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

Michalis Georgiou; Anthony G. Robson; Kaoru Fujinami; Shaun M. Leo; Ajoy Vincent; Fadi Nasser; Thales Antônio Cabral De Guimarães; Samer Khateb; Nikolas Pontikos; Yu Fujinami-Yokokawa; Xiao Liu; Kazushige Tsunoda; Takaaki Hayashi; Mauricio E. Vargas; Alberta A.H.J. Thiadens; Emanuel R. de Carvalho; Xuan Thanh An Nguyen; Gavin Arno; Omar A. Mahroo; Maria Inmaculada Martin-Merida; Belen Jimenez-Rolando; Gema Gordo; Ester Carreño; Ayuso Carmen; Dror Sharon; Susanne Kohl; Rachel M. Huckfeldt; Bernd Wissinger; Camiel J.F. Boon; Eyal Banin; Mark E. Pennesi; Arif O. Khan; Andrew R. Webster; Eberhart Zrenner; Elise Héon; Michel Michaelides

doi:10.1016/j.ajo.2020.11.022

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

Michalis Georgiou, Anthony G. Robson, Kaoru Fujinami, Shaun M. Leo, Ajoy Vincent, Fadi Nasser, Thales Antônio Cabral De Guimarães, Samer Khateb, Nikolas Pontikos, Yu Fujinami-Yokokawa, Xiao Liu, Kazushige Tsunoda, Takaaki Hayashi, Mauricio E. Vargas, Alberta A.H.J. Thiadens, Emanuel R. de Carvalho, Xuan Thanh An Nguyen, Gavin Arno, Omar A. Mahroo, Maria Inmaculada Martin-MeridaBelen Jimenez-Rolando, Gema Gordo, Ester Carreño, Ayuso Carmen, Dror Sharon, Susanne Kohl, Rachel M. Huckfeldt, Bernd Wissinger, Camiel J.F. Boon, Eyal Banin, Mark E. Pennesi, Arif O. Khan, Andrew R. Webster, Eberhart Zrenner, Elise Héon, Michel Michaelides^*

^*Corresponding author for this work

Ophthalmology

Research output: Contribution to journal › Article › Academic › peer-review

22 Citations (Scopus)

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.

Original language	English
Pages (from-to)	95-107
Number of pages	13
Journal	American Journal of Ophthalmology
Volume	225
DOIs	https://doi.org/10.1016/j.ajo.2020.11.022
Publication status	Published - 1 May 2021

Bibliographical note

Funding Information:
All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: M.G. is supported by the Onassis Foundation and the Leventis Foundation. M.M. A.R.W. O.A.M. and A.G.R. are supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and Moorfields Eye Charity. M.M. is supported by The Wellcome Trust (099173/Z/12/Z), Retina UK, and the Foundation Fighting Blindness (Baltimore, Maryland, USA). N.P. is supported by a Moorfields Eye Charity Career Development Award (R190031A). G.A. is supported by a Fight for Sight (UK) Early Career Investigator Award (5045/46). O.A.M. is supported by The Wellcome Trust (206619/Z/17/Z). M.P. is supported by an unrestricted grant from Research to Prevent Blindness to Casey Eye Institute and National Eye Institute grant number P30EY010572. A.C. is supported by the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health FIS (PI16/00425), FIS (PI19/00321); the regional government of Madrid RAREGenomics-CM (CAM, B2017/BMD-3721); the Spanish National Organization of the Blind, and the Ramon Areces Foundation. This work was supported by a grant from the Foundation Fighting Blindness USA (BR-GE-0214-0639-TECH) to D.S. and E.B. R.M.H. is supported by a Foundation Fighting Blindness Career Development Award (CD-CMM-0918-0747-MEEI). This work was also supported by the Excellence Program of the German Government (DFG EXC 307, Center for Integrative Science) to E.Z.; by the Tistou and Charlotte Kerstan Foundation to F.N.; and the German Research Council (DFG, KFO134) and the German Ministry of Education and Research (01GM0850) to B.W. A.V. is supported by the Foundation Fighting Blindness (CD-CL-0617-0727-HSC). E.H. is supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research and Fighting Blindness Canada. The views expressed are those of the authors and not the funding organizations. Financial Disclosures: M.G. and M.M. consult for MeiraGTx. K.F. consults for Astellas Pharma Inc, Kubota Pharmaceutical Holdings Co, Ltd, Acucela Inc, Novartis AG, and Janssen Pharmaceuticals. E.C. consults for AbbVie and Alimera. E.Z. consults for Acucela Inc, IVERIC_bio Inc, Janssen Pharmaceuticals, ProQR Therapeutics NV, Gyroscope Therapeutics Ltd, and Biogen MA Inc. A.V. consults for Adverum Biotechnologies Inc. S.Ko. consults for Novartis AG. The other authors have no conflicts of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship. M.M. E.Z. S.Ko. and C.B. are members of the European Reference Network for Rare Eye Diseases.

