Abstract

The aim of this study was to identify the origin of a high-frequency attenuation in the flicker electroretinogram (ERG) of patients with X-linked retinoschisis (XLRS) through an analysis of nonlinearities in the ERG response. The ERGs of six patients with XLRS and six age-similar control subjects were recorded in response to stimuli that consisted of pairs of sinusoids that had varying temporal frequencies and that differed by either 8 or 16 Hz. Compared with the control subjects, the patients with XLRS showed a significant reduction in the amplitude of the difference frequency to high-frequency stimuli that paralleled the high-frequency attenuation of their ERG response fundamental. This result indicates that a response attenuation at an initial linear filter, most likely photoreceptoral, was a major determinant of the reduced ERG amplitude of the XLRS patients at high temporal frequencies. Additional analyses of nonlinearities in the ERG responses provided evidence of a postreceptoral component to the flicker ERG deficits of the XLRS patients, as well.

© 2001 Optical Society of America

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  1. The Retinoschisis Consortium, “Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis,” Hum. Mol. Genet. 7, 1185–1192 (1998).
  2. M. Yanoff, E. K. Rahn, L. E. Zimmerman, “Histopathology of juvenile retinoschisis,” Arch. Ophthalmol. 79, 49–53 (1968).
    [CrossRef] [PubMed]
  3. W. A. Manschot, “Pathology of hereditary juvenile retinoschisis,” Arch. Ophthalmol. 88, 131–138 (1972).
    [CrossRef] [PubMed]
  4. G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
    [CrossRef] [PubMed]
  5. C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
    [CrossRef] [PubMed]
  6. R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).
  7. C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
    [CrossRef] [PubMed]
  8. U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
    [CrossRef] [PubMed]
  9. U. Kellner, M. H. Foerster, “Cone dystrophies with negative photopic electroretinogram,” Brit. J. Ophthalmol. 77, 404–409 (1993).
    [CrossRef]
  10. N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).
  11. K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
    [CrossRef]
  12. K. R. Alexander, G. A. Fishman, S. Grover, “Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis,” Vision Res. 40, 2861–2868 (2000).
    [CrossRef] [PubMed]
  13. T. Hirose, E. Wolf, A. Hara, “Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance,” Doc. Ophthalmol. Proc. Ser. 13, 173–184 (1977).
  14. N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
    [CrossRef] [PubMed]
  15. Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).
  16. D. C. Hood, D. G. Birch, “Phototransduction in human cones measured using the a-wave of the ERG,” Vision Res. 35, 2801–2810 (1995).
    [CrossRef] [PubMed]
  17. R. A. Bush, P. A. Sieving, “Inner retinal contributions to the primate photopic fast flicker electroretinogram,” J. Opt. Soc. Am. A 13, 557–565 (1996).
    [CrossRef]
  18. M. Kondo, P. A. Sieving, “Primate photopic sinewave flicker ERG: vector modeling analysis of component origins using glutamate analogs,” Invest. Ophthalmol. Visual Sci. 42, 305–312 (2001).
  19. S. A. Burns, A. E. Elsner, M. R. Kreitz, “Analysis of non-linearities in the flicker ERG,” Optom. Vision Sci. 69, 95–105 (1992).
    [CrossRef]
  20. S. A. Burns, A. E. Elsner, “Response of the retina at low temporal frequencies,” J. Opt. Soc. Am. A 13, 667–672 (1996).
    [CrossRef]
  21. As discussed by Burns and Elsner,20 this approach assumes that there is only one site of nonlinearity and that it is static. These assumptions are probably not entirely true, but slight violations of these assumptions do not invalidate this approach.20
  22. C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).
  23. Y. Chang, S. A. Burns, M. R. Kreitz, “Red–green flicker photometry and nonlinearities in the flicker electroretinogram,” J. Opt. Soc. Am. A 10, 1413–1422 (1993).
    [CrossRef] [PubMed]
  24. B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
    [CrossRef] [PubMed]
  25. J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
    [CrossRef]
  26. W. H. Swanson, T. Ueno, V. C. Smith, J. Pokorny, “Temporal modulation sensitivity and pulse-detection thresholds for chromatic and luminance perturbations,” J. Opt. Soc. Am. A 4, 1992–2005 (1987).
    [CrossRef] [PubMed]

2001 (1)

M. Kondo, P. A. Sieving, “Primate photopic sinewave flicker ERG: vector modeling analysis of component origins using glutamate analogs,” Invest. Ophthalmol. Visual Sci. 42, 305–312 (2001).

