KCNV2-Associated Retinopathy: Genetics, Electrophysiology, and Clinical Course—KCNV2 Study Group Report 1

Abstract

Purpose To investigate genetics, electrophysiology, and clinical course of KCNV2- associated retinopathy in a cohort of children and adults. Study design This was a multicenter international clinical cohort study. Methods Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects. Results In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades. Conclusion In KCNV2 -associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.

KCNV2-Associated Retinopathy: Detailed Retinal Phenotype and Structural Endpoints—KCNV2 Study Group Report 2

“…1 identified a normal rate of age-associated change on full-field ERGs, consistent with largely stable peripheral retinal dysfunction across 6 decades. 4 Stockman and associates 40 psychophysically characterized the disease and suggested an intact phototransduction process. Patients with retinal atrophy (OCT Grade 5) are unlikely to benefit from gene therapy, given the lack of foveal photoreceptors and the relatively stable peripheral retinal function.…”

“…Report No. 1 investigated the genetic background of the disease but was not able to identify any definite genotype-phenotype correlations; 4 these would however be valuable both to inform advice to patients on their prognosis and to potentially aid stratification of trial participants, for example, by their rate of progression/greater disease severity. In addition, the presence of intrafamilial variability is a common feature in inherited retinal diseases and has not previously been explored in KCNV2 -retinopathy.…”

“…Report No. 1 of the study 4 highlighted the early disease onset (<12 years of age), the severity of the clinical phenotype, the genetic background, and established a cohort of patients with a wide geographic distribution. Full-field electroretinograms (ERGs) are diagnostic and pathognomonic.…”

“…1 showed a normal rate of age-associated ERG change, consistent with largely stable peripheral rod and cone system dysfunction across 6 decades. 4 The purpose of the current study (Report No. 2) is to characterize the retinal architecture and the associated disease natural history.…”

Compound heterozygous KCNV2 variants contribute to cone dystrophy with supernormal rod responses in a Chinese family

“…Subsequent studies confirmed CDSRR as a retinal disorder inherited in an autosomal recessive manner with special electroretinogram (ERG) responses, which constitutes subnormal rod b‐wave in dim flash, reduced, and delayed cone responses, but a normal or increased rod amplitude at a high‐intensity stimuli (Wissinger et al, 2008 ). Moreover, due to structural retinal abnormalities and macular retinal pigment epithelial change or atrophy caused by CDSRR (Vincent et al, 2013 ), patients are typically affected by mild to moderate myopia, dyschromatopsia, nyctalopia, photophobia, and nystagmus before 12 years of their lives (range from 0 to 11 years, the mean age of onset was 3.9 years old; Georgiou et al, 2021 ; Lenis et al, 2013 ; Michaelides et al, 2005 ; Robson et al, 2010 ). In addition, broad heterogeneity in phenotypes has been confirmed.…”