Funding Information:
All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: M.G. is supported by the Onassis Foundation and the Leventis Foundation . M.M., A.R.W., O.A.M., and A.G.R. are supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and Moorfields Eye Charity. M.M. is supported by The Wellcome Trust (099173/Z/12/Z), Retina UK, and the Foundation Fighting Blindness (Baltimore, Maryland, USA). N.P. is supported by a Moorfields Eye Charity Career Development Award (R190031A). G.A. is supported by a Fight for Sight (UK) Early Career Investigator Award (5045/46). O.A.M. is supported by The Wellcome Trust (206619/Z/17/Z). M.P. is supported by an unrestricted grant from Research to Prevent Blindness to Casey Eye Institute and National Eye Institute grant number P30EY010572. A.C. is supported by the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health FIS (PI16/00425), FIS (PI19/00321); the regional government of Madrid RAREGenomics-CM (CAM, B2017/BMD-3721); the Spanish National Organization of the Blind, and the Ramon Areces Foundation. This work was supported by a grant from the Foundation Fighting Blindness USA (BR-GE-0214-0639-TECH) to D.S. and E.B. R.M.H. is supported by a Foundation Fighting Blindness Career Development Award (CD-CMM-0918-0747-MEEI). This work was also supported by the Excellence Program of the German Government (DFG EXC 307, Center for Integrative Science) to E.Z.; by the Tistou and Charlotte Kerstan Foundation to F.N.; and the German Research Council (DFG, KFO134) and the German Ministry of Education and Research (01GM0850) to B.W. A.V. is supported by the Foundation Fighting Blindness (CD-CL-0617-0727-HSC). E.H. is supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research and Fighting Blindness Canada. The views expressed are those of the authors and not the funding organizations. Financial Disclosures: M.G. and M.M. consult for MeiraGTx. K.F. consults for Astellas Pharma Inc, Kubota Pharmaceutical Holdings Co, Ltd, Acucela Inc, Novartis AG, and Janssen Pharmaceuticals. E.C. consults for AbbVie and Alimera. E.Z. consults for Acucela Inc, IVERIC_bio Inc, Janssen Pharmaceuticals, ProQR Therapeutics NV, Gyroscope Therapeutics Ltd, and Biogen MA Inc. A.V. consults for Adverum Biotechnologies Inc. S.Ko. consults for Novartis AG. The other authors have no conflicts of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship.

Publisher Copyright:
© 2020 The Author(s)

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10.1016/j.ajo.2020.11.022

Cite this

Georgiou, M., Robson, A. G., Fujinami, K., Leo, S. M., Vincent, A., Nasser, F., Cabral De Guimarães, T. A., Khateb, S., Pontikos, N., Fujinami-Yokokawa, Y., Liu, X., Tsunoda, K., Hayashi, T., Vargas, M. E., Thiadens, A. A. H. J., de Carvalho, E. R., Nguyen, X. T. A., Arno, G., Mahroo, O. A., ... Michaelides, M. (2021). KCNV2-Associated Retinopathy: Genetics, Electrophysiology, and Clinical Course—KCNV2 Study Group Report 1. American Journal of Ophthalmology, 225, 95-107. https://doi.org/10.1016/j.ajo.2020.11.022

@article{d1acd5f2a56a48f79fc54b3e447c4153,

title = "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.",

author = "Michalis Georgiou and Robson, {Anthony G.} and Kaoru Fujinami and Leo, {Shaun M.} and Ajoy Vincent and Fadi Nasser and {Cabral De Guimar{\~a}es}, {Thales Ant{\^o}nio} and Samer Khateb and Nikolas Pontikos and Yu Fujinami-Yokokawa and Xiao Liu and Kazushige Tsunoda and Takaaki Hayashi and Vargas, {Mauricio E.} and Thiadens, {Alberta A.H.J.} and {de Carvalho}, {Emanuel R.} and Nguyen, {Xuan Thanh An} and Gavin Arno and Mahroo, {Omar A.} and Martin-Merida, {Maria Inmaculada} and Belen Jimenez-Rolando and Gema Gordo and Ester Carre{\~n}o and Ayuso Carmen and Dror Sharon and Susanne Kohl and Huckfeldt, {Rachel M.} and Bernd Wissinger and Boon, {Camiel J.F.} and Eyal Banin and Pennesi, {Mark E.} and Khan, {Arif O.} and Webster, {Andrew R.} and Eberhart Zrenner and Elise H{\'e}on and Michel Michaelides",

