Abstract
Purpose
To report clinical and genetic features including long-term full-field electroretinography (FF-ERG) findings of a patient with cone dystrophy with supernormal rod responses (CDSRR).
Methods
Ophthalmological medical records including FF-ERG were retrospectively reviewed. Genetic analysis using whole-exome sequencing (WES) was performed. Identified KCNV2 variants were confirmed by Sanger sequencing.
Results
A 30-year-old female patient was referred to our hospital for assessment of decreased vision from childhood. Funduscopy showed macular atrophy in both eyes. FF-ERG showed decreased amplitudes and delayed peak time of b-waves for dark-adapted (DA) 0.01 ERG, increased b/a-wave ratio with a slightly diminished a-wave for DA 3.0 and DA 25.7 ERG, residual a-waves and almost extinguished b-waves for light-adapted (LA) 3.0 ERG, and extremely diminished amplitudes in LA 30-Hz flicker responses. At 45 years of age, funduscopy showed progressive macular atrophy, whereas the responses for her FF-ERG remained unchanged compared to those observed at 30 years of age. WES identified the compound heterozygous KCNV2 variants (p.W67X and p.D174GfsX198) in the patient. These variants have previously been unreported as pathogenic variants. Each parent had one of the variants. Subsequently, the patient was finally diagnosed with CDSRR with the novel compound heterozygous KCNV2 variants.
Conclusions
Biallelic loss-of-function KCNV2 variants (p.W67X and p.D174GfsX198) were identified as the cause of CDSRR. Long-term FF-ERG findings demonstrated there were no ERG changes during 15 years of observation, indicating that there was no evidence of progressive peripheral retinal dysfunction, in spite of worsening macular atrophy.
References
Gouras P, Eggers HM, MacKay CJ (1983) Cone dystrophy, nyctalopia, and supernormal rod responses. A new retinal degeneration. Arch Ophthalmol 101:718–724
Michaelides M, Johnson S, Simunovic MP, Bradshaw K, Holder G, Mollon JD, Moore AT, Hunt DM (2005) Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals. Eye (Lond) 19:2–10
Robson AG, Webster AR, Michaelides M, Downes SM, Cowing JA, Hunt DM, Moore AT, Holder GE (2010) “Cone dystrophy with supernormal rod electroretinogram”: a comprehensive genotype/phenotype study including fundus autofluorescence and extensive electrophysiology. Retina 30:51–62
Vincent A, Robson AG, Holder GE (2013) Pathognomonic (diagnostic) ERGs. A review and update. Retina 33:5–12
Gayet-Primo J, Yaeger DB, Khanjian RA, Puthussery T (2018) Heteromeric KV2/KV8.2 channels mediate delayed rectifier potassium currents in primate photoreceptors. J Neurosci 38:3414–3427
Wu H, Cowing JA, Michaelides M, Wilkie SE, Jeffery G, Jenkins SA, Mester V, Bird AC, Robson AG, Holder GE, Moore AT, Hunt DM, Webster AR (2006) 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 79:574–579
Ottschytsch N, Raes A, Van Hoorick D, Snyders DJ (2002) Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome. Proc Natl Acad Sci USA 99:7986–7991
Czirjak G, Toth ZE, Enyedi P (2007) Characterization of the heteromeric potassium channel formed by kv2.1 and the retinal subunit kv8.2 in Xenopus oocytes. J Neurophysiol 98:1213–1222
Holter P, Kunst S, Wolloscheck T, Kelleher DK, Sticht C, Wolfrum U, Spessert R (2012) The retinal clock drives the expression of Kcnv2, a channel essential for visual function and cone survival. Invest Ophthalmol Vis Sci 53:6947–6954
Wissinger B, Schaich S, Baumann B, Bonin M, Jagle H, Friedburg C, Varsanyi B, Hoyng CB, Dollfus H, Heckenlively JR, Rosenberg T, Rudolph G, Kellner U, Salati R, Plomp A, De Baere E, Andrassi-Darida M, Sauer A, Wolf C, Zobor D, Bernd A, Leroy BP, Enyedi P, Cremers FP, Lorenz B, Zrenner E, Kohl S (2011) Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response. Hum Mutat 32:1398–1406
