Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates.

Maximilian Pfau,Ehsan Ullah,Catherine A Cukras,Aarti S Hinduja,Brett G Jeffrey,Brian P Brooks,Wadih M Zein,Amy Turriff,Laryssa A Huryn,Robert B Hufnagel,Marisa P Boyle,Michelle A Chen,Hermann E.A Siebel

doi:10.1172/jci.insight.155373

Abstract

BACKGROUNDOutcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4–associated (ABCA4-associated) retinopathy. We aimed to quantify ellipsoid zone (EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4-associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age.METHODSWe analyzed 132 eyes from 66 patients (of 67 enrolled) with molecularly confirmed ABCA4-associated retinopathy from a prospective natural history study with a median [IQR] follow-up of 4.2 years [3.1, 5.1]. Longitudinal spectral-domain optical coherence tomography volume scans (37 B-scans, 30° × 15°) were segmented using a deep learning (DL) approach. For genotype-phenotype analysis, a model of ABCA4 variants was applied with the age of criterion EZ-loss (6.25 mm2) as the dependent variable.RESULTSPatients exhibited an average (square-root-transformed) EZ-loss progression rate of [95% CI] 0.09 mm/y [0.06, 0.11]. Outer nuclear layer (ONL) thinning extended beyond the area of EZ-loss. The average distance from the EZ-loss boundary to normalization of ONL thickness (to ±2 z score units) was 3.20° [2.53, 3.87]. Inner segment (IS) and outer segment (OS) thinning was less pronounced, with an average distance from the EZ-loss boundary to layer thickness normalization of 1.20° [0.91, 1.48] for the IS and 0.60° [0.49, 0.72] for the OS. An additive model of allele severity explained 52.7% of variability in the age of criterion EZ-loss.CONCLUSIONPatients with ABCA4-associated retinopathy exhibited significant alterations of photoreceptors outside of EZ-loss. DL-based analysis of photoreceptor laminae may help monitor disease progression and estimate the severity of ABCA4 variants.TRIAL REGISTRATIONClinicalTrials.gov identifier: NCT01736293.FUNDINGNational Eye Institute Intramural Research Program and German Research Foundation grant PF950/1-1.

Highlights

Stargardt disease (Stargardt disease-1, STGD1; MIM #248200) is the most common cause of inherited macular dystrophy, with a prevalence between 1 in 8000 to 10,000 [1]
(iv) this study provides a framework to impute the age of criterion ellipsoid zone (EZ)-loss to quantify the severity of individual ABCA4 variants in an interval-scaled manner
spectral-domain optical coherence tomography (SD-OCT) volume scans could not be obtained from 1 study participant with poor fixation nasal to the optic disc; this participant was excluded from the present analysis (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.155373DS1)

Summary

Introduction

Stargardt disease (Stargardt disease-1, STGD1; MIM #248200) is the most common cause of inherited macular dystrophy, with a prevalence between 1 in 8000 to 10,000 [1] This autosomal-recessive disease is caused by mutations in the ABCA4 gene (ATP-binding cassette, sub-family A, member 4; OMIM #601691) coding for transmembrane transporter protein [2]. Patients may present clinically with a wide range of phenotypes, including early-onset cone-rod dystrophy [3], juvenile-onset retinal dystrophy affecting predominantly foveal function, or late-onset STGD1 with foveal sparing [4,5,6] This heterogeneity complicates the choice of outcome measures applicable across this broad phenotypic spectrum. We aimed to quantify ellipsoid zone (EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age

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