note = "Funding Information: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: M.G. is supported by the Onassis Foundation and the Leventis Foundation. M.M. A.R.W. O.A.M. and A.G.R. are supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and Moorfields Eye Charity. M.M. is supported by The Wellcome Trust (099173/Z/12/Z), Retina UK, and the Foundation Fighting Blindness (Baltimore, Maryland, USA). N.P. is supported by a Moorfields Eye Charity Career Development Award (R190031A). G.A. is supported by a Fight for Sight (UK) Early Career Investigator Award (5045/46). O.A.M. is supported by The Wellcome Trust (206619/Z/17/Z). M.P. is supported by an unrestricted grant from Research to Prevent Blindness to Casey Eye Institute and National Eye Institute grant number P30EY010572. A.C. is supported by the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health FIS (PI16/00425), FIS (PI19/00321); the regional government of Madrid RAREGenomics-CM (CAM, B2017/BMD-3721); the Spanish National Organization of the Blind, and the Ramon Areces Foundation. This work was supported by a grant from the Foundation Fighting Blindness USA (BR-GE-0214-0639-TECH) to D.S. and E.B. R.M.H. is supported by a Foundation Fighting Blindness Career Development Award (CD-CMM-0918-0747-MEEI). This work was also supported by the Excellence Program of the German Government (DFG EXC 307, Center for Integrative Science) to E.Z.; by the Tistou and Charlotte Kerstan Foundation to F.N.; and the German Research Council (DFG, KFO134) and the German Ministry of Education and Research (01GM0850) to B.W. A.V. is supported by the Foundation Fighting Blindness (CD-CL-0617-0727-HSC). E.H. is supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research and Fighting Blindness Canada. The views expressed are those of the authors and not the funding organizations. Financial Disclosures: M.G. and M.M. consult for MeiraGTx. K.F. consults for Astellas Pharma Inc, Kubota Pharmaceutical Holdings Co, Ltd, Acucela Inc, Novartis AG, and Janssen Pharmaceuticals. E.C. consults for AbbVie and Alimera. E.Z. consults for Acucela Inc, IVERIC_bio Inc, Janssen Pharmaceuticals, ProQR Therapeutics NV, Gyroscope Therapeutics Ltd, and Biogen MA Inc. A.V. consults for Adverum Biotechnologies Inc. S.Ko. consults for Novartis AG. The other authors have no conflicts of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship. M.M. E.Z. S.Ko. and C.B. are members of the European Reference Network for Rare Eye Diseases. Funding Information: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: M.G. is supported by the Onassis Foundation and the Leventis Foundation . M.M., A.R.W., O.A.M., and A.G.R. are supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and Moorfields Eye Charity. M.M. is supported by The Wellcome Trust (099173/Z/12/Z), Retina UK, and the Foundation Fighting Blindness (Baltimore, Maryland, USA). N.P. is supported by a Moorfields Eye Charity Career Development Award (R190031A). G.A. is supported by a Fight for Sight (UK) Early Career Investigator Award (5045/46). O.A.M. is supported by The Wellcome Trust (206619/Z/17/Z). M.P. is supported by an unrestricted grant from Research to Prevent Blindness to Casey Eye Institute and National Eye Institute grant number P30EY010572. A.C. is supported by the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health FIS (PI16/00425), FIS (PI19/00321); the regional government of Madrid RAREGenomics-CM (CAM, B2017/BMD-3721); the Spanish National Organization of the Blind, and the Ramon Areces Foundation. This work was supported by a grant from the Foundation Fighting Blindness USA (BR-GE-0214-0639-TECH) to D.S. and E.B. R.M.H. is supported by a Foundation Fighting Blindness Career Development Award (CD-CMM-0918-0747-MEEI). This work was also supported by the Excellence Program of the German Government (DFG EXC 307, Center for Integrative Science) to E.Z.; by the Tistou and Charlotte Kerstan Foundation to F.N.; and the German Research Council (DFG, KFO134) and the German Ministry of Education and Research (01GM0850) to B.W. A.V. is supported by the Foundation Fighting Blindness (CD-CL-0617-0727-HSC). E.H. is supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research and Fighting Blindness Canada. The views expressed are those of the authors and not the funding organizations. Financial Disclosures: M.G. and M.M. consult for MeiraGTx. K.F. consults for Astellas Pharma Inc, Kubota Pharmaceutical Holdings Co, Ltd, Acucela Inc, Novartis AG, and Janssen Pharmaceuticals. E.C. consults for AbbVie and Alimera. E.Z. consults for Acucela Inc, IVERIC_bio Inc, Janssen Pharmaceuticals, ProQR Therapeutics NV, Gyroscope Therapeutics Ltd, and Biogen MA Inc. A.V. consults for Adverum Biotechnologies Inc. S.Ko. consults for Novartis AG. The other authors have no conflicts of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2021",

