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(Investigative Ophthalmology and Visual Science. 2005;46:1480-1485.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-0638
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Cone and Rod Dysfunction in Fundus Albipunctatus with RDH5 Mutation: An Electrophysiological Study

Yasuhiro Niwa, Mineo Kondo, Shinji Ueno, Makoto Nakamura, Hiroko Terasaki, and Yozo Miyake

From the Department of Ophthalmology, Nagoya University School of Medicine, Nagoya, Japan.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. A prior study showed that some patients with fundus albipunctatus (FA) have severely reduced full-field cone ERGs. The purpose of this study was to investigate the frequency of cone dysfunction and to determine the cause of the reduced full-field cone ERGs in patients with FA and whether the rod system is affected in patients with FA.

METHODS. Sixteen consecutive patients with FA (from 1993 to 2003; eight males, eight females; mean age, 25.4 years) with an RDH5 gene mutation were studied. The amplitudes and implicit times of the standard cone ERGs in the patients with FA were compared to those obtained from normal subjects (n = 55). The a-waves of cone ERGs were also elicited by a bright flash and were fitted to a mathematical model of the a-wave. Rod ERG responses were elicited by dim blue flashes after 3 hours of dark adaptation.

RESULTS. The amplitude of the b-wave of the cone ERG in the FA group varied considerably from within the normal limits to markedly decreased. Six of 16 patients with FA had b-wave amplitudes that were smaller than the lowest limit of the control subjects. The degree of cone dysfunction tended to be more severe in older patients. The analysis of the cone a-wave demonstrated that Rm (maximal response amplitude) in the patients with FA with reduced standard cone ERGs was significantly smaller than that in control subjects. Rod ERGs were also reduced in the patients with FA who had reduced cone ERGs.

CONCLUSIONS. In patients with FA, 38% had extensive cone dysfunction. The reduced full-field cone ERGs were mainly due to the loss of cone photoreceptors, and the rod system was also affected in some patients.

Fundus albipunctatus (FA) is a type of congenital stationary night blindness characterized by multiple whitish yellow spots located in the retinal pigment epithelium (RPE) and by a delayed course of dark adaptation.1 2 3 4 These patients show severely depressed rod function during conventional dark-adaptation testing, but after 2 to 3 hours of adaptation, rod sensitivity improves to normal levels. The inheritance pattern is autosomal recessive, and it has been reported that most FA is caused by mutations in the RDH5 gene, which encodes 11-cis retinol dehydrogenase (11-cis-RDH).5 6 11-cis-RDH is expressed predominantly in the RPE and is known to be essential for the regeneration of visual pigments in the vertebrate retina.7 8 9

The electroretinographic (ERG) findings are very indicative in patients with FA. The amplitude of the scotopic ERG recorded with bright-flash stimuli is significantly reduced when recorded after 30 minutes of dark adaptation, but it becomes larger and falls within the normal range after prolonged dark adaptation (>2 hours).10 This phenomenon has been attributed to the delayed regeneration of rod visual pigment due to mutations in the RDH5 gene. It has also been reported that the regeneration of not only the rod, but also the cone visual pigments are significantly delayed in patients with FA, suggesting that the 11-cis RDH is also involved in the regeneration of cone visual pigments.5 11

It has long been believed that the cone ERG responses are well preserved in FA. However, we have demonstrated that some patients with FA have severely reduced cone ERGs.12 In addition, we have recently shown that FA, with or without reduced cone ERGs, is caused by mutations in the RDH5 gene.13 14 These results prompted us to perform further quantitative ERG studies in our cases of FA. The purpose of this study was to analyze the amplitudes and implicit times of the cone-mediated ERG responses in 16 consecutive patients with FA who were seen in our hospital from 1993 to 2003, and to determine the incidence of the extensive cone dysfunction. We then used a-wave analysis to determine whether the reduced standard cone ERGs were due to loss of cone photoreceptors. Finally, we determined whether there is degeneration in the rod system in patients with FA.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Sixteen consecutive patients with FA (eight males and eight females) with mutation in the RDH5 gene and examined in our institution (Nagoya University Hospital) from 1993 to 2003, were studied. Two patients (P14 and P15) were siblings, and the remaining 14 were unrelated. Patients with FA seen earlier than 1993 were excluded, because our ERG recording system was changed in 1993, and thus quantitative comparisons could not be performed.

