Multi-modal adaptive optics imaging in GUCA1A-associated autosomal dominant cone-rod dystrophy

Abstract

Purpose : Mutations in the guanylate cyclase activator 1A (GUCA1A) gene cause an autosomal dominant cone-rod dystrophy (adCRD). Here, we use adaptive optics scanning light ophthalmoscopy (AOSLO) to investigate the cellular phenotype of GUCA1A-adCRD.

Methods : The proband, age 51, and her asymptomatic children (son, age 15; daughter, age 16) underwent a comprehensive ophthalmic examination. The maculae were imaged using a custom-built, multimodal AOSLO system, spectral-domain optical coherence tomography (OCT) and fundus autofluorescence (FAF)(short-wavelength, SW and near-infrared, NIR). AOSLO images were registered, montaged, and 131 regions of interest (ROIs) were selected. Cones were manually identified (MOSAIC, Translational Imaging Innovations) and cone density calculated. Visual function was measured with light- and dark-adapted chromatic perimetry and full-field electroretinography (ERG).

Results : Visual acuity was abnormal in the mother (~20/50), normal in her children. On OCT there was outer nuclear layer thinning at the fovea (mother=14% of normal mean, children=74%) and parafovea (all patients=~50%), and interruption of the ellipsoid zone and interdigitation zone (IZ) signals at the fovea in the mother, subtle IZ loss in her children. A granular SW-FAF signal present within ~1.5mm of eccentricity was centered by denser hypo-FAF in the central foveas. NIR-FAF abnormalities were less severe. There was an absolute central scotoma extending to ~2° in the mother and parafoveal losses of cone-mediated sensitivities in all patients; rod-mediated sensitivities were within normal limits. Rod ERGs were normal; cone ERGs were abnormally reduced. Heterozygous mutations in GUCA1A (p.Tyr99Cys) were identified in all patients. AOSLO revealed severe loss of cones in all ROIs. The proband’s foveal cone density was ~15% of normal (children=~50%). Parafoveal cone densities fell rapidly in all patients to ≤2% of normal by 4° of eccentricity. The proband’s cones and a subset of the children’s cones showed visible inner segments but severely reduced or absent confocal waveguided reflectance.

Conclusions : AOSLO confirmed a primary abnormality at the cone outer segment preceding photoreceptor loss in GUCA1A-adCRD. The results support an early and perhaps homogeneous loss of cones across the central retina causing proportionally greater cone losses in the less dense cone photoreceptor population of the parafovea.

This is a 2020 ARVO Annual Meeting abstract.