Skip to main content

Advertisement

SpringerLink
Log in

Two-color pupillometry in enhanced S-cone syndrome caused by NR2E3 mutations

  • Original Research Article
  • Published:
Documenta Ophthalmologica Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to evaluate pupillary light reflexes (PLRs) mediated by rod, cone, and intrinsically photosensitive retinal ganglion cell pathways as indices of outer- and inner-retinal function in patients who have enhanced S-cone syndrome (ESCS) due to NR2E3 mutations.

Methods

Four patients with ESCS (ages 16–23 years) participated in the study. Subjects were tested with long- and short-wavelength single-flash full-field ERG stimuli under light-adapted conditions. They were also tested with an established pupillometry protocol involving 1-s duration, long- and short-wavelength stimuli under dark- and light-adapted conditions. The PLR was measured as a function of stimulus luminance. Transient PLRs were measured under all conditions, and sustained PLRs were measured under the highest luminance dark-adapted condition.

Results

Two-color light-adapted full-field ERGs demonstrated larger amplitude responses for short-wavelength stimuli relative to long-wavelength stimuli of the same photopic luminance, with three of four ESCS patients having super-normal a-wave amplitudes to the short-wavelength stimulus. b/a wave ratios were reduced in all four cases. Transient PLRs elicited by low-luminance stimuli under dark-adapted conditions (rod-mediated) were unrecordable, whereas the sustained PLRs elicited by high-luminance stimuli (melanopsin-mediated) were normal. Cone-mediated PLRs were recordable for all four patients, but generally lower than normal in amplitude. However, the cone-mediated PLR was larger for the short-wavelength stimulus compared to the photopically matched long-wavelength stimulus at high luminances, a pattern that was not observed for control subjects. None of the PLR conditions demonstrated “super-normal” responses.

Conclusion

ESCS patients appear to have generally well-preserved cone- and melanopsin-mediated PLRs, indicating intact inner-retinal function. Two-color pupillometry demonstrates greater sensitivity to short-wavelength light under higher-luminance conditions and could complement the ERG as a tool for evaluating retinal function in ESCS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, Beck G, Hockey R, Hanna DB, Gorman S, Duhl D, Carmi R, Bennett J, Weleber RG, Fishman GA, Wright AF, Stone EM, Sheffield VC (2000) Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 24(2):127–131

    Article  CAS  PubMed  Google Scholar 

  2. Webber AL, Hodor P, Thut CJ, Vogt TF, Zhang T, Holder DJ, Petrukhin K (2008) Dual role of Nr2e3 in photoreceptor development and maintenance. Exp Eye Res 87(1):35–48

    Article  CAS  PubMed  Google Scholar 

  3. Haider NB, Mollema N, Gaule M, Yuan Y, Sachs AJ, Nystuen AM, Naggert JK, Nishina PM (2009) Nr2e3-directed transcriptional regulation of genes involved in photoreceptor development and cell-type specific phototransduction. Exp Eye Res 89(3):365–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kanda A, Swaroop A (2009) A comprehensive analysis of sequence variants and putative disease-causing mutations in photoreceptor-specific nuclear receptor NR2E3. Mol Vis 15:2174–2184

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hood DC, Cideciyan AV, Roman AJ, Jacobson SG (1995) Enhanced S cone syndrome: evidence for an abnormally large number of S cones. Vis Res 35(10):1473–1481

    Article  CAS  PubMed  Google Scholar 

  6. Greenstein VC, Zaidi Q, Hood DC, Spehar B, Cideciyan AV, Jacobson SG (1996) The enhanced S cone syndrome: an analysis of receptoral and post-receptoral changes. Vis Res 36(22):3711–3722

    Article  CAS  PubMed  Google Scholar 

  7. Cheng H, Khan NW, Roger JE, Swaroop A (2011) Excess cones in the retinal degeneration rd7 mouse, caused by the loss of function of orphan nuclear receptor Nr2e3, originate from early-born photoreceptor precursors. Hum Mol Genet 20(21):4102–4115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jacobson SG, Marmor MF, Kemp CM, Knighton RW (1990) SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Investig Ophthalmol Vis Sci 31(5):827–838

