A Form of Congenital Stationary Night Blindness with

Investigative Ophthalmology & Visual Science, Vol. 31. No. 2. February 1990 Copyright © Association for Research in Vision and Ophthalmology

A Form of Congenital Stationary Night Blindness with Apparent Defect of Rod Phototransduction Neol 5. Peachey, Gerold A. Fishman, Paul E. Kilbride, Kenneth R. Alexander, Kathleen M. Keehan, and Deborah J. Derlacki We report findings obtained from an individual with an unusual form of congenital stationary night blindness (CSNB). Although the rhodopsin density difference of this subject was normal, there was no evidence of rod-mediated visual function. Dark-adapted thresholds were cone-mediated, and darkadapted electroretinograms (ERGs) represented activity of the cone system exclusively. ERG a- and b-waves obtained under light-adapted conditions were normal. The absence of a rod a-wavc but the presence of normal rhodopsin density, in combination with normal cone function, indicates that this form of CSNB likely involves a defect of phototransduction that is limited to the rods. In addition, light-adapted b-wavc responses to high luminance flashes were larger than dark-adapted responses, whereas a-wavc amplitudes were reduced by light adaptation. These ERG results address proposed mechanisms by which light adaptation might enhance cone system responses. Invest Ophthalmol Vis Sci 31:237-246, 1990 Patients with congenital stationary night blindness (CSNB) most frequently have a primary defect of the rod system that is characterized functionally by a reduction in the b-wave of the rod system electroretinogram (ERG) and an elevation of absolute threshold.1"10 However, rhodopsin density, as measured by fundus reflectometry, and the amplitude of the rod system a-wave often are normal. 410 It has been proposed that a defect of neurotransmission between rod photoreceptors and second-order neurons accounts for these findings."12 In addition to rod system abnormalities, patients with CSNB can also have cone system dysfunction, as evidenced by elevated conemediated thresholds and reductions in the amplitude of the cone system ERG. 4 ' 613 " 16 Carr et al4 reported findings from a subject (PM) with CSNB, who differed from the most typical forms of CSNB. Although rhodopsin density and kinetics were normal in this individual, the a-wave, as well as the b-wave, were greatly reduced in amplitude under

dark-adapted conditions. The authors interpreted these results as evidence for a distinct form of CSNB in which there is a defect of rod phototransduction. In addition, the cone flicker ERG of this subject was reduced in amplitude, and the cone branch of the dark adaptation curve was elevated above normal, indicating that the defect was not limited to the rod system. To our knowledge, a case similar to that of Carr et al4 has not been reported subsequently. In the current article, we describe an individual with similar findings, except that all measures of cone system function were normal. Further, unlike PM, who came from a dominant pedigree, our subject was an isolated case. Thus, it appears that this subject likely has a unique form of CSNB involving a defect of phototransduction that affects selectively the rod photoreceptors. Materials and Methods Subject

From the Department of Ophthalmology, University of Illinois at Chicago College of Medicine, Chicago, Illinois. Supported in part by National Research Service Award EY-05952, grant EY-06589, training grant EY-O7O38, and core grant EY-01792 from the National Eye Institute, National Institutes of Health, Bethesda, Maryland, and by a grant from the National Rctinitis Pigmentosa Foundation Fighting Blindness. Baltimore, Maryland. Submitted for publication: March 17, 1989; accepted June 29, 1989. Reprint requests: Neal S. Peachey, PhD, Department of Ophthalmology, University of Illinois at Chicago College of Medicine, 1855 W. Taylor Street, Chicago, IL 60612.

