Highlighting the Supernormal Intensity Response of the photopic ERG a-wave in Enhanced S-cone Syndrome (ESCS)

Abstract

Purpose : Enhanced S-cone Syndrome (ESCS) is a rare autosomal recessive inherited retinal dystrophy. It is associated with a pathognomonic full field electroretinogram (ffERG). In 1994, prior to identification of NR2E3 as the main causative gene, Hood et al. (PMID: 7645276) described ERG a-wave findings in three ESCS patients establishing the presence of an abnormally large number of S-cones. Our study aims to describe the supernormal a-wave response amplitude ratio of a high-intensity bright light flash normalized to that of the ISCEV standard in a prospectively followed and molecularly confirmed ESCS cohort.

Methods : Twelve (5 female, 7 male) molecularly confirmed ESCS patients and six healthy controls sat for photopic ERG with both an ISCEV standard (LA3.0, 2.50 cd.s.m^-2) and a bright stimulus (LA30.0, 31.47 cd.s.m^-2). ERGs were obtained with Burian-Allen electrodes. An exact Mann-Whitney U two-tailed test was used to compare normative (6 eyes) and right eye ESCS data, and a paired Wilcoxon test was used to compare ESCS right and left eye data.

Results : Two NR2E3 variants were prominent in our study, namely splicing variant c.119-2A>C in seven patients (homozygous in four) and c.932G>A in four patients (homozygous in two).
Mean age of ESCS patients at time of ERG testing was 41 years and ranged from 17-65 years; for healthy controls mean age was 35 (range 25-54 years). ERG responses were extinguished for three patients older than 60 years of age.
LA3.0 a-wave mean (SEM) amplitude was 39.83 (4.99) uV in the normative cohort and 24.61 (4.40) uV in the ESCS eyes (U=9, p=0.0360). LA30.0 a-wave mean (SEM) amplitude was 72.61 (8.45) uV in the normative cohort and 133.6 (35.51) uV in the ESCS eyes (U=21, p=0.5287). The mean (SEM) ratio of a-wave amplitudes of LA30.0/LA3.0 measured 1.870 (0.16) in the healthy eyes and 4.506 (0.75) in the ESCS right eyes (U=2, p=0.0016). Left eye ratio was 5.832 (1.02). In our cohort, the higher ratio persists as long as enough S-cones are present to drive a measurable photopic response. There was no significant difference between ESCS eyes (p=0.3594).

Conclusions : The ratio of the LA30.0/LA3.0 photopic a-wave amplitudes is simple to obtain and can be an additional marker for the clinical diagnosis of ESCS, as well as a potential therapeutic outcome measure. It may be useful supplement for better AI-predictions of genes associated with inherited retinal diseases.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.