    CAS  Google Scholar 

  9. Bonilha VL, Fishman GA, Rayborn ME, Hollyfield JG (2009) Retinal pathology of a patient with Goldmann-Favre syndrome. Ophthalmic Genet 30(4):172–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Milam AH, Rose L, Cideciyan AV, Barakat MR, Tang WX, Gupta N, Aleman TS, Wright AF, Stone EM, Sheffield VC, Jacobson SG (2002) The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration. Proc Natl Acad Sci USA 99(1):473–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Audo I, Michaelides M, Robson AG, Hawlina M, Vaclavik V, Sandbach JM, Neveu MM, Hogg CR, Hunt DM, Moore AT, Bird AC, Webster AR, Holder GE (2008) Phenotypic variation in enhanced S-cone syndrome. Investig Ophthalmol Vis Sci 49(5):2082–2093

    Article  Google Scholar 

  12. Pachydaki SI, Bhatnagar PA, Barbazetto IA, Klaver CC, Freund BK, Yannuzzi LA (2009) Long-term follow-up in enhanced S-cone syndrome. Retin Cases Brief Rep 3(2):118–120

    Article  PubMed  Google Scholar 

  13. Jacobson SG, Román AJ, Román MI, Gass JD, Parker JA (1991) Relatively enhanced S cone function in the Goldmann-Favre syndrome. Am J Ophthalmol 111(4):446–453

    Article  CAS  PubMed  Google Scholar 

  14. 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):1–12

    Article  PubMed  Google Scholar 

  15. Vincent A, Robson AG, Holder GE (2013) Pathognomonic (diagnostic) ERGs. A review and update. Retina 33(1):5–12

    Article  PubMed  Google Scholar 

  16. Marmor MF, Jacobson SG, Foerster MH, Kellner U, Weleber RG (1990) Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. Am J Ophthalmol 110(2):124–134

    Article  CAS  PubMed  Google Scholar 

  17. Park JC, Moura AL, Raza AS, Rhee DW, Kardon RH, Hood DC (2011) Toward a clinical protocol for assessing rod, cone, and melanopsin contributions to the human pupil response. Investig Ophthalmol Vis Sci 52(9):6624–6635

    Article  Google Scholar 

  18. Genead MA, Fishman GA, McAnany JJ (2010) Efficacy of topical dorzolamide for treatment of cystic macular lesions in a patient with enhanced S-cone syndrome. Doc Ophthalmol 121(3):231–240

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kiszkielis M, Lubiński W, Penkala K (2013) Topical dorzolamide treatment of macular cysts in the enhanced S-cone syndrome patient. Doc Ophthalmol 126(3):241–246

    Article  PubMed  PubMed Central  Google Scholar 

  20. Iannaccone A, Fung KH, Eyestone ME, Stone EM (2009) Treatment of adult-onset acute macular retinoschisis in enhanced S-cone syndrome with oral acetazolamide. Am J Ophthalmol 147(2):307–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kawasaki A, Kardon RH (2007) Intrinsically photosensitive retinal ganglion cells. J Neuroophthalmol 27(3):195–204

    Article  PubMed  Google Scholar 

  22. Park JC, McAnany JJ (2015) Effect of stimulus size and luminance on the rod-, cone-, and melanopsin-mediated pupillary light reflex. J Vis 15(3):1–13

    Article  Google Scholar 

  23. Lei S, Goltz HC, Chandrakumar M, Wong AM (2015) Test–retest reliability of hemifield, central-field, and full-field chromatic pupillometry for assessing the function of melanopsin-containing retinal ganglion cells. Investig Ophthalmol Vis Sci 56(2):1267–1273

    Article  Google Scholar 

  24. Sustar M, Perovšek D, Cima I, Stirn-Kranjc B, Hawlina M, Brecelj J (2015) Electroretinography and optical coherence tomography reveal abnormal post-photoreceptoral activity and altered retinal lamination in patients with enhanced S-cone syndrome. Doc Ophthalmol 130(3):165–177

