Retinal Structure and Function in Achromatopsia

Abstract

Purpose To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy. Design Cross-sectional study. Participants Forty subjects with ACHM. Methods All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (i) continuous inner segment ellipsoid (ISe), (ii) ISe disruption, (iii) ISe absence, (iv) presence of a hyporeflective zone (HRZ), and (v) outer retinal atrophy including retinal pigment epithelial (RPE) loss. Foveal and outer nuclear layer (ONL) thickness was measured, and presence of hypoplasia determined. Main Outcome Measures Photoreceptor appearance on SD-OCT imaging; foveal and ONL thickness; presence of foveal hypoplasia; retinal sensitivity and fixation stability; and association of these parameters with age and genotype. Results Forty subjects with mean age of 24.9 years (range 6 to 52) were included. Disease-causing variants were found in CNGA3 (n=18), CNGB3 (n=15), GNAT2 (n=4), and PDE6C (n=1). No variants were found in 2 individuals. 22.5% of subjects had a continuous ISe layer at the fovea; 27.5% had ISe disruption; 20% had an absent ISe layer; 22.5% had a HRZ; and 7.5% had outer retinal atrophy. No significant differences in age (p=0.77), mean retinal sensitivity (p=0.21) or fixation stability (p=0.34) across the 5 SD-OCT categories were evident. No significant correlation was found between age and foveal thickness (p=0.84), or between age and foveal ONL thickness (p=0.12). Conclusions The lack of clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring their impact.

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration

“…The external limiting membrane and INL were selected for reference because these layers are considered to be the least altered in early disease and their intensities are relatively constant across a wide eccentricity. 27,36 Other authors have suggested the use of the vitreous or retinal nerve fiber layer (RNFL) as a reference for intensity profiles. 37,38 We avoided using the vitreous as a reference given the reflectivity of this region depended on the presence of a posterior vitreous detachment.…”

Achromatopsia: On the Doorstep of a Possible Therapy

“…Several clinical studies in recent years have investigated outer retinal architecture and foveal morphology in detail using high-resolution optical coherence tomography (OCT) and adaptive optics [12,13,14,27,29,30,31,32,33,34]. The macular appearance in OCT can show either normal lamination or variable degrees of disruption of the photoreceptor layers and loss of retinal pigment epithelium.…”

“…Most recently, mutations in the activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), have also been asscociated with ACHM [28]. Although ACHM is considered a functionally stationary disease affecting only the cone system, recent studies have described age-dependent progressive changes in retinal architecture, including photoreceptor cell loss as well as macular changes [12,13,14]. …”

“…Most recently, gene replacement therapy performed on animal models for three ACHM genes (CNGA3, CNGB3, and GNAT2) have shown promising results [15,16,17,18,19]. Accurate genetic and clinical diagnosis of patients will therefore enhance and enable therapeutic intervention in the near future [1,3,4,12,13]. …”

Cortical processing of global form, motion and biological motion under low light levels

“…These measures have become increasingly used as indicators of visual function beyond early processing in primary visual cortex. With the advance of new treatments for rod and cone dystrophies, such as gene therapy (Bainbridge et al, 2015;Cideciyan et al, 2008;Jacobson et al, 2012;Komáromy et al, 2010;Sundaram et al, 2014;Zelinger et al, 2015) it is becoming increasingly important to understand how different aspects of visual function, including higher cortical visual functions, are influenced by rod and cone loss. Gaining an understanding of visual function in observers with healthy vision under light conditions designed to activate rods and/or cones will provide important baseline information for comparison with retinal dystrophy patients before and after treatment with new therapies.…”