The subject, JH, is a 16-year-old white male with a history of night blindness for as long as he could remember. An ophthalmologic examination showed no abnormalities of the cornea, anterior chamber, iris, lens, vitreous, optic disc, retinal vessels, macula, or peripheral retina. Intraocular pressures were normal, and Snellen visual acuity was correctable to 20/10 - 2 in each eye with -0.50 +0.50 X 90. Visual fields tested on a Goldmann perimeter were normal using both 4-e-II and 2-e-II test targets. The subject's mother was examined also. Her vi-

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sual acuity was 20/20 in each eye, and no abnormalities were seen on ophthalmologic examination of her cornea, lens, and retina. In addition, ERGs obtained under stimulus conditions that isolate responses of the rod or cone system were entirely normal. No other family member (including the father, two halfsisters, a maternal uncle, two paternal uncles, a paternal aunt, all grandparents, and all maternal greatgrandparents) was known to complain of poor night vision. All subjects were tested only after the procedure had been explained fully and consent had been given. Dark-Adapted Threshold Profile

Dark-adapted detection thresholds were measured using a Tiibinger perimeter (Oculus, West Germany). The diameter of the circular test stimulus subtended 1.7°; its duration was 500 msec; and its wavelength was 500 or 656 nm. Fixation was guided with a dim long-wavelength target that was either a 0.5°-diameter spot or, for foveal viewing, a concentric diamondshaped pattern of four spots, each 0.2° in diameter and separated by 2°. Luminances of the test stimuli were calibrated with a Spectra Spot photometer. The pupil of the test eye was dilated by instilling 1 % tropicamide and 2.5% phenylephrine hydrochloride drops. After 40 min of dark adaptation, thresholds for the 500- and 656-nm test stimuli were obtained alternately, in the dark, at 15 retinal locations between 60° nasal and 45° temporal along the horizontal meridian. Thresholds were measured with an ascending method of limits; ie, the luminance of the test stimulus was increased in 0.1-log-unit steps from below threshold until the subject reported detection. Threshold was defined as the mean of three such determinations. Electroretinography

ERGs were recorded using a Burian-Allen contact lens electrode; a reference lead was placed on the subject's forehead, and the left earlobe was grounded. A Nicolet (Madison, Wisconsin) Compact Four signal averaging system was used to store the electrical signals. Ganzfeld stimulus flashes were either white (xenon), short-wavelength band-pass (Lee [Andover, England] filter no. 116; peak transmittance at 495 nm), or long-wavelength-pass (Lee filter no. 105; 50% cut-on at 560 nm). The measured spectral transmittances of the Lee filters have been published previously (see Fig. 1 of Ref. 17). Flash luminance was attenuated using internal strobe settings and Wratten neutral density filters (Eastman Kodak, Rochester, NY). Stimulus flashes were presented either in the dark or against a ganzfeld background. Flash lumi-

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nances were calibrated with a radiometer (EG&G [Princeton, NJ] model 550) equipped with a luminance probe and flash integrator. The scotopic luminances of the stimuli were determined using the nominal spectral radiance of the xenon flash,18 the spectral transmittance of each filter, and the scotopic luminosity function.18 The luminance of the background was measured with a Spectra Spot photometer. The pupil of the test eye was dilated with the instillation of 1% tropicamide and 2.5% phenylephrine hydrochloride drops. After 30 min of dark adaptation, the contact lens electrode was inserted under dim red illumination, and dark-adapted luminance-response functions were obtained using white, short-wavelength, and long-wavelength flashes. Dark-adapted cone flicker responses were next obtained using a 0.40 log cd sec/m2 white stimulus flickering at 31.1 Hz. Finally, after allowing a 10-min period for light adaptation, 19 light-adapted luminance-response functions were obtained to stimuli presented against a background of 1.34 log cd/m2. Fundus Reflectometry

Rhodopsin density differences were obtained from comparison of the reflectances of the dark-adapted and bleached peripheral fundus. A computerized, television-based imaging fundus reflectometer was used to obtain images of the fundus. Briefly, a microchannel-plate-intensified solid-state video camera viewed the fundus through the optics of a modified Zeiss (Oberkochen, West Germany) fundus camera.20 A fiberoptic light guide illuminated by a computer-controlled optical system replaced the light source of the fundus camera. The output of the video camera was digitized, displayed on a video monitor, and stored in the computer. The field of view subtended 22° horizontally and 16° vertically. The pupil of tne test eye was dilated and accommodation paralyzed by the topical instillation of 2.5% phenylephrine hydrochloride and 1% cyclopentolate hydrochloride drops. Head position was controlled with a dental-impression bite board and a pair of adjustable forehead rests. The test eye fixated upon a dim target such that the measurement region was centered at approximately 20° in the temporal retina. A second fixation target was presented to the contralateral eye and positioned to coincide with the fixation target for the test eye. The retinal position of the measurement region was determined from a series of overlapping fundus images that were obtained between the fovea and the measurement region. These images were aligned using blood vessels that were common to the regions of overlap. Following a 40-min period of dark adaptation, three series of digitized images of the dark-adapted

