The Cone Photoreceptor Mosaic in Aniridia

Abstract

Purpose: Investigate in-vivo cone photoreceptor structure in familial aniridia caused by a deletion in the PAX6 gene to elucidate the complexity of between-individual variation in retinal phenotype. Design: Descriptive case-control study Participants: Eight persons with congenital aniridia (5 males; aged 40-66) from one family and 33 normal controls (14 males, aged 14-69 yrs), including seven unaffected family members (3 males; aged 14-53yrs). Methods: DNA was isolated from saliva samples and used in PCR to amplify and sequence exons and intron/exon junctions of the PAX6 gene. Fluorescent DNA sequencing was performed on both DNA strands. High-resolution retinal images were acquired with Heidelberg Spectralis (SD-OCT2) and Adaptive optics scanning light ophthalmoscopy (AOSLO). Cone density (CD; cones/mm 2) and mosaic regularity were estimated along nasaltemporal meridians within the central 0-5° eccentricity. Horizontal SD-OCT line scans were segmented to analyze severity of foveal hypoplasia and measure retinal layer thicknesses. Main Outcomes and Measures: Within-family variability in macular retinal layer thicknesses, cone photoreceptor density and mosaic regularity in aniridia compared with normal controls. Results: DNA sequencing revealed a known PAX6 mutation (IV2-2delA). Those with aniridia had variable iris phenotype ranging from almost normal appearance to no iris. Four with aniridia had FH grade 2, two had grade 3 and one had grade 4. Visual acuity ranged from 0.20-0.86 logMAR. AOSLO images were acquired of five family members with aniridia. Foveal CD varied between 19899 and 55128 cones/mm with overlap between the foveal hypoplasia grades. CD was ≥3 SD below the normal mean within 0.5°, ≥2 SD below the normal mean at 0.5°-4°, and >1SD below the normal mean at 5° retinal eccentricity. Conclusions: The results show considerable variability in foveal development within a family carrying the same PAX6 mutation. This, together with the structural and functional variability within each grade of foveal hypoplasia, underlines the importance of advancing knowledge about retinal cellular phenotype in aniridia. a AAK = Aniridia-associated keratopathy; b CAD-LV = low vision version of the Color Assessment and Diagnosis test; c RG = red-green; d Values derived from data collected by Pedersen et al.

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

“…mutation, a 2 bp deletion in intron 2, presented with variable iris involvement, which ranged from almost normal to no iris, as well as different degrees of foveal hypoplasia [114,115]. In contrast, Lagali et al recently found a correlation between PAX6 variants and the severity and progression of ARK [116,117]. In a cohort of 46 aniridia patients, the authors found a minimal level of keratopathy and an increase in cornea thickness in all aniridia patients from early age.…”

“…However, aniridia patients can present with a wide phenotypic spectrum without clear correlation between genotype and phenotype, even in patients within the same family [15]. Accordingly, a recent report from Pedersen et al showed that family members with the same PAX6 mutation, a 2 bp deletion in intron 2, presented with variable iris involvement, which ranged from almost normal to no iris, as well as different degrees of foveal hypoplasia [115,116]. In contrast, Lagali et al recently found a correlation between PAX6 variants and the severity and progression of ARK [117,118].…”

The Relationship Between Perifoveal L-Cone Isolating Visual Acuity and Cone Photoreceptor Spacing—Understanding the Transition Between Healthy Aging and Early AMD

“…The registered and averaged AOSLO images were scaled for each participant’s retinal magnification ratio in the same way as the OCT images. The processed images were stitched together into a mosaic aligned to the corresponding infrared en-face image acquired simultaneously with the OCT B-scans ( Pedersen et al, 2019 ). The foveal center was identified anatomically on images as described previously ( Pedersen et al, 2019 ).…”

“…The processed images were stitched together into a mosaic aligned to the corresponding infrared en-face image acquired simultaneously with the OCT B-scans ( Pedersen et al, 2019 ). The foveal center was identified anatomically on images as described previously ( Pedersen et al, 2019 ). Individual cones were identified via a semi-automatic algorithm ( Li and Roorda, 2007 ; Garrioch et al, 2012 ).…”

“…This lack of understanding is compounded by most studies being cross-sectional in design, where the small effect size expected for a given individual is likely to be dwarfed by inter-individual variability. For example, individual differences in cone density are large, even in young, healthy eyes ( Li and Roorda, 2007 ; Dees et al, 2011 ; Song et al, 2011 ; Zhang et al, 2015 ; Elsner et al, 2017 ; Pedersen et al, 2019 ). Refractive errors, such as myopia affect cone distribution ( Chui et al, 2008 ; Wang et al, 2019 ) and are associated with myopic macular degeneration ( Fricke et al, 2018 ).…”