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.

To determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability.DESIGN: Prospective cohort study. METHODS: Children and adults with molecularly confirmed STGD1 (n [ 90) underwent longitudinal FAF imaging with subsequent semiautomated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n [ 86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n [ 56), adults with childhood-onset STGD1 (n [ 15), and adults with adult-onset (n [ 19). Fifty FAF images were selected randomly and analyzed by 2 observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype-phenotype correlations, and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations.RESULTS: The mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n [ 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n [ 19). The intra-and interob-Supplemental Material available at AJO.com.

Purpose Mutations in six genes have been associated with achromatopsia (ACHM): CNGA3 , CNGB3 , PDE6H , PDE6C , GNAT2 , and ATF6. ATF6 is the most recent gene to be identified, though thorough phenotyping of this genetic subtype is lacking. Here, we sought to test the hypothesis that ATF6 -associated ACHM is a structurally distinct form of congenital ACHM. Methods Seven genetically confirmed subjects from five nonconsanguineous families were recruited. Foveal hypoplasia and the integrity of the ellipsoid zone (EZ) band (a.k.a., IS/OS) were graded from optical coherence tomography (OCT) images. Images of the photoreceptor mosaic were acquired using confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Parafoveal cone and rod density values were calculated and compared to published normative data as well as data from two subjects harboring CNGA3 or CNGB3 mutations who were recruited for comparative purposes. Additionally, nonconfocal dark-field AOSLO images of the retinal pigment epithelium were obtained, with quantitative analysis performed in one subject with ATF6 -ACHM. Results Foveal hypoplasia was observed in all subjects with ATF6 mutations. Absence of the EZ band within the foveal region (grade 3) or appearance of a hyporeflective zone (grade 4) was seen in all subjects with ATF6 using OCT. There was no evidence of remnant foveal cone structure using confocal AOSLO, although sporadic cone-like structures were seen in nonconfocal split-detection AOSLO. There was a lack of cone structure in the parafovea, in direct contrast to previous reports. Conclusions Our data demonstrate a near absence of cone structure in subjects harboring ATF6 mutations. This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6- ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3 - or CNGB3 -ACHM.