{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T10:35:26Z","timestamp":1774953326755,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T00:00:00Z","timestamp":1558396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recessively-inherited NR2E3 gene mutations cause an unusual retinopathy with abnormally-increased short-wavelength sensitive cone (S-cone) function, in addition to reduced rod and long\/middle-wavelength sensitive cone (L\/M-cone) function. Progress toward clinical trials to treat patients with this otherwise incurable retinal degeneration prompted the need to determine efficacy outcome measures. Comparisons were made between three computerized perimeters available in the clinic. These perimeters could deliver short-wavelength stimuli on longer-wavelength adapting backgrounds to measure whether S-cone vision can be quantified. Results from a cohort of normal subjects were compared across the three perimeters to determine S-cone isolation and test-retest variability. S-cone perimetry data from NR2E3-ESCS (enhanced S-cone syndrome) patients were examined and determined to have five stages of disease severity. Using these stages, strategies were proposed for monitoring efficacy of either a focal or retina-wide intervention. This work sets the stage for clinical trials.<\/jats:p>","DOI":"10.3390\/ijms20102497","type":"journal-article","created":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T10:52:51Z","timestamp":1558435971000},"page":"2497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Short-Wavelength Sensitive Cone (S-cone) Testing as an Outcome Measure for NR2E3 Clinical Treatment Trials"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7368-3007","authenticated-orcid":false,"given":"Alejandro J.","family":"Roman","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian A.","family":"Powers","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn P.","family":"Semenov","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Sheplock","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeryia","family":"Aksianiuk","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert C.","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Sumaroka","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra V.","family":"Garafalo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-0905","authenticated-orcid":false,"given":"Artur V.","family":"Cideciyan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel G.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1167\/iovs.17-21560","article-title":"Outcome measures for clinical trials of Leber congenital amaurosis caused by the intronic mutation in the CEP290 gene","volume":"58","author":"Jacobson","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ajo.2017.02.003","article-title":"Defining outcomes for clinical trials of Leber congenital amaurosis caused by GUCY2D mutations","volume":"177","author":"Jacobson","year":"2017","journal-title":"Am. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ajo.2018.06.017","article-title":"Efficacy outcome measures for clinical trials of USH2A caused by the common C.2299delG mutation","volume":"193","author":"Calzetti","year":"2018","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1167\/iovs.07-1132","article-title":"Report from the NEI\/FDA Ophthalmic clinical trial design and endpoints symposium","volume":"49","author":"Csaky","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1136\/bjo.60.5.345","article-title":"Diagnostic features of the Favre-Goldmann syndrome","volume":"60","author":"Fishman","year":"1976","journal-title":"Brit. J. Ophthalmol."},{"key":"ref_6","first-page":"827","article-title":"SWS (blue) cone hypersensitivity in a newly identified retinal degeneration","volume":"31","author":"Jacobson","year":"1990","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0002-9394(14)76980-6","article-title":"Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity","volume":"110","author":"Marmor","year":"1990","journal-title":"Am. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S0002-9394(14)72379-7","article-title":"Relatively enhanced S cone function in the Goldmann-Favre syndrome","volume":"111","author":"Jacobson","year":"1991","journal-title":"Am. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/0042-6989(95)98727-Q","article-title":"Enhanced S cone syndrome: Evidence for an abnormally large number of S cones","volume":"35","author":"Hood","year":"1995","journal-title":"Vision. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1073\/pnas.022533099","article-title":"The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration","volume":"99","author":"Milam","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.exer.2009.04.006","article-title":"Nr2e3-directed transcriptional regulation of genes involved in photoreceptor development and cell-type specific phototransduction","volume":"89","author":"Haider","year":"2009","journal-title":"Exp. Eye Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/humu.9285","article-title":"Mutation analysis of NR2E3 and NRL genes in enhanced S Cone syndrome","volume":"24","author":"Wright","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1167\/iovs.18-24518","article-title":"Cone vision changes in the enhanced S-cone syndrome caused by NR2E3 gene mutations","volume":"59","author":"Garafalo","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mollema, N.J., Yuan, Y., Jelcick, A.S., Sachs, A.J., von Alpen, D., Schorderet, D., Escher, P., and Haider, N.B. (2011). Nuclear receptor Rev-erb Alpha (Nr1d1) functions in concert with Nr2e3 to regulate transcriptional networks in the retina. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017494"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrn2880","article-title":"Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina","volume":"11","author":"Swaroop","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1016\/j.celrep.2016.10.074","article-title":"NRL-regulated transcriptome dynamics of developing rod photoreceptors","volume":"17","author":"Kim","year":"2016","journal-title":"Cell. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cruz, N.M., Yuan, Y., Leehy, B.D., Baid, R., Kompella, U., DeAngelis, M.M., Escher, P., and Haider, N.B. (2014). Modifier genes as therapeutics: The nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087942"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1167\/tvst.5.3.8","article-title":"Diagnosis of normal and abnormal color vision with cone-specific VEPs","volume":"5","author":"Rabin","year":"2016","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1364\/JOSAA.33.001989","article-title":"Perifoveal L- and M-cone-driven temporal contrast sensitivities at different retinal illuminances","volume":"33","author":"Huchzermeyer","year":"2016","journal-title":"J. Opt. Soc. Am. A Opt. Image Sci. Vis."},{"key":"ref_20","first-page":"64","article-title":"The directional sensitivity of the retina and the spectral sensitivities of the rods and cones","volume":"127","author":"Stiles","year":"1939","journal-title":"Proc. Royal Soc. Lond"},{"key":"ref_21","first-page":"1869","article-title":"Color perimetry for assessment of primary open-angle glaucoma","volume":"31","author":"Sample","year":"1990","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1097\/00055735-199604000-00010","article-title":"Diagnostic value of short-wavelength automated perimetry","volume":"7","author":"Johnson","year":"1996","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/S0161-6420(86)33522-X","article-title":"Automated light- and dark-adapted perimetry for evaluating retinitis pigmentosa","volume":"93","author":"Jacobson","year":"1986","journal-title":"Ophthalmology."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/00061198-199612000-00004","article-title":"Optimum parameters for short wavelength automated perimetry","volume":"5","author":"Sample","year":"1996","journal-title":"J. Glaucoma."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/00061198-200002000-00012","article-title":"Isolation of short-wavelength sensitive mechanisms in normal and glaucomatous visual field regions","volume":"9","author":"Demirel","year":"2000","journal-title":"J. Glaucoma."},{"key":"ref_26","unstructured":"Tukey, J.W. (1977). Exploratory Data Analysis, Addison-Wesley."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"McGuigan, D.B., Heon, E., Cideciyan, A.V., Ratnapriya, R., Lu, M., Sumaroka, A., Roman, A.J., Batmanabane, V., Garafalo, A.V., and Stone, E.M. (2017). EYS mutations causing autosomal recessive retinitis pigmentosa: Changes of retinal structure and function with disease progression. Genes, 8.","DOI":"10.3390\/genes8070178"},{"key":"ref_28","unstructured":"Wyzecki, G., and Stiles, W.S. (1982). Concepts and methods, quantitative data and formulae. Color Science, John Wiley & Sons. [2nd ed.]."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Parker, R.A., Weir, C.J., Rubio, N., Rabinovich, R., Pinnock, H., Hanley, J., McCloughan, L., Drost, E.M., Mantoani, L.C., and MacNee, W. (2016). Application of mixed effects limits of agreement in the presence of multiple sources of variability: Exemplar from the comparison of several devices to measure respiratory rate in COPD patients. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168321"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/10\/2497\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:53:48Z","timestamp":1760187228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/10\/2497"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,21]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["ijms20102497"],"URL":"https:\/\/doi.org\/10.3390\/ijms20102497","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,21]]}}}