Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy

Abstract

PurposeTo describe the earliest features of ABCA4-associated retinopathy.DesignCase series.ParticipantsChildren with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy.MethodsThe retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients.Main Outcome MeasuresVisual acuity, OCT, FAF, electroretinography, and AOSLO results.ResultsEight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave–to–A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results.ConclusionsIn childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.

The absence of fundus abnormalities in Stargardt disease

“…Recently, Khan et al reported the earliest features of ABCA4-associated retinopathy [20]. In their study, they included eight children (six prospectively) to describe their ophthalmologic features.…”

Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings

“…This indicates that the photoreceptor layer never becomes entirely atrophic as in other macular dystrophies such as Stargardt disease and achromatopsias. 13,[30][31][32] The normally preserved RPE and partially preserved photoreceptor layer even in the late stage are the most essential characteristics of OMD. This preservation accounts for the fact that almost all patients with OMD are able to read large letters even in the late stage.…”

Novel Insight into Morphological Features and Vascular Profile of Selected Macular Dystrophies Using Swept-Source Optical Coherence Tomography and Optical Coherence Tomography Angiography

“…Currently, the available diagnostic modalities rely on inference extrapolated from indirect evidence to determine disease stage and progression. For instance, FFA depicts disease patterns based on varying degrees of fluorescence; FAF identifies diseased or dead RPE cells based on varying intensities of lipofuscin autofluorescence, whereas electrophysiology records the amplitude and latency of electric transduction in retinal layers to identify different dystrophies [1][2][3][8][9][10][11]. The common factor among these diagnostic tools is that they reveal useful information only when retinal function due to a given dystrophy has already been compromised.…”

“…More recently, fundus autofluorescence (FAF) increasingly became an invaluable noninvasive tool in the follow-up scheme of these patients [1][2][3][4][5][6][7]. FAF captures the stimulated emission of light from lipofuscin molecules that accumulate excessively in cases of retinal pigment epithelium (RPE) dysfunction and depicts specific autofluorescence patterns that are characteristic for each disease [8][9][10][11]. To date, there is no known effective treatment for macular dystrophies other than the management of complications, for example, choroidal neovascularization (CNV) secondary to Best's disease and visual rehabilitation using low-vision aids [1,2].…”