Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates
Maximilian Pfau, … , Brett G. Jeffrey, Brian P. Brooks
Maximilian Pfau, … , Brett G. Jeffrey, Brian P. Brooks
Published January 25, 2022
Citation Information: JCI Insight. 2022;7(2):e155373. https://doi.org/10.1172/jci.insight.155373.
View: Text | PDF
Clinical Medicine Ophthalmology

Photoreceptor degeneration in ABCA4-associated retinopathy and its genetic correlates

Abstract

BACKGROUND Outcome 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.METHODS We 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.RESULTS Patients 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.CONCLUSION Patients 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 REGISTRATION ClinicalTrials.gov identifier: NCT01736293.FUNDING National Eye Institute Intramural Research Program and German Research Foundation grant PF950/1-1.

Authors

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

×

Figure 3

Retinal layer abnormalities outside the area of ellipsoid zone (EZ) loss.

Options: View larger image (or click on image) Download as PowerPoint
Retinal layer abnormalities outside the area of ellipsoid zone (EZ) loss...
The line plots show the normalized retinal layer thicknesses (y axis) outside the area of EZ-loss in eyes with STGD1 as a function of the distance to the EZ-loss boundary (x axis). The horizontal, red, dashed lines denote ±2 z score units (i.e., the normative range). The vertical, black, dashed lines indicate the distances 0.43°, 1.29°, 2.58°, 5.16°, and 7.73° (multiples of a Goldmann III stimulus diameter) to the EZ-loss boundary, which correspond to the average distance to normalization of thickness for the inner retina (INNER), outer nuclear layer (ONL), and photoreceptor inner segments (IS) and outer segments (OS). For these distances, changes over time in layer thicknesses are shown in Figure 4. Of note, INNER, ONL, IS, and OS are all severely thinned even outside the area of EZ-loss. The retinal pigment epithelium (RPE) shows thickening outside of EZ-loss. For the choroid (CHO), no marked changes in terms of thickness are evident. These plots are based on the data from the baseline of the natural history up to the last visit of each patient (N of patients = 66).