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fundus were obtained. For each series, the fundus was illuminated by monochromatic light from each of 13 interference filters, with half-bandwidths of approximately 10 nm and center wavelengths that ranged from 460-700 nm in approximately 20-nm steps. The exposure duration of each wavelength was 100 msec (six video fields), during which time a fundus image was electronically integrated. Each complete wavelength series was obtained in approximately 9 sec. The computer adjusted the light radiance at each wavelength so that the camera operated near the center of its linear range. The measurement lights produced minimal bleaching of rhodopsin and were considerably below the maximum permissible exposure for retinal irradiance.21 After the measurements of dark-adapted fundus reflectance, the eye was exposed for 30 sec to a bleaching light of 6.3 log scotopic td (Ditric Optics long-pass interference filter with a 50% cut-on at 540 nm), which was sufficient to bleach more than 95% of the rod visual pigment. Immediately after the offset of the bleaching light, a series of 13 monochromatic images of the bleached fundus was obtained. This bleaching and measurement sequence was repeated two additional times. For each subject, all digitized fundus images were aligned with a selected anchor image to compensate for any small eye movements that may have occurred between the periods of fundus illumination. An artificial eye with dimensions and optics comparable to those of a human eye and with a surface of known reflectance (Halon powder) was used to correct spatially the images for nonuniformities in the radiometric response of the imaging system. The three darkadapted images obtained from each subject at each wavelength were then averaged to provide a mean dark-adapted fundus image for that individual. The three images of the bleached fundus were averaged similarly. Density difference spectra, defined as the log ratios of the bleached versus dark-adapted fundus reflectances at the 13 illumination wavelengths, were obtained from the mean fundus images of each subject for a series of retinal regions (2° X 2°) that lay between 14° and 22° of eccentricity. Results Threshold Profile

Figure 1 presents dark-adapted absolute thresholds, measured in photopic units, across the horizontal meridian. The hatched areas represent the mean threshold (±2 SD) for ten normal subjects for test stimuli of 500 nm (lower hatched area) and 656 nm (upper hatched area). A comparison of threshold differences for the two wavelengths of test stimulus indi-

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Retinal Eccentricity (deg) Fig. I. Dark-adapted absolute thresholds measured across the horizontal meridian for JH for 500-nm (open circles) and 656-nm (filled circles) test stimuli 1.7° in diameter and 500 msec in duration. Hatched areas represent mean ± 2 SD for dark-adapted thresholds for ten normal subjects to the 500-nm (lower hatched area) and 656-nm (upper hatched area) test stimuli. Stippled area represents range of thresholds obtained from 14 normal subjects to the 656-nm stimulus presented against a rod-desensitizing white background field (-2.07 log cd/m2). Nasal and temporal refer to retinal location of stimuli.

cates the receptor system that mediated detection for each.22-23 For the normal subjects, thresholds for both test stimuli measured outside of the fovea were rodmediated (threshold difference of 2.5 log units). In the fovea, normal thresholds for the 656-nm stimulus were cone-mediated, while thresholds for the 500-nm stimulus were rod-mediated (threshold difference less than 2.5 but greater than 0 log units). Thresholds for JH, shown as the open circles (500-nm stimulus) and filled circles (656-nm stimulus) in Figure 1, lie considerably above those of the normals. These thresholds were cone-mediated at all retinal locations, as indicated by equivalent threshold values for the two test stimuli. To determine whether the thresholds for JH corresponded to normal cone system function, we compared his thresholds to those obtained from normals under conditions that allow the assessment of cone absolute thresholds.24 The stippled area in Figure 1 between 20° nasal and 20° temporal represents the range of thresholds obtained from 14 normal subjects to the 656-nm stimulus presented against a rod-