    Article  CAS  PubMed  Google Scholar 

  25. Kawasaki A, Crippa SV, Kardon R, Leon L, Hamel C (2012) Characterization of pupil responses to blue and red light stimuli in autosomal dominant retinitis pigmentosa due to NR2E3 mutation. Investig Ophthalmol Vis Sci 53(9):5562–5569

    Article  CAS  Google Scholar 

  26. Collison FT, Park JC, Fishman GA, McAnany JJ, Stone EM (2015) Full-field pupillary light responses, luminance thresholds, and light discomfort thresholds in CEP290 Leber congenital amaurosis patients. Investig Ophthalmol Vis Sci 56(12):7130–7136

    Article  Google Scholar 

  27. Hull S, Arno G, Sergouniotis PI, Tiffin P, Borman AD, Chandra A, Robson AG, Holder GE, Webster AR, Moore AT (2014) Clinical and molecular characterization of enhanced S-cone syndrome in children. JAMA Ophthalmol 132(11):1341–1349

    Article  CAS  PubMed  Google Scholar 

  28. Khan AO, Aldahmesh M, Meyer B (2007) The enhanced S-cone syndrome in children. Br J Ophthalmol 91(3):394–396

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cassiman C, Spileers W, De Baere E, de Ravel T, Casteels I (2013) Peculiar fundus abnormalities and pathognomonic electrophysiological findings in a 14-month-old boy with NR2E3 mutations. Ophthalmic Genet 34(1–2):105–108

    Article  PubMed  Google Scholar 

  30. Kimura E, Young RS (1999) S-cone contribution to pupillary responses evoked by chromatic flash offset. Vis Res 39(6):1189–1197

    Article  CAS  PubMed  Google Scholar 

  31. Verdon W, Howarth PA (1988) The pupil’s response to short wavelength cone stimulation. Vis Res 28(10):1119–1128

    Article  CAS  PubMed  Google Scholar 

  32. Cao D, Nicandro N, Barrionuevo PA (2015) A five-primary photostimulator suitable for studying intrinsically photosensitive retinal ganglion cell functions in humans. J Vis 15(1):15.1.27

    Article  PubMed  Google Scholar 

  33. Spitschan M, Jain S, Brainard DH, Aguirre GK (2014) Opponent melanopsin and S-cone signals in the human pupillary light response. Proc Natl Acad Sci USA 111(43):15568–15572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The Pangere Family Foundation, Gary, Indiana (GAF), National Institutes of Health Research Grants EY019510 (JM) and EY001792 (UIC core grant) and an unrestricted departmental grant from Research to Prevent Blindness provided financial support in the form of monetary funding. The sponsors had no role in the design or conduct of this research.

Author information

Authors and Affiliations

  1. The Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse, 1850 West Roosevelt Rd., Chicago, IL, 60608, USA

    Frederick T. Collison & Gerald A. Fishman

  2. Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago College of Medicine, 1905 West Taylor St., Chicago, IL, 60612, USA

    Jason C. Park, Gerald A. Fishman & J. Jason McAnany

  3. Stephen A. Wynn Institute for Vision Research, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, 375 Newton Rd. 4111 MERF, Iowa City, IA, 52242, USA

    Edwin M. Stone

Authors
  1. Frederick T. Collison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason C. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerald A. Fishman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edwin M. Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Jason McAnany
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald A. Fishman.

Ethics declarations

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Statement of human rights

The study was performed in accordance with Universal Declaration of Human Rights.

Statement on the welfare of animals

This article does not contain any studies with animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Collison, F.T., Park, J.C., Fishman, G.A. et al. Two-color pupillometry in enhanced S-cone syndrome caused by NR2E3 mutations. Doc Ophthalmol 132, 157–166 (2016). https://doi.org/10.1007/s10633-016-9535-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10633-016-9535-0

Keywords

Search

Navigation