Achromatopsia is an autosomal recessive condition, characterised by reduced visual acuity, impaired colour vision, photophobia and nystagmus. The symptoms can be profoundly disabling, and there is no cure currently available. However, the recent development of gene-based interventions may lead to improved outcomes in the future. This article aims to provide a comprehensive review of the clinical features of the condition, its genetic basis and the underlying pathogenesis. We also explore the insights derived from animal models, including the implications for gene supplementation approaches. Finally, we discuss current human gene therapy trials.

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.

PurposeTo longitudinally characterize structural retinal changes in achromatopsia (ACHM) over extended follow-up.MethodsFifty molecularly confirmed ACHM subjects underwent serial spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Foveal structure on SD-OCT was graded and compared for evidence of progression, and foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness were serially measured. FAF patterns were characterized and compared over time.ResultsMean SD-OCT follow-up was 61.6 months (age range at baseline, 6–52 years). Forty-five of the subjects had serial FAF (mean follow-up: 48.5 months). Only 6 (12%) of the subjects demonstrated qualitative change on serial foveal SD-OCT scans. Among the entire cohort, there was no statistically significant change over time in FTRT (P = 0.2459) or hyporeflective zone (HRZ) diameter (P = 0.3737). There was a small—but statistically significant—increase in ONL thickness (P = 0.0084). Three different FAF patterns were observed: centrally increased FAF (13/45), normal FAF (14/45), and well-demarcated reduced FAF (18/45), with the latter group displaying a small gradual increase in the area of reduced FAF of 0.055 mm2 over 43.4 months (P = 0.0011).ConclusionsThis longitudinal study of retinal structure in ACHM represents the largest cohort and longest follow-up period to date. Our findings support the presiding notion that ACHM is essentially a stationary condition regarding retinal structure, and any change over time is likely to be small, slow, and variable across patients. This may potentially afford a wider window for therapeutic intervention.