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Normal

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desensitizing white background field of —2.07 log cd/m2. Since thresholds for JH fall within the stippled area, it appears that the dark-adapted thresholds obtained from JH within this region represent normal cone-mediated absolute thresholds. Electrorctinography

ERGs obtained in response to white flashes presented to the dark-adapted eye are shown in Figure 2 for a typical normal subject (left) and for JH (right). The luminance of the flash used to evoke each waveform is indicated by the point where the trace intersects the vertical axis. It is apparent that the responses

obtained from JH are grossly different in waveform and greatly reduced in amplitude compared to those recorded from the normal subject. First, flashes of higher luminance were required to evoke a clear response from JH. Second, while the amplitude of the a-wave increased with increasing flash luminance, that of the b-wave first increased and then decreased. As a result, at the highest flash luminances, the awave was larger in amplitude than was the b-wave. Responses obtained to white flashes presented to the light-adapted eye are shown in Figure 3 for a typical normal subject (left) and for JH (right). The luminance of the flash used to evoke each waveform is indicated again by the point where the trace inter-

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sects the vertical axis. The responses obtained from JH under light-adapted conditions are similar in waveform to those obtained from the normal subject. Based on comparison with our normal population, these ERG responses, obtained under conditions which isolate the cone system,'7 were normal in amplitude and implicit time. As an illustration, Figure 4 presents light-adapted b-wave amplitudes (A) and implicit times (B) as a function of flash luminance for JH (filled circles) and for a group of 30 normal subjects (hatched areas). Both b-wave amplitudes and implicit times obtained from JH fall within the normal range. Light-adapted a-waves for JH were normal also in amplitude and implicit time (not shown). Consistent with these normal cone-isolated ERG responses, dark-adapted 31.1-Hz flicker responses obtained from JH were of normal amplitude (137 /uV; normal range: 71-189 /iV) and normal implicit time (28.6 msec; normal range: 26.3-37.1 msec). In order to determine whether the dark-adapted ERG responses shown in Figure 2 represented rod or cone system activity, we examined their spectral characteristics. Figure 5 presents pairs of ERG responses obtained to chromatic flashes of equivalent photopic luminance (one response was obtained to a

long-wavelength stimulus flash and the other to a short-wavelength flash). The responses on the left were obtained under dark-adapted conditions; those on the right were obtained under light-adapted conditions. Under each adaptation condition, the waveforms of the ERGs obtained in response to the photopically matched flashes were quite similar, indicating that both the dark-adapted and light-adapted responses obtained from JH reflect cone system activity. The results shown in Figure 6 extend this analysis further by comparing a-wave (Fig. 6A) and b-wave (Fig. 6B) luminance-response functions obtained from JH using short-wavelength (squares), longwavelength (triangles) and white (circles) stimuli. These functions are plotted in photopic luminance units. As expected for a cone-mediated response, the light-adapted functions (open symbols) obtained from JH superimpose when plotted in this manner. The dark-adapted response functions (filled symbols) are similarly coincident when plotted in photopic units, confirming that these responses also reflect cone system activity. Since the ERG responses obtained from JH reflected only cone-mediated activity, the results pre-

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smaller than those obtained in the dark at all flash luminances. Correspondingly, light adaptation shifted the b-wave luminance-response function to the right (Fig. 6B), such that b-wave responses to low-luminance flashes were of smaller amplitude. However, the amplitudes of the b-waves obtained to high-luminance flashes were larger under lightadapted conditions than in the dark. The light-adapted responses shown in Figure 6 were obtained after 10 min of light adaptation. However, it is well known that b-wave amplitude increases during light adaptation with a relatively slow time course.1925'26 In order to examine this in JH, we plotted (Fig. 7) b-wave amplitude to a high-luminance (0.40 log cd sec/m2) white flash presented in the dark (filled circle) and during continued exposure to a ganzfeld background (open circles). Within 1 min of light adaptation, the amplitude of the b-wave had increased from the dark-adapted value. Following this initial change, b-wave amplitude gradually in150

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sented in Figure 6 provide an opportunity to examine the effects of light adaptation on cone system responses. Light adaptation shifted the a-wave luminance-response function to the right, as expected (Fig. 6A), such that the amplitudes of the a-waves obtained in the presence of the background were

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100 20 msec Fig. 5. ERGs obtained from JH under dark-adapted (left) or light-adapted conditions (right). Each pair of overlapping traces includes one response to a short-wavelength flash (0.09 log cd scc/m2) and one to a long-wavelength flash (0.16 log cd sec/m2). Vertical bars represent time of flash presentation.

