Photoreceptor Structure inGNAT2-Associated Achromatopsia

Abstract

The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. METHODS. Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. RESULTS. All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7−12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 μm (28.57−113.33, ± 25.46 μm) and 86.47 μm (28.57−113.33, ± 24.65 μm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 μm, 350 μm, and 500 μm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×10 3 cones/mm 2 , respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. CONCLUSIONS. The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.

Long-Term Investigation of Retinal Function in Patients with Achromatopsia

“… 15 , 16 In CNGA3 and CNGB3 genotypes, variable degrees of ellipsoid zone (EZ) disruption and residual cone structure have been observed. 16 – 20 GNAT2 -ACHM typically presents with a continuous EZ, 21 , 22 in contrast to PDE6C -ACHM and ATF6 -ACHM, for which most of the patients have no residual foveal cones. 11 , 23 Evidence of structural changes over time has been suggested by some studies 24 , 25 but not others.…”

Intraobserver Repeatability and Interobserver Reproducibility of Foveal Cone Density Measurements in CNGA3- and CNGB3-Associated Achromatopsia

“…[21][22][23][24] Marked variability in the cone mosaic has been observed across patients with ACHM. 23,[25][26][27][28] Nonconfocal split-detection AOSLO demonstrated that inner segment structure remained in these "dark spaces." The degree of remnant inner segment structure may be important for participant selection for gene therapy trials and could be used to identify patients most likely to benefit from cone-directed rescue.…”

“… 21 – 24 Marked variability in the cone mosaic has been observed across patients with ACHM. 23 , 25 – 28 Nonconfocal split-detection AOSLO demonstrated that inner segment structure remained in these “dark spaces.” The degree of remnant inner segment structure may be important for participant selection for gene therapy trials and could be used to identify patients most likely to benefit from cone-directed rescue. Peak foveal cone density is a widely used metric, both as an anchor for locating other regions of interest and as a statistic in its own right; however, there have been relatively few studies examining the repeatability of these measurements.…”

Preservation of the Foveal Avascular Zone in Achromatopsia Despite the Absence of a Fully Formed Pit

“…Most notably, only individuals with CNGA3 or CNGB3 genotypes were included. While there are reported differences in cone structure in the GNAT2, 59,60 ATF6, 61 and PDE6C forms of ACHM, 62 it is unknown whether a FAZ is present in individuals with ACHM caused by these genotypes. Additionally, there are reports of residual cone function in patients with ACHM, 63 and patients with GNAT2-associated ACHM have been reported to have cone-mediated visual function at high radiances (although only at low temporal frequencies).…”