month = may,

day = "1",

doi = "10.1016/j.ajo.2020.11.022",

language = "English",

volume = "225",

pages = "95--107",

journal = "American Journal of Ophthalmology",

issn = "0002-9394",

publisher = "Elsevier Inc.",

}

Georgiou, M, Robson, AG, Fujinami, K, Leo, SM, Vincent, A, Nasser, F, Cabral De Guimarães, TA, Khateb, S, Pontikos, N, Fujinami-Yokokawa, Y, Liu, X, Tsunoda, K, Hayashi, T, Vargas, ME, Thiadens, AAHJ, de Carvalho, ER, Nguyen, XTA, Arno, G, Mahroo, OA, Martin-Merida, MI, Jimenez-Rolando, B, Gordo, G, Carreño, E, Carmen, A, Sharon, D, Kohl, S, Huckfeldt, RM, Wissinger, B, Boon, CJF, Banin, E, Pennesi, ME, Khan, AO, Webster, AR, Zrenner, E, Héon, E & Michaelides, M 2021, 'KCNV2-Associated Retinopathy: Genetics, Electrophysiology, and Clinical Course—KCNV2 Study Group Report 1', American Journal of Ophthalmology, vol. 225, pp. 95-107. https://doi.org/10.1016/j.ajo.2020.11.022

TY - JOUR

T1 - KCNV2-Associated Retinopathy

T2 - Genetics, Electrophysiology, and Clinical Course—KCNV2 Study Group Report 1

AU - Georgiou, Michalis

AU - Robson, Anthony G.

AU - Fujinami, Kaoru

AU - Leo, Shaun M.

AU - Vincent, Ajoy

AU - Nasser, Fadi

AU - Cabral De Guimarães, Thales Antônio

AU - Khateb, Samer

AU - Pontikos, Nikolas

AU - Fujinami-Yokokawa, Yu

AU - Liu, Xiao

AU - Tsunoda, Kazushige

AU - Hayashi, Takaaki

AU - Vargas, Mauricio E.

AU - Thiadens, Alberta A.H.J.

AU - de Carvalho, Emanuel R.

AU - Nguyen, Xuan Thanh An

AU - Arno, Gavin

AU - Mahroo, Omar A.

AU - Martin-Merida, Maria Inmaculada

AU - Jimenez-Rolando, Belen

AU - Gordo, Gema

AU - Carreño, Ester

AU - Carmen, Ayuso

AU - Sharon, Dror

AU - Kohl, Susanne

AU - Huckfeldt, Rachel M.

AU - Wissinger, Bernd

AU - Boon, Camiel J.F.

AU - Banin, Eyal

AU - Pennesi, Mark E.

AU - Khan, Arif O.

AU - Webster, Andrew R.

