Adaptive Optics Retinal Imaging inCNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability

Abstract

Citation: Georgiou M, Litts KM, Kalitzeos A, et al. Adaptive optics retinal imaging in CNGA3-associated achromatopsia: retinal characterization, interocular symmetry, and intrafamilial variability. Invest Ophthalmol Vis Sci. 2019;60:383-396. https://doi.org/ 10.1167/iovs.18-25880 PURPOSE. To investigate retinal structure in subjects with CNGA3-associated achromatopsia and evaluate disease symmetry and intrafamilial variability.METHODS. Thirty-eight molecularly confirmed subjects underwent ocular examination, optical coherence tomography (OCT), and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans were used for evaluating foveal hypoplasia, grading foveal ellipsoid zone (EZ) disruption, and measuring outer nuclear layer (ONL) thickness. AOSLO images were used to quantify peak foveal cone density, intercell distance (ICD), and the coefficient of variation (CV) of ICD.RESULTS. Mean (6SD) age was 25.9 (613.1) years. Mean (6 SD) best corrected visual acuity (BCVA) was 0.87 (60.14) logarithm of the minimum angle of resolution. Examination with OCT showed variable disruption or loss of the EZ. Seven subjects were evaluated for disease symmetry, with peak foveal cone density, ICD, CV, ONL thickness, and BCVA not differing significantly between eyes. A cross-sectional evaluation of AOSLO imaging showed a mean (6SD) peak foveal cone density of 19,844 (613,046) cones/mm 2 . There was a weak negative association between age and peak foveal cone density (r ¼ À0.397, P ¼ 0.102), as well as between EZ grade and age (P ¼ 0.086).CONCLUSIONS. The remnant cone mosaics were irregular and variably disrupted, with significantly lower peak foveal cone density than unaffected individuals. Variability was also seen among subjects with identical mutations. Therefore, subjects should be considered on an individual basis for stratification in clinical trials. Interocular symmetry suggests that both eyes have comparable therapeutic potential and the fellow eye can serve as a valid control. Longitudinal studies are needed, to further examine the weak negative association between age and foveal cone structure observed here.

Photoreceptor Structure inGNAT2-Associated Achromatopsia

“…Foveal hypoplasia is a common feature in ACHM cohorts: all reported subjects with ATF6-ACHM, 23 and two thirds of the reported CNGA3-and CNGB3-ACHM subjects, have foveal hypoplasia. 10,22,28 In our cohort of GNAT2-ACHM, no case of foveal hypoplasia was observed, a finding similar to PDE6C-ACHM. 24 GNAT2 encodes guanine nucleotidebinding protein G(t) subunit alpha-2, which is part of the transducin complex, a G-protein participating in the visual cycle.…”

“…In contrast, in CNGA3and CNGB3-ACHM, peak cone density is severely reduced, with mean densities lower than the reported values for R1 (190 μm away from the fovea) in our cohort. 22,28 Scotoma on mesopic microperimetry was reported in all examined patients with GNAT2 (4/4), whereas only in 1 of 33 subjects examined with CNGA3-and CNGB3-ACHM. 10 In addition, BCVA, contrast sensitivity, reading acuity, and mean sensitivity were lower in the GNAT2 compared with the CNGA3 or CNGB3 groups.…”

“…7 Similar structural intrafamilial variability has also been reported in pedigrees of CNGA3-ACHM. 22 Due to the recessive inheritance and the rarity of ACHM, data for intrafamilial variability are limited. The above finding of loss of foveal EZ in patient P6, combined with the stable imaging findings over follow-up (Fig.…”

“…[18][19][20][21] Marked variability in the cone mosaic has been observed across patients; among the two most common genotypes, CNGA3 and CNGB3. 10,19,22 In contrast, in ATF6-ACHM and PDE6C-ACHM, few if any residual foveal cones were identified. 23,24 The GNAT2-ACHM genotype is associated with the relatively least disrupted photoreceptor mosaic.…”

Cone Identification in Choroideremia: Repeatability, Reliability, and Automation Through Use of a Convolutional Neural Network

“…2,3 Main advantages of AO ophthalmoscopy include the ability to observe single cells in vivo and to track those same cells over time. Indeed, AO ophthalmoscopy has been used to describe the degeneration of cone photoreceptor structure using metrics, such as cone density or spacing, in numerous inherited retinal diseases, including retinitis pigmentosa, [4][5][6][7] Stargardt's, [8][9][10] achromatopsia, [11][12][13][14] and choroideremia (CHM), [15][16][17] among others. 2,3 In addition, investigators have demonstrated longitudinal imaging of the same photoreceptors over time.…”