2000 (3)

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

K. R. Alexander, G. A. Fishman, S. Grover, “Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis,” Vision Res. 40, 2861–2868 (2000).
[CrossRef] [PubMed]

1999 (3)

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
[CrossRef]

B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
[CrossRef] [PubMed]

1998 (1)

The Retinoschisis Consortium, “Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis,” Hum. Mol. Genet. 7, 1185–1192 (1998).

1997 (1)

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

1996 (2)

1995 (1)

D. C. Hood, D. G. Birch, “Phototransduction in human cones measured using the a-wave of the ERG,” Vision Res. 35, 2801–2810 (1995).
[CrossRef] [PubMed]

1993 (3)

Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).

U. Kellner, M. H. Foerster, “Cone dystrophies with negative photopic electroretinogram,” Brit. J. Ophthalmol. 77, 404–409 (1993).
[CrossRef]

Y. Chang, S. A. Burns, M. R. Kreitz, “Red–green flicker photometry and nonlinearities in the flicker electroretinogram,” J. Opt. Soc. Am. A 10, 1413–1422 (1993).
[CrossRef] [PubMed]

1992 (2)

J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
[CrossRef]

S. A. Burns, A. E. Elsner, M. R. Kreitz, “Analysis of non-linearities in the flicker ERG,” Optom. Vision Sci. 69, 95–105 (1992).
[CrossRef]

1990 (1)

U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
[CrossRef] [PubMed]

1988 (1)

C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).

1987 (2)

W. H. Swanson, T. Ueno, V. C. Smith, J. Pokorny, “Temporal modulation sensitivity and pulse-detection thresholds for chromatic and luminance perturbations,” J. Opt. Soc. Am. A 4, 1992–2005 (1987).
[CrossRef] [PubMed]

N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
[CrossRef] [PubMed]

1986 (1)

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

1977 (1)

T. Hirose, E. Wolf, A. Hara, “Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance,” Doc. Ophthalmol. Proc. Ser. 13, 173–184 (1977).

1972 (1)

W. A. Manschot, “Pathology of hereditary juvenile retinoschisis,” Arch. Ophthalmol. 88, 131–138 (1972).
[CrossRef] [PubMed]

1968 (1)

M. Yanoff, E. K. Rahn, L. E. Zimmerman, “Histopathology of juvenile retinoschisis,” Arch. Ophthalmol. 79, 49–53 (1968).
[CrossRef] [PubMed]

Alexander, K. R.

K. R. Alexander, G. A. Fishman, S. Grover, “Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis,” Vision Res. 40, 2861–2868 (2000).
[CrossRef] [PubMed]

Arnold, E. B.

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

Baker, C. L.

C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).

Birch, D. G.

D. C. Hood, D. G. Birch, “Phototransduction in human cones measured using the a-wave of the ERG,” Vision Res. 35, 2801–2810 (1995).
[CrossRef] [PubMed]

Bradshaw, K.

K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
[CrossRef]

Brigell, M. G.

N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
[CrossRef] [PubMed]

Brownstein, S.

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

Brümmer, S.

U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
[CrossRef] [PubMed]

Burgers, N.

J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
[CrossRef]

Burns, S. A.

Bush, R. A.

Chang, Y.

Condon, G. P.

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

Dacey, D. M.

B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
[CrossRef] [PubMed]

Derlacki, D. J.

N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
[CrossRef] [PubMed]

Ellis, J. A.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Elsner, A. E.

S. A. Burns, A. E. Elsner, “Response of the retina at low temporal frequencies,” J. Opt. Soc. Am. A 13, 667–672 (1996).
[CrossRef]

S. A. Burns, A. E. Elsner, M. R. Kreitz, “Analysis of non-linearities in the flicker ERG,” Optom. Vision Sci. 69, 95–105 (1992).
[CrossRef]

Ewing, C. C.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

Farber, D. B.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Felius, J.

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

Fishman, G. A.

K. R. Alexander, G. A. Fishman, S. Grover, “Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis,” Vision Res. 40, 2861–2868 (2000).
[CrossRef] [PubMed]

N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
[CrossRef] [PubMed]

Foerster, M. H.

U. Kellner, M. H. Foerster, “Cone dystrophies with negative photopic electroretinogram,” Brit. J. Ophthalmol. 77, 404–409 (1993).
[CrossRef]

U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
[CrossRef] [PubMed]

Gehrig, A.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

George, N.

K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
[CrossRef]

Gibson, A.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Grayson, C.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Grover, S.

