Diminished light adaptation effect seen in cone-driven responses in GRK1-associated Oguchi disease: evidence for possible rod input to cone adaptation pathways

Abstract

Purpose : The Light Adaptation Effect (LAE) refers to the growth in amplitude, over several minutes, of electroretinogram (ERG) responses to flashes delivered in the presence of a photopic background following prior dark adaptation. It is not known whether rod-driven mechanisms contribute. We investigated this effect in a patient in whom the light-sensitive rod outer segment current was permanently abolished due to constitutive activation of phototransduction.

Methods : A 36 year old patient with a clinical diagnosis of Oguchi disease underwent international standard ERG testing and also the following experimental electrophysiological protocol. The patient dark adapted for 20 minutes and was then exposed to a standard white background (30 cd m^-2). White flashes (3 cd m^-2 s) were delivered (in groups of 36 flashes, repeated every 2 minutes) for the next 20 minutes. Pupils were pharmacologically dilated and responses recorded using conductive fibre electrodes. Responses were compared with those obtained in identical protocols from 8 healthy subjects (aged 21-39).

Results : International standard electrophysiological testing in the patient showed reduced dark-adapted responses and light-adapted responses that were within normal limits. Genetic screening revealed no pathogenic variants in SAG (encoding the protein arrestin), but novel heterozygous mutations in GRK1 (encoding rhodopsin kinase) were observed. For the experimental ERG protocol, in the healthy subjects, the b-wave amplitude approximately doubled over the recording period, with a median increase in amplitude of 90%. In the patient, the amplitude increased by less than 15% in both eyes.

Conclusions : The patient showed a markedly diminished LAE compared with healthy volunteers. We hypothesise that this was due to constitutively abolished rod outer segment current (with consequent rod hyperpolarisation) in both light and dark, and suggests that in healthy subjects, the LAE is driven by changes in rod signalling from dark to light. We have previously found a normal LAE in a patient with unilaterally impaired rod-driven inner retinal signalling, and speculate that the relevant rod-driven signals might input into the cone pathway at an earlier stage possibly via gap junctions between photoreceptors.

This is a 2020 ARVO Annual Meeting abstract.