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Fig. 6. Luminance-response functions for a-waves (A) and bwaves (B) obtained from JH. Stimulus flashes were cither white (circles), short-wavelength (squares), or long-wavelength (triangles). Filled symbols were obtained under dark-adapted conditions; open symbols were obtained under light-adapted conditions.

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Fig. 8. Rhodopsin density difference spectra obtained within a 2° X 2° square area of retina centered 20° temporal for JH (filled circles). Hatched area indicates range of four normal subjects.

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Time (min) Fig. 7. Amplitude of the b-wave obtained from JH to a white 0.40 log cd scc/m2flashpresented cither under dark-adapted conditions (filled circle at 0 min) or as a function of time following onset of the background field (open circles). The solid line indicates the leastsquaresfitexponential equation to the light-adapted data. The time constant of this equation was 2.75 min.

creased to a stable value that was approximately double that seen in the dark. An exponential equation, fitted to only the light-adapted data, described the increase of b-wave amplitude during light adaptation reasonably well (solid line). The time constant of this solution was 2.75 min, which is a value similar to that obtained from normal subjects under these conditions.19

discrete locations between 14° and 22° temporal along the horizontal meridian. Within this larger region, the density difference spectra obtained from the normal subjects, as well as those from JH, were similar in shape to that shown in Figure 8, indicating that the density difference was due to rhodopsin. The hatched area in Figure 9 presents the range of density differences at the peak of the spectrum (519 nm) for four normal subjects. The results for JH (filled circles)

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Figure 8 presents rhodopsin density difference spectra obtained at 20° in the temporal retina. The density difference at each wavelength represents the average of a 2° X 2° region for each subject. The hatched area represents the range obtained from four normal subjects. The spectral peak at 519 nm and the magnitude of the density difference are similar to reflectometric measures of rhodopsin reported previously for normal subjects at this eccentricity.1027 The density difference spectrum for JH (filled circles) falls within the normal range, indicating a normal rhodopsin content within the test region, despite the fact that dark-adapted thresholds were cone-mediated (Fig. 1). In order to determine whether JH had normal rhodopsin density in areas other than that shown in Figure 8, we also obtained density difference spectra at

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0.00 12 14 16 18 20 22 24 Eccentricity (deg) Fig. 9. Density difference obtained at 519 nm for retinal locations between 14° and 22° temporal along the horizontal meridian. Hatched area represents range of four normal subjects. Filled circles represent results for JH from a 2° X 2° square area centered at the eccentricity indicated on the abscissa.

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fall within this range, indicating that rhodopsin density was normal within this larger region. Discussion In our subject, the lack of any demonstrable rodmediated function, the normal rhodopsin density, the normal ophthalmic examination, and the nonprogressive nature of his disorder are consistent with the diagnosis of CSNB. However, there are important differences between JH and more typical forms of CSNB. First of all, this subject did not generate a rod-mediated a-wave. In addition, all measures of cone function obtained from JH were normal, whereas cone function can be impaired to an appreciable degree in other forms of CSNB (see Introduction). Therefore, JH appears to have an unusual form of CSNB in which the function of the rod system is nondetectable while that of the cone system is intact. In many respects, JH is similar to subject PM, reported by Carr et al.4 Both had elevated dark-adapted thresholds and a pronounced reduction in the amplitude of the dark-adapted ERG a-wave, despite normal rhodopsin densities. In JH, we have demonstrated that both dark-adapted thresholds and darkadapted ERGs were cone-mediated, as likely was the case for PM. These results support the hypothesis that there is a defect in phototransduction within the rod photoreceptors.4 However, whereas PM appeared to have an elevated cone plateau during dark adaptation and a flicker ERG of reduced amplitude,4 cone system function in JH was normal. In addition, PM was from a dominant pedigree,4 whereas JH seemed to be an isolated case, probably of autosomal recessive inheritance. Based on these considerations, JH and PM likely represent genetically distinct subtypes of CSNB, each involving a defect in rod phototransduction. The enzymatic cascade involved in phototransduction consists of a series of biochemical reactions.28-29 Therefore, it is difficult to specify the precise nature of the defect(s) in subjects with this unusual form of CSNB. Nevertheless, studies on Drosophila provide evidence that genetic mutations can affect discrete stages within the cascade.30 In particular, norpA (no receptor potential A) mutants do not generate a photorcceptor response,3132 despite sufficient photopigment concentration to support response generation.33-34 In Drosophila norpA mutants, the gene encoding phospholipase C appears to be defective.35 Although it is perhaps unlikely that the same abnormality is involved in these individuals with CSNB, it is probable that future research will elucidate the genetic abnormality underlying the presumed phototransduction defect(s) described here.