Wissinger B, Dangel S, Jagle H, Hansen L, Baumann B, Rudolph G, Wolf C, Bonin M, Koeppen K, Ladewig T, Kohl S, Zrenner E, Rosenberg T (2008) Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2. Invest Ophthalmol Vis Sci 49:751–757
McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130:1–12
Takeuchi T, Hayashi T, Bedell M, Zhang K, Yamada H, Tsuneoka H (2010) A novel haplotype with the R345 W mutation in the EFEMP1 gene associated with autosomal dominant drusen in a Japanese family. Invest Ophthalmol Vis Sci 51:1643–1650
Katagiri S, Yoshitake K, Akahori M, Hayashi T, Furuno M, Nishino J, Ikeo K, Tsuneoka H, Iwata T (2013) Whole-exome sequencing identifies a novel ALMS1 mutation (p. Q2051X) in two Japanese brothers with Alstrom syndrome. Mol Vis 19:2393–2406
Katagiri S, Akahori M, Sergeev Y, Yoshitake K, Ikeo K, Furuno M, Hayashi T, Kondo M, Ueno S, Tsunoda K, Shinoda K, Kuniyoshi K, Tsurusaki Y, Matsumoto N, Tsuneoka H, Iwata T (2014) Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa. PLoS ONE 9:e108721
Verriest G, Van Laethem J, Uvijls A (1982) A new assessment of the normal ranges of the Farnsworth–Munsell 100-hue test scores. Am J Ophthalmol 93:635–642
Vincent A, Wright T, Garcia-Sanchez Y, Kisilak M, Campbell M, Westall C, Heon E (2013) Phenotypic characteristics including in vivo cone photoreceptor mosaic in KCNV2-related “cone dystrophy with supernormal rod electroretinogram”. Invest Ophthalmol Vis Sci 54:898–908
Nakamura N, Tsunoda K, Fujinami K, Shinoda K, Tomita K, Hatase T, Usui T, Akahori M, Iwata T, Miyake Y (2013) Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram. Nippon Ganka Gakkai Zasshi 117:629–640
Ben Salah S, Kamei S, Senechal A, Lopez S, Bazalgette C, Bazalgette C, Eliaou CM, Zanlonghi X, Hamel CP (2008) Novel KCNV2 mutations in cone dystrophy with supernormal rod electroretinogram. Am J Ophthalmol 145:1099–1106
Sergouniotis PI, Holder GE, Robson AG, Michaelides M, Webster AR, Moore AT (2012) High-resolution optical coherence tomography imaging in KCNV2 retinopathy. Br J Ophthalmol 96:213–217
Michaelides M, Holder GE, Webster AR, Hunt DM, Bird AC, Fitzke FW, Mollon JD, Moore AT (2005) A detailed phenotypic study of “cone dystrophy with supernormal rod ERG”. Br J Ophthalmol 89:332–339
Xu D, Su D, Nusinowitz S, Sarraf D (2017) Central ellipsoid loss associated with cone dystrophy and KCNV2 mutation. Retin Cases Brief Rep 12:S59–S62
Sieving PA, Murayama K, Naarendorp F (1994) Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave. Vis Neurosci 11:519–532
Zobor D, Kohl S, Wissinger B, Zrenner E, Jagle H (2012) Rod and cone function in patients with KCNV2 retinopathy. PLoS ONE 7:e46762
Fujinami K, Tsunoda K, Nakamura N, Kato Y, Noda T, Shinoda K, Tomita K, Hatase T, Usui T, Akahori M, Itabashi T, Iwata T, Ozawa Y, Tsubota K, Miyake Y (2013) Molecular characteristics of four Japanese cases with KCNV2 retinopathy: report of novel disease-causing variants. Mol Vis 19:1580–1590
Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, Makiyama Y, Morooka S, Matsuda F, Yoshimura N (2016) Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies. Mol Vis 22:150–160
Acknowledgements
This work was supported by grants from the Practical Research Project for Rare/Intractable Diseases (17ek0109282h0001 for TI) from the Japan Agency for Medical Research and Development (AMED), and the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (17K11434 and 17K11441 for TH).
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Kutsuma, T., Katagiri, S., Hayashi, T. et al. Novel biallelic loss-of-function KCNV2 variants in cone dystrophy with supernormal rod responses. Doc Ophthalmol 138, 229–239 (2019). https://doi.org/10.1007/s10633-019-09679-6
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DOI: https://doi.org/10.1007/s10633-019-09679-6