Exploring rod system dysfunction in patients with CRX-associated retinopathy

Abstract

Purpose : To describe retinal dysfunction in patients with mutations in the cone-rod homeobox-containing (CRX) gene, and present results from extended experimental electroretinogram (ERG) protocols designed to extract the dark-adapted rod system response in a subset of patients.

Methods : Patients with CRX mutations, managed in the genetics clinic at Moorfields Eye Hospital, were identified from 22 families and classified according to the presence of either missense (group 1) or nonsense or frame-shifting mutations (Group 2). International standard full field ERGs were performed in 25 patients. Four patients underwent additional electrophysiological testing with white xenon flashes (3-50 cd m^-2 s) in the dark-adapted (DA) state (stimulating both rod and cone systems) followed by delivery of the same stimuli on a dim blue LED background (30 scotopic cd m^-2; <2 photopic cd m^-2), to saturate the rods with minimal effect on the cones. Mathematical subtraction from the DA responses yields estimated dark-adapted rod system responses. ERGs from the experimental protocols were compared with normative data from 200 healthy adult participants from the TwinsUK cohort.

Results : Data from 25 patients were analysed. Fourteen patients had subnormal dark-adapted ERG a-waves (6 from group 1 and 8 from group 2); 7 had electronegative strong-flash responses (4 from Group 1 and 3 from Group 2).In 4 patients, the waveform was not electronegative, but the b:a ratio was low (2 in each group). Extended ERG recordings in 4 patients showed subnormal rod-isolated a-waves, demonstrating that reduction in standard strong flash a-waves could not be attributed solely to loss of cone system contribution. In one patient, who had an electronegative standard strong flash ERG, the negative waveform persisted after subtraction of the cone system response.

Conclusions : CRX-associated retinopathy present with a spectrum of ERG phenotypes reflecting its diverse roles in the development and maintenance of the photoreceptors. Extended ERG protocols may be used to isolate rod system function and reveal different functional phenotypes including loss of rod photoreceptor function and rod system dysfunction that is post-phototransduction. The findings are consistent with recent studies demonstrating a role for CRX in the presynaptic active zone formation at the photoreceptor-bipolar cell synapse.

This is a 2020 ARVO Annual Meeting abstract.