K. R. Alexander, G. A. Fishman, S. Grover, “Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis,” Vision Res. 40, 2861–2868 (2000).
[CrossRef] [PubMed]

Hara, A.

T. Hirose, E. Wolf, A. Hara, “Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance,” Doc. Ophthalmol. Proc. Ser. 13, 173–184 (1977).

Hess, R.

C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).

Hicks, D.

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

Hirose, T.

T. Hirose, E. Wolf, A. Hara, “Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance,” Doc. Ophthalmol. Proc. Ser. 13, 173–184 (1977).

Hood, D. C.

D. C. Hood, D. G. Birch, “Phototransduction in human cones measured using the a-wave of the ERG,” Vision Res. 35, 2801–2810 (1995).
[CrossRef] [PubMed]

Horiguchi, M.

Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).

Jamison, J. A.

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

Jurklies, B.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Kearns, A. F.

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

Kellner, U.

U. Kellner, M. H. Foerster, “Cone dystrophies with negative photopic electroretinogram,” Brit. J. Ophthalmol. 77, 404–409 (1993).
[CrossRef]

U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
[CrossRef] [PubMed]

Khan, N. W.

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

Kondo, M.

M. Kondo, P. A. Sieving, “Primate photopic sinewave flicker ERG: vector modeling analysis of component origins using glutamate analogs,” Invest. Ophthalmol. Visual Sci. 42, 305–312 (2001).

Kreitz, M. R.

Y. Chang, S. A. Burns, M. R. Kreitz, “Red–green flicker photometry and nonlinearities in the flicker electroretinogram,” J. Opt. Soc. Am. A 10, 1413–1422 (1993).
[CrossRef] [PubMed]

S. A. Burns, A. E. Elsner, M. R. Kreitz, “Analysis of non-linearities in the flicker ERG,” Optom. Vision Sci. 69, 95–105 (1992).
[CrossRef]

Lee, B. B.

B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
[CrossRef] [PubMed]

Lorenz, B.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Manschot, W. A.

W. A. Manschot, “Pathology of hereditary juvenile retinoschisis,” Arch. Ophthalmol. 88, 131–138 (1972).
[CrossRef] [PubMed]

Marquardt, A.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Miyake, Y.

Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).

Molday, L. L.

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

Molday, R. S.

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

Moore, A.

K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
[CrossRef]

Odom, J. V.

J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
[CrossRef]

Olsen, B. T.

C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).

Ota, I.

Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).

Peachey, N. S.

N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
[CrossRef] [PubMed]

Pokorny, J.

B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
[CrossRef] [PubMed]

W. H. Swanson, T. Ueno, V. C. Smith, J. Pokorny, “Temporal modulation sensitivity and pulse-detection thresholds for chromatic and luminance perturbations,” J. Opt. Soc. Am. A 4, 1992–2005 (1987).
[CrossRef] [PubMed]

Rahn, E. K.

M. Yanoff, E. K. Rahn, L. E. Zimmerman, “Histopathology of juvenile retinoschisis,” Arch. Ophthalmol. 79, 49–53 (1968).
[CrossRef] [PubMed]

Reid, S. N. M.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Reits, D.

J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
[CrossRef]

Riemslag, F. C. C.

J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
[CrossRef]

Rutherford, A.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Sauer, C. G.

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Shiroyama, N.

Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).

Sieving, P. A.

M. Kondo, P. A. Sieving, “Primate photopic sinewave flicker ERG: vector modeling analysis of component origins using glutamate analogs,” Invest. Ophthalmol. Visual Sci. 42, 305–312 (2001).

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

R. A. Bush, P. A. Sieving, “Inner retinal contributions to the primate photopic fast flicker electroretinogram,” J. Opt. Soc. Am. A 13, 557–565 (1996).
[CrossRef]

Smith, V. C.

B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
[CrossRef] [PubMed]

W. H. Swanson, T. Ueno, V. C. Smith, J. Pokorny, “Temporal modulation sensitivity and pulse-detection thresholds for chromatic and luminance perturbations,” J. Opt. Soc. Am. A 4, 1992–2005 (1987).
[CrossRef] [PubMed]

Sowden, J. C.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Swanson, W. H.

Trump, D.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
[CrossRef]

Ueno, T.

Wang, N. S.

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

Warneke-Wittstock, R.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Weber, B. H.

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Weber, B. H. F.

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

Wessing, A.

U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
[CrossRef] [PubMed]

Wolf, E.

