Sadat Yazdouni
Introduction
Inherited retinal dystrophies are a heterogeneous group of disorders with varying genetic, clinical, and electrophysiological profiles. KCNV2 retinopathy represents a unique subset of these dystrophies, first described in 1983 by Gouras et al., and later linked to mutations in the KCNV2 gene (1). KCNV2 encodes the voltage-gated potassium channel subunit Kv8.2, which interacts with Kv2.1 to modulate retinal photoreceptor activity. Dysfunction of this channel complex results in aberrant photoreceptor signalling, primarily affecting cones and, to a lesser extent, rods (2).
Epidemiology and Prevalence
KCNV2 retinopathy is an exceptionally rare condition, with an estimated prevalence of less than 1 in 850,000 individuals worldwide. The condition has been reported in various populations, with no clear ethnic predilection. However, due to its rarity and the overlapping features with other retinal dystrophies, KCNV2 retinopathy is likely underdiagnosed. Advances in genetic testing have improved the identification of affected individuals and have contributed to a better understanding of its true prevalence (3).
Pathophysiology
The Kv8.2 subunit encoded by KCNV2 plays a critical role in regulating photoreceptor function by forming heterotetrameric potassium channels with Kv2.1 (4). These channels are essential for maintaining the membrane potential and facilitating proper phototransduction in retinal cells.
Mutations in KCNV2 lead to either a complete loss of function or a dominant-negative effect on the Kv2.1/Kv8.2 channel complex(5). The resulting dysfunction disrupts potassium ion homeostasis within photoreceptor cells, impairing the hyperpolarisation response necessary for normal visual signal processing. Cone photoreceptors, which are more metabolically active than rods, are particularly vulnerable to the effects of potassium channel dysfunction, leading to their preferential degeneration in the early stages of the disease.
The supernormal rod responses observed in ERG testing can be attributed to compensatory mechanisms in rod photoreceptors. Despite initial preservation, rods eventually succumb to secondary degenerative processes, likely driven by the chronic metabolic stress and altered ion flux associated with the dysfunctional channel. This progressive degeneration contributes to the worsening of night vision and further visual impairment in later stages of the disease (6).
Clinical Features
Patients typically present in the first or second decade of life with symptoms of reduced visual acuity, photophobia, and dyschromatopsia. Night blindness may be reported in later stages. Fundoscopy often reveals subtle abnormalities, including macular atrophy and pigmentary changes. Optical coherence tomography (OCT) demonstrates thinning of the outer retinal layers, particularly in the macula (7).
Diagnosis
The diagnosis of KCNV2 retinopathy relies on a combination of clinical findings, ERG, and genetic testing. Key ERG features include reduced cone responses and supernormal rod responses at high stimulus intensities. Genetic analysis confirming biallelic mutations in KCNV2 establishes a definitive diagnosis (8).
Management
Currently, there is no cure for KCNV2 retinopathy. Management focuses on visual rehabilitation and symptomatic relief, such as the use of tinted lenses for photophobia.
Future Therapeutics
Emerging therapeutic options for KCNV2 retinopathy are primarily centred around gene therapy and pharmacological interventions. Gene augmentation therapy aims to deliver a functional copy of the KCNV2 gene to affected photoreceptor cells using adeno-associated viral (AAV) vectors. Preclinical studies have demonstrated promising results, including partial restoration of photoreceptor function and prevention of degeneration in animal models (9).
Pharmacological approaches are also under investigation, targeting the downstream effects of channel dysfunction to preserve photoreceptor viability. Small molecules that stabilise ion channel function or modulate compensatory pathways are currently in the early stages of development (10). Additionally, advances in stem cell therapy offer potential for regenerating damaged retinal tissue in the future (11).
Despite these promising avenues, challenges remain, including efficient delivery of gene therapy to cone-rich regions of the retina and long-term safety concerns. Ongoing clinical trials will provide critical insights into the feasibility and efficacy of these interventions.
Conclusion
KCNV2 retinopathy represents a rare but clinically significant form of inherited retinal dystrophy. Improved understanding of its molecular basis has paved the way for potential therapeutic strategies. Future research should prioritise the development of targeted treatments to mitigate disease progression and improve patient outcomes.
References
1. Gouras P, Eggers HM, Mackay CJ. Cone Dystrophy, Nyctalopia, and Supernormal Rod Responses: A New Retinal Degeneration. Archives of Ophthalmology [Internet]. 1983 May 1 [cited 2025 Jan 17];101(5):718–24. Available from: https://jamanetwork.com/journals/jamaophthalmology/fullarticle/634588
2. Wu H, Cowing JA, Michaelides M, Wilkie SE, Jeffery G, Jenkins SA, et al. Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause “cone dystrophy with supernormal rod electroretinogram” in humans. Am J Hum Genet [Internet]. 2006 Sep 1 [cited 2025 Jan 17];79(3):574–9. Available from: http://www.cell.com/article/S000292970762758X/fulltext
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8. Guimaraes TACD, Georgiou M, Robson AG, Michaelides M. KCNV2 retinopathy: clinical features, molecular genetics and directions for future therapy. Ophthalmic Genet [Internet]. 2020 May 3 [cited 2025 Jan 17];41(3):208. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7446039/
9. Carvalho L, Rashwan R, Lim XR, Brunet A, Miller AL, Bhatt Y, et al. Pre-clinical efficacy testing of AAV-based gene therapy for KCNV2-deficiency. Invest Ophthalmol Vis Sci. 2023 Jun 1;64(8):477–477.
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11. Sharma A, Jaganathan BG. Stem Cell Therapy for Retinal Degeneration: The Evidence to Date. Biologics [Internet]. 2021 [cited 2025 Jan 17];15:299. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8327474/