Clinical and histopathologic characteristics of autosomal dominant cone-rod dystrophy caused by mutations in the CRX gene

Abstract

Purpose : Cone-rod homeobox (CRX) is an essential protein for the development and maintenance of rod and cone photoreceptors. Mutations in the gene can lead to several forms of inherited retinal degeneration. In this multicenter study, we describe the phenotypic, genotypic and histopathological characteristics of CRX-associated retinal dystrophies.

Methods : In order to characterize the phenotypic and genotypic features, medical records were reviewed. Clinical data and imaging was collected from multiple European centers to describe the phenotypic and genotypic spectrum. Furthermore, immunohistochemistry was performed on the retina of a patient with CRX-associated retinal dystrophy, to visualize photoreceptor degeneration. Tissue fragments were excised from the macular and peripheral areas of the patient’s retina and an age- and gender-matched control. Cryosections were obtained and immunostained for rod, cone and bipolar cell specific proteins and imaged with a confocal microscope.

Results : In 39 patients from 31 families, 21 different autosomal dominant CRX variants were identified, including missense and frameshift mutations. Phenotypes were highly heterogeneous, ranging from mild, late-onset macular dystrophy to Leber congenital amaurosis leading to congenital blindness. Age at onset ranged from at birth to the 8^th decade. Mean visual acuity was 0.16±0.21 Snellen at a mean age of 52.3±19.9 years.
Immunohistochemical analysis of the eye of a 17-year-old patient with a deletion of exons three and four in one allele of CRX revealed extensive photoreceptor degeneration and loss of laminar integrity in the neuroretina. The degeneration was concentrated in the central retina, where the thickness of the outer nuclear layer was markedly reduced. Near the macula, complete loss of rods and short-wavelength cones was observed. Mislocalized photoreceptor nuclei and outer segment proteins were observed throughout the retina.

Conclusions : This study found a large phenotypic variation in patients with mutations in CRX. Histopathological analysis demonstrated widespread photoreceptor cell loss, especially in the central retina. These findings mimic features commonly found in animal models for CRX-associated retinal disease and align with clinical observations.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.