KCNV2-associated retinopathy natural history and biomarkers using an extended KCNV electrophysiology testing protocol.

Abstract

Purpose : KCNV2-associated retinopathy is an autosomal recessive inherited retinal disease that is classically called as cone dystrophy with supernormal rod response (CDSRR). We are searching for the best biomarker, functional or anatomical, to evaluate disease progression with future disease modifying treatments.

Methods : Retrospective review of 8 patients from 7 families with genetically confirmed KCNV2-associated retinopathy. The data include best corrected visual acuity (BCVA), KCNV extended full-field electroretinogram (ffERG) intensity series with dimmest flash as DA (dark adapted) 0.002, pattern ERG (pERG), fundus imaging: retinal photo and fundus autofluorescence (FAF), and optical coherence tomography (OCT).

Results : We found 7 distinct allelic changes which have been previously reported including Ala259Thr, Ala261Asp, Gln109X, Arg320Cys, Gly461X, Trp188X, and complete gene deletion. Legal blindness was reached before the age of 25. Bull’s eye maculopathy was prominent in FAF. Variable disruption of fovea was apparent in all patients. Patient 3 and 6 had above normal b-wave amplitude the while other patients show upper range of normal. B-wave latency was delayed in dimmer stimulus, becoming (upper) normal in the brighter ones except 2 oldest patients. A-wave latency was consistently delayed in all stimuli. The b:a wave ratio was above normal range or on upper normal range.
Overall, we found 3 electrophysiology biomarkers for monitoring KCNV2 retinopathy natural history using an original KCNV specific extended testing protocol. First, the disproportionate b-wave amplitude jump between the two dimmest stimuli (DA 0.002 and 0.01) Second, the a-wave and b-wave peak time delay. Third, the relatively higher than normal b:a wave ratio. The normalisation of these 3 biomarkers could indicate therapeutic efficiency.

Conclusions : We found the window for potential therapy for KCNV patients is within the first 3 decades of life. We found no specific phenotype associated with a specific genetic variant. However, we did find a disproportionate increase of b-wave amplitude, with increasing light intensities as described as the “supernormal” rod response in KCNV patients. Also, delayed a- & b-wave latency are common in the KCNV2-associated retinopathy and may serve as specific biomarkers in our disease specific electrophysiology testing protocol.

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