T. Hirose, E. Wolf, A. Hara, “Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance,” Doc. Ophthalmol. Proc. Ser. 13, 173–184 (1977).

Yanoff, M.

M. Yanoff, E. K. Rahn, L. E. Zimmerman, “Histopathology of juvenile retinoschisis,” Arch. Ophthalmol. 79, 49–53 (1968).
[CrossRef] [PubMed]

Yates, J. R. W.

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

Zimmerman, L. E.

M. Yanoff, E. K. Rahn, L. E. Zimmerman, “Histopathology of juvenile retinoschisis,” Arch. Ophthalmol. 79, 49–53 (1968).
[CrossRef] [PubMed]

Zrenner, E.

C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).

Arch. Ophthalmol. (4)

M. Yanoff, E. K. Rahn, L. E. Zimmerman, “Histopathology of juvenile retinoschisis,” Arch. Ophthalmol. 79, 49–53 (1968).
[CrossRef] [PubMed]

W. A. Manschot, “Pathology of hereditary juvenile retinoschisis,” Arch. Ophthalmol. 88, 131–138 (1972).
[CrossRef] [PubMed]

G. P. Condon, S. Brownstein, N. S. Wang, A. F. Kearns, C. C. Ewing, “Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and ultrastructural findings in three eyes,” Arch. Ophthalmol. 104, 576–583 (1986).
[CrossRef] [PubMed]

N. S. Peachey, G. A. Fishman, D. J. Derlacki, M. G. Brigell, “Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis,” Arch. Ophthalmol. 105, 513–516 (1987).
[CrossRef] [PubMed]

Brit. J. Ophthalmol. (1)

U. Kellner, M. H. Foerster, “Cone dystrophies with negative photopic electroretinogram,” Brit. J. Ophthalmol. 77, 404–409 (1993).
[CrossRef]

Doc. Ophthalmol. (1)

K. Bradshaw, N. George, A. Moore, D. Trump, “Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG,” Doc. Ophthalmol. 98, 153–173 (1999).
[CrossRef]

Doc. Ophthalmol. Proc. Ser. (1)

T. Hirose, E. Wolf, A. Hara, “Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance,” Doc. Ophthalmol. Proc. Ser. 13, 173–184 (1977).

Graefes Arch. Clin. Exp. Ophthalmol. (1)

U. Kellner, S. Brümmer, M. H. Foerster, A. Wessing, “X-linked congenital retinoschisis,” Graefes Arch. Clin. Exp. Ophthalmol. 228, 432–437 (1990).
[CrossRef] [PubMed]

Hum. Mol. Genet. (2)

C. Grayson, S. N. M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R. W. Yates, D. B. Farber, D. Trump, “Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells,” Hum. Mol. Genet. 9, 1873–1879 (2000).
[CrossRef] [PubMed]

The Retinoschisis Consortium, “Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis,” Hum. Mol. Genet. 7, 1185–1192 (1998).

Invest. Ophthalmol. Visual Sci. (2)

Y. Miyake, N. Shiroyama, I. Ota, M. Horiguchi, “Focal macular electroretinogram in X-linked congenital retinoschisis,” Invest. Ophthalmol. Visual Sci. 34, 512–515 (1993).

M. Kondo, P. A. Sieving, “Primate photopic sinewave flicker ERG: vector modeling analysis of component origins using glutamate analogs,” Invest. Ophthalmol. Visual Sci. 42, 305–312 (2001).

Invest. Ophthalmol. Visual Sci. Suppl. (2)

N. W. Khan, J. Felius, J. A. Jamison, E. B. Arnold, P. A. Sieving, “Human photopic flicker ERG harmonic analysis,” Invest. Ophthalmol. Visual Sci. Suppl. 40, S714 (1999).

R. S. Molday, L. L. Molday, C. G. Sauer, D. Hicks, B. H. F. Weber, “Characterization and localization of RS1, the protein encoded by the gene for X-linked juvenile retinoschisis,” Invest. Ophthalmol. Visual Sci. Suppl. 41, S330 (2000).

J. Opt. Soc. Am. A (4)

J. Physiol. (London) (1)

C. L. Baker, R. Hess, B. T. Olsen, E. Zrenner, “Current source density analysis of linear and non-linear components of the primate electroretinogram,” J. Physiol. (London) 407, 155–176 (1988).

