Hyperautofluorescent Dots are Characteristic in Ceramide Kinase Like-associated Retinal Degeneration

Abstract

There is a lack of studies which seek to discern disease expression in patients with mutations that alter retinal ceramide metabolism, specifically in the ceramide kinase like (CERKL) gene. This cross-sectional case series reports a novel phenotypic manifestation of CERKL-associated retinopathy. Four unrelated patients with homozygous CERKL mutations underwent a complete ocular exam, spectral-domain optical coherence tomography, short-wavelength fundus autofluorescence (SW-AF), quantitative autofluorescence (qAF), and full-field electroretinogram (ffERG). Decreased visual acuity and early-onset maculopathy were present in all patients. All four patients had extensive hyperautofluorescent foci surrounding an area of central atrophy on SW-AF imaging, which has not been previously characterized. An abnormal spatial distribution of qAF signal was seen in one patient, and abnormally elevated qAF8 signal in another patient. FfERG recordings showed markedly attenuated rod and cone response in all patients. We conclude that these patients exhibit several features that, collectively, may warrant screening of CERKL as a first candidate: early-onset maculopathy, severe generalized retinal dysfunction, peripheral lacunae, intraretinal pigment migration, and hyperautofluorescent foci on SW-AF.

A New Cerkl Mouse Model Generated by CRISPR-Cas9 Shows Progressive Retinal Degeneration and Altered Morphological and Electrophysiological Phenotype

“…Further work on the effect of reported mutations on the function of different CERKL isoforms may explain why in some patients the phenotypic traits are clinically associated with RP or CRD, which differ in whether rods (peripheral retina) or cones (macula) are first affected, respectively (see Supplementary Table S2 for a complete list of CERKL mutations and reported retinal phenotypes in human patients). However, genotype–phenotype correlation in human patients may be particularly difficult for CERKL , as the same pathogenic mutation in homozygosis can cause either autosomal recessive RP with high macular affectation 25 or autosomal recessive CRD, 7 , 32 not only in different families but also in sibling patients within the same family, 33 the main conclusion being that CERKL function is relevant for both types of photoreceptors. Also, the severity of retinopathy and visual loss in humans differ even in homozygous patients of the same family.…”

Primary versus Secondary Elevations in Fundus Autofluorescence

“…Thus, mutations in that gene would be expected to cause oxidative damage leading to photoreceptor cell death and retinal degeneration [154]. So far, only a handful of patients have been studied with the qAF protocols but the results indicate increased macular qAF levels in regions of advanced disease associated with RPE and photoreceptor degeneration (Figure 7C) [149]. Indeed, five out of six patients described in the literature have demonstrated borderline or substantially higher qAF values [149,155].…”

“…Mutations in the ceramide kinase-like (CERKL) gene have been reported to cause autosomal recessive RP and cone-rod dystrophy [147,148]. Clinical presentation involves early-onset maculopathy with severe generalized retinal dysfunction, peripheral lacunae, and hyperAF foci on SW-AF (Figure 7D) [149]. Current knowledge of the CERKL gene indicates it has protective functions for photoreceptor cells against oxidative stress through several pathways [150][151][152][153].…”

“…So far, only a handful of patients have been studied with the qAF protocols but the results indicate increased macular qAF levels in regions of advanced disease associated with RPE and photoreceptor degeneration (Figure 7C) [149]. Indeed, five out of six patients described in the literature have demonstrated borderline or substantially higher qAF values [149,155]. These results, along with the hyperAF foci in SW-AF images, support the theory of secondarily increased AF caused by disabled and/or degenerating photoreceptor cells.…”

Founder Mutation Effect Seen ByCERKLGene Mutation Causing Retinal Dystrophy in North Indian Population

“…Patients had mutations in the following - Homozygous c.847□JC□J>□JT (p.R283*) in two patients, c.769□JC□J>□JT (p.R257*) in one patient, and c.1303□JC□J>□JT (p.R435*) in one patient. (8) Sen et al described a novel variant, c.899-IG>A in the CERKL gene causing IRD. (9) Most recently, Varela et al described CERKL variants from the United Kingdom.…”