AU - Zrenner, Eberhart

AU - Héon, Elise

AU - Michaelides, Michel

N1 - Funding Information: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: M.G. is supported by the Onassis Foundation and the Leventis Foundation. M.M. A.R.W. O.A.M. and A.G.R. are supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and Moorfields Eye Charity. M.M. is supported by The Wellcome Trust (099173/Z/12/Z), Retina UK, and the Foundation Fighting Blindness (Baltimore, Maryland, USA). N.P. is supported by a Moorfields Eye Charity Career Development Award (R190031A). G.A. is supported by a Fight for Sight (UK) Early Career Investigator Award (5045/46). O.A.M. is supported by The Wellcome Trust (206619/Z/17/Z). M.P. is supported by an unrestricted grant from Research to Prevent Blindness to Casey Eye Institute and National Eye Institute grant number P30EY010572. A.C. is supported by the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health FIS (PI16/00425), FIS (PI19/00321); the regional government of Madrid RAREGenomics-CM (CAM, B2017/BMD-3721); the Spanish National Organization of the Blind, and the Ramon Areces Foundation. This work was supported by a grant from the Foundation Fighting Blindness USA (BR-GE-0214-0639-TECH) to D.S. and E.B. R.M.H. is supported by a Foundation Fighting Blindness Career Development Award (CD-CMM-0918-0747-MEEI). This work was also supported by the Excellence Program of the German Government (DFG EXC 307, Center for Integrative Science) to E.Z.; by the Tistou and Charlotte Kerstan Foundation to F.N.; and the German Research Council (DFG, KFO134) and the German Ministry of Education and Research (01GM0850) to B.W. A.V. is supported by the Foundation Fighting Blindness (CD-CL-0617-0727-HSC). E.H. is supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research and Fighting Blindness Canada. The views expressed are those of the authors and not the funding organizations. Financial Disclosures: M.G. and M.M. consult for MeiraGTx. K.F. consults for Astellas Pharma Inc, Kubota Pharmaceutical Holdings Co, Ltd, Acucela Inc, Novartis AG, and Janssen Pharmaceuticals. E.C. consults for AbbVie and Alimera. E.Z. consults for Acucela Inc, IVERIC_bio Inc, Janssen Pharmaceuticals, ProQR Therapeutics NV, Gyroscope Therapeutics Ltd, and Biogen MA Inc. A.V. consults for Adverum Biotechnologies Inc. S.Ko. consults for Novartis AG. The other authors have no conflicts of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship. M.M. E.Z. S.Ko. and C.B. are members of the European Reference Network for Rare Eye Diseases. Funding Information: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: M.G. is supported by the Onassis Foundation and the Leventis Foundation . M.M., A.R.W., O.A.M., and A.G.R. are supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and Moorfields Eye Charity. M.M. is supported by The Wellcome Trust (099173/Z/12/Z), Retina UK, and the Foundation Fighting Blindness (Baltimore, Maryland, USA). N.P. is supported by a Moorfields Eye Charity Career Development Award (R190031A). G.A. is supported by a Fight for Sight (UK) Early Career Investigator Award (5045/46). O.A.M. is supported by The Wellcome Trust (206619/Z/17/Z). M.P. is supported by an unrestricted grant from Research to Prevent Blindness to Casey Eye Institute and National Eye Institute grant number P30EY010572. A.C. is supported by the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health FIS (PI16/00425), FIS (PI19/00321); the regional government of Madrid RAREGenomics-CM (CAM, B2017/BMD-3721); the Spanish National Organization of the Blind, and the Ramon Areces Foundation. This work was supported by a grant from the Foundation Fighting Blindness USA (BR-GE-0214-0639-TECH) to D.S. and E.B. R.M.H. is supported by a Foundation Fighting Blindness Career Development Award (CD-CMM-0918-0747-MEEI). This work was also supported by the Excellence Program of the German Government (DFG EXC 307, Center for Integrative Science) to E.Z.; by the Tistou and Charlotte Kerstan Foundation to F.N.; and the German Research Council (DFG, KFO134) and the German Ministry of Education and Research (01GM0850) to B.W. A.V. is supported by the Foundation Fighting Blindness (CD-CL-0617-0727-HSC). E.H. is supported by the Henry Brent Chair in Innovative Pediatric Ophthalmology Research and Fighting Blindness Canada. The views expressed are those of the authors and not the funding organizations. Financial Disclosures: M.G. and M.M. consult for MeiraGTx. K.F. consults for Astellas Pharma Inc, Kubota Pharmaceutical Holdings Co, Ltd, Acucela Inc, Novartis AG, and Janssen Pharmaceuticals. E.C. consults for AbbVie and Alimera. E.Z. consults for Acucela Inc, IVERIC_bio Inc, Janssen Pharmaceuticals, ProQR Therapeutics NV, Gyroscope Therapeutics Ltd, and Biogen MA Inc. A.V. consults for Adverum Biotechnologies Inc. S.Ko. consults for Novartis AG. The other authors have no conflicts of interest to disclose. All authors attest that they meet the current ICMJE criteria for authorship. Publisher Copyright: © 2020 The Author(s)

PY - 2021/5/1

Y1 - 2021/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85101977838&partnerID=8YFLogxK

U2 - 10.1016/j.ajo.2020.11.022

DO - 10.1016/j.ajo.2020.11.022

M3 - Article

C2 - 33309813

AN - SCOPUS:85101977838

SN - 0002-9394

VL - 225

SP - 95

EP - 107

JO - American Journal of Ophthalmology

JF - American Journal of Ophthalmology

ER -

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

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