmentary degeneration (Stage IV). The OCT examinations showed macular atrophy that developed into a serious choroid structure disorder. ERG showed normal rod and cone responses at the early stage, while cone and rod dystrophy occurred at the advanced stage. FFA, fluorescein fundus angiography.