Nat. Genet. (1)

C. G. Sauer, A. Gehrig, R. Warneke-Wittstock, A. Marquardt, C. C. Ewing, A. Gibson, B. Lorenz, B. Jurklies, B. H. Weber, “Positional cloning of the gene associated with X-linked juvenile retinoschisis,” Nat. Genet. 17, 164–170 (1997).
[CrossRef] [PubMed]

Optom. Vision Sci. (2)

J. V. Odom, D. Reits, N. Burgers, F. C. C. Riemslag, “Flicker electroretinograms: a systems analytic approach,” Optom. Vision Sci. 69, 106–116 (1992).
[CrossRef]

S. A. Burns, A. E. Elsner, M. R. Kreitz, “Analysis of non-linearities in the flicker ERG,” Optom. Vision Sci. 69, 95–105 (1992).
[CrossRef]

Proc. Natl. Acad. Sci. USA (1)

B. B. Lee, D. M. Dacey, V. C. Smith, J. Pokorny, “Horizontal cells reveal cone type-specific adaptation in primate retina,” Proc. Natl. Acad. Sci. USA 96, 14611–14616 (1999).
[CrossRef] [PubMed]

Vision Res. (2)

D. C. Hood, D. G. Birch, “Phototransduction in human cones measured using the a-wave of the ERG,” Vision Res. 35, 2801–2810 (1995).
[CrossRef] [PubMed]

K. R. Alexander, G. A. Fishman, S. Grover, “Temporal frequency deficits in the electroretinogram of the cone system in X-linked retinoschisis,” Vision Res. 40, 2861–2868 (2000).
[CrossRef] [PubMed]

Other (1)

As discussed by Burns and Elsner,20 this approach assumes that there is only one site of nonlinearity and that it is static. These assumptions are probably not entirely true, but slight violations of these assumptions do not invalidate this approach.20

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Figures (6)

Fig. 1
Fig. 1

A, a representative stimulus waveform, illustrating the sum of 40 and 48 Hz sinusoids, each at 50% modulation and added in sine phase. The stimulus was presented continuously, but only the 500-ms recording epoch is shown. B, the ERG response of a typical control subject to this stimulus. The waveform represents the average of 12 500-ms sweeps.

Fig. 2
Fig. 2

A, amplitude spectrum of the stimulus shown in Fig. 1. B, amplitude spectrum of the ERG waveform shown in Fig. 1. Arrows and numbers refer to the major frequency components present in the spectra. P/T refers to peak-to-trough (full) amplitude.

Fig. 3
Fig. 3

A, mean log amplitude of the ERG response fundamental as a function of log stimulus temporal frequency for the XLRS patients (solid circles) and control subjects (open circles), with temporal frequency indicated on the top x axis. B, mean phase of the ERG response fundamental as a function of log stimulus frequency, with symbols as in A. Error bars represent ±1 SEM and are plotted only when larger than the symbols. The curves in B represent least-squares regression lines fitted to the phase data at 16 Hz and higher on linear coordinates.

Fig. 4
Fig. 4

A, mean log amplitude of the 8-Hz difference frequency as a function of log stimulus frequency for the XLRS patients (solid triangles) and control subjects (open triangles), with temporal frequency indicated on the top x axis. The hatched region represents the mean noise level ±1 SEM of the XLRS patients at 8 Hz (see text for details). B, mean phase of the 8-Hz difference frequency as a function of log stimulus frequency. Data points are plotted with respect to the mean temporal frequency of the sinusoidal components in each pair. Error bars in both plots represent ±1 SEM and are plotted only when larger than the symbols.

Fig. 5
Fig. 5

A, mean log amplitude of the 16-Hz difference frequency as a function of log stimulus frequency for the XLRS patients (solid inverted triangles) and control subjects (open inverted triangles), with temporal frequency indicated on the top x axis. The hatched region represents the mean noise level ±1 SEM of the XLRS patients at 16 Hz (see text for details). B, mean phase of the 16-Hz difference frequency as a function of log stimulus frequency. Data points are plotted with respect to the mean temporal frequency of the sinusoidal components in each pair. Error bars in both plots represent ±1 SEM and are plotted only when larger than the symbols.

Fig. 6
Fig. 6

Comparison of the amplitude of the 8-Hz difference frequency (triangles) with the amplitude of the response fundamental (circles) for the XLRS patients (solid symbols) and control subjects (open symbols). Data for the response fundamental have been replotted directly from Fig. 3. Data for the difference frequency have been replotted from Fig. 4 but have been displaced vertically as described in the text. Error bars represent ±1 SEM.

Tables (1)

Tables Icon

Table 1 Patient Characteristics

Metrics