Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy

Kamron N Khan,Melissa Kasilian,Omar A.R Mahroo,Preena Tanna,Angelos Kalitzeos,Anthony G Robson,Kazushige Tsunoda,Takeshi Iwata,Anthony T Moore,Kaoru Fujinami,Michel Michaelides

doi:10.1016/j.ophtha.2017.11.020

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.

Highlights

Stargardt disease (STGD1; Online Mendelian Inheritance in Man identifier, 248200) is an autosomal recessive retinal dystrophy resulting from dysfunction in the photoreceptorspecific ATP-binding cassette transporter ABCA4
Retinal function was tested by full-field electroretinography and pattern electroretinography (PERG), obtained using either gold-foil electrodes, incorporating the current International Society for Clinical Electrophysiology of Vision (ISCEV) standards in 3 patients, or with Ganzfeld stimulation and lower eyelid skin electrodes in the 2 youngest children, according to pediatric protocols previously described.7e9 Genetic testing was performed by targeted exome sequencing for individuals at Moorfields Eye Hospital (MEH) (Stargardt/Macular dystrophy panel, version 3; Casey Eye Institute Molecular Diagnostics Laboratory, Portland, Oregon), or by whole exome sequencing for patients at Tokyo Medical Center as reported previously.[10]
Despite many significant advances, the Arrows denote outer edges of the region imaged on adaptive optics scanning laser ophthalmoscopy (AOSLO)

Summary

Introduction

Stargardt disease (STGD1; Online Mendelian Inheritance in Man identifier, 248200) is an autosomal recessive retinal dystrophy resulting from dysfunction in the photoreceptorspecific ATP-binding cassette transporter ABCA4. More than 1000 mutations in ABCA4 have been reported, associated with phenotypes that include macular, cone, or coneerod dystrophies.[1] Symptoms may develop as early as the first decade of life, but more commonly occur in the second or third decade. Because most reported cases of STGD1 manifest signs of macular atrophy at presentation, there is little information about earlier stages of disease. We present a series of patients with molecularly confirmed ABCA4-associated retinopathy without macular atrophy in which detailed retinal imaging and functional testing have provided new insights into the earliest stages of disease.

Methods

Results

Conclusion