Rod-Cone Dystrophy with Initially Preserved Visual Acuity Despite Early Macular Involvement Suggests Recessive CERKL Mutations

Purpose: To highlight that recessive CERKL mutations cause an early-onset rod-cone dystrophy with initially preserved visual acuity despite early macular involvement, an unusual and distinct initial phenotypic presentation.

Methods: A retrospective case series.

Results: Two young Saudi Arabian adults complained of worsening night blindness over the preceding few years, one of whom had been symptomatic since early childhood. Both had retinal pigment epithelium (RPE) mottling/granularity, vascular attenuation, few bone spicules, and frank macular RPE atrophic changes despite relatively preserved visual acuity. Electroretinography was non-recordable, and ocular coherence tomography confirmed retinal thinning, particularly of the outer nuclear layer in the fovea. Each patient harbored a different homozygous CERKL mutation (p.L245P, p.C333*). The few prior reports that detail the presenting phenotype of CERKL mutations describe children or young adults with the similar unusual presenting constellation of findings: rod-cone dystrophy and frank macular atrophy but relatively preserved visual acuity. With time, central vision is affected.

Conclusions: The initial presenting features of CERKL-related retinopathy are distinct and unusual. Recognition of this initial presenting phenotype can facilitate earlier molecular diagnosis and genetic counseling.     

Evidence for the contribution of non-covalent steroid interactions between DNA and topoisomerase in the genotoxicity of steroids

Fifty two steroids and 9 Vitamin D analogs were docked into ten crystallographically-defined DNA dinucleotide sites and two human topoisomerase II ATP binding sites using two computational programs, Autodock and Surflex. It is shown that both steroids and Vitamin D analogs exhibit a propensity for non-covalent intercalative binding to DNA. A higher predicted binding affinity was found, however, for steroids and the ATP binding site of topoisomerase; in fact these drugs exhibited among the highest topo II binding observed in over 1370 docked drugs. These findings along with genotoxicity data from 26 additional steroids not subjected to docking analysis, support a mechanism wherein the long known, but poorly understood, clastogenicity of steroids may be attributable to inhibition of topoisomerase. A “proof of principle” experiment with dexamethasone demonstrated this to be the likely mechanism of clastogenicity of, at least, this steroid. The generality of this proposed mechanism of genotoxicity across the steroids and vitamin-D analogs is discussed.