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In JH, the amplitude of the b-wave increased during the course of light adaptation (Fig. 7), with a normal magnitude and time course for these stimulus conditions.19 In addition, the absence of detectable rod-mediated activity provided an opportunity to examine cone system ERGs in the dark-adapted state. Particularly noteworthy is our finding that b-wave amplitudes to high luminance flashes were smaller under dark-adapted than under light-adapted conditions (Fig. 6B). Since cone system function appeared to be normal in JH, it is likely that cone b-wave amplitudes in normal subjects likewise are smaller in the dark-adapted than in the light-adapted state. These observations provide evidence concerning mechanisms that have been proposed to explain the growth of the cone system ERG during light adaptation. For example, Gouras and MacKay26 suggested that the increase in ERG amplitude reflected a redepolarization of cone membrane potential toward the dark-adapted level after an initial hyperpolarization by the background field. According to this hypothesis, one would expect that dark-adapted cone system responses would be as large as or larger than lightadapted responses. In contrast, we have found that in response to the highest luminance flashes, cone system b-waves obtained from JH were smallest in the dark-adapted state (Figs. 6B, 7). Therefore, it seems unlikely that cone membrane redepolarization alone can explain the amplitude increase of the ERG bwave during light adaptation. As an alternative explanation, Miyake and co-workers3637 have suggested that the amplitude increase reflects the removal of an inhibitory influence of the rod system. However, such a mechanism is unlikely to account for the results from JH, who did not generate rod system responses. The changes in the response properties of cone system b-waves of JH were similar to those described for cone system ERGs obtained from the isolated frog retina by Hood38 and for cone horizontal cell responses obtained from fish by Mangel and Dowling,39 Yang et al,4041 and Tornqvist et al.42 In all cases, responses to high luminance full-field stimuli obtained from a light-adapted retina were larger in amplitude than were those obtained under dark-adapted conditions. Furthermore, during light adaptation, response amplitude increased gradually for several minutes. In no case could the increase in cone system response be attributed to the removal of a suppressive effect of the rod system. In the frog, the rod system of the isolated retina had been inactivated by prior bleaching;38 in the fish, background fields that were below cone threshold (but well above rod threshold) had no effect on cone horizontal cell responses;40 as noted above, JH did not generate rod system re-

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sponses. Dowling and co-workers suggested that the increase in cone horizontal cell response may have been mediated by a decreased release of dopamine by interplexiform cells in the light-adapted state.39"42 It is possible that a similar mechanism may underlie the cone b-wave results obtained from JH, which were intriguingly similar to the electrophysiologic results obtained from nonmammalian vertebrates. Additional studies of this unique individual with normal cone system function but an apparent defect of rod phototransduction is expected to provide further insights into the properties of the dark-adapted human cone system. Key words: congenital stationary night blindness (CSNB), eleclroretinogram (ERG), phototransduction, rhodopsin

Acknowledgments The authors are grateful to Professor Harris Ripps for comments on the manuscript and to Dr. C. Ronald Lindberg, who referred the individual studied in the investigation.

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