The ophthalmic examination included best corrected visual acuity, slit lamp biomicroscopy, indirect ophthalmoscopy, fundus photography, visual field testing with a Goldmann perimeter, dark-adaptation test, and full-field ERGs.

The clinical characteristics of the 16 patients are shown in Table 1 . The age of the patients ranged from 8 to 70 years (mean, 25.4 years). The corrected visual acuity was 1.0 (20/20) or better in both eyes in 13 patients; the other three patients had reduced acuity in at least one eye that ranged from 0.1 (20/200) to 0.7 (20/29). Four (25%) of 16 patients had macular changes ophthalmoscopically. This percentage is nearly the same as in our previous study,15 which found that between 1979 and 1993, 26% of patients with FA had macular lesions. Ten of the 16 patients (P1–P5, P7, P9, P11, P12, and P15) have been reported in previous papers.13 14


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  		TABLE 1. Clinical Characteristics and the RDH5 Mutations in Patients with FA

 
Fifty-five normal subjects (age, 10–69 years; mean, 32.3 years) served as the normal control. All these subjects had no eye diseases, and their visual acuities were 20/20 or better.

Informed consent was obtained from all subjects after a full explanation of the purpose and procedures of the study. All studies were conducted in accordance with the principles embodied in the Declaration of Helsinki.

Genetic Analysis
Genomic DNAs were extracted from leukocytes of peripheral blood from the patients. Exons 2, 3, 4, and 5 of the RDH5 gene were amplified by polymerase chain reaction (PCR) on a thermal cycler (DNA Thermal Cycler 9700; Applied Biosystems, Inc., Foster City, CA). Primers were purchased from Life Technologies Oriental, Inc. (Tokyo, Japan). Approximately 200 ng of genomic DNA were amplified in a 50-µL reaction. The PCR products were purified with a kit (High Pure; Roche Molecular Biochemicals GmbH, Mannheim, Germany) and then directly sequenced with a DNA sequencing kit (Big Dye Terminator Cycle Sequencing Ready Reaction Kit, Applied Biosystems, Inc.), and an automated DNA sequencer (model 373; Applied Biosystems, Inc.). Primers for the sequence reactions were the same as those for the PCR reactions.

Standard Cone ERGs
ERGs were elicited by full-field (Ganzfeld) stimuli, and recorded with a Burian-Allen bipolar contact lens electrode (Hansen Ophthalmic Development Laboratories, Iowa City, IA). Standard cone ERGs were recorded according to the guidelines of the International Society of Clinical Electrophysiology of Vision (ISCEV).16

After 10 minutes of light adaptation, standard cone ERGs were elicited by white flash stimuli of 1.9 cd-s/m2 (2.0 log phot td-s) on a steady background of 18 cd/m2 (3.3 log scot td). Four responses were averaged. The amplitude and implicit times of the b-wave of the cone ERGs were measured.

a-Wave Analysis of Cone ERGs Elicited by Bright Stimuli
To study the cone photoreceptor activity in patients with FA, a model of the activation phase of phototransduction17 18 was used. The ERGs were elicited with full-field (Ganzfeld) stimuli (Model SG-2002; LKC Technologies Inc., Gaithersburg, MD), and recorded with a bipolar contact lens electrode (Doran Instruments, Littleton, MA). The a-wave was recorded in response to a strong white flash of 3.9 log phot td-s on a steady white background of 3.3 log scot td. To minimize the influence of prolonged cone photopigment regeneration, the cone a-waves were recorded after a long period (3 hours) of dark adaptation and immediately (500 ms) after turning on the background illumination.

The cone a-wave was fitted with the following equation

where i is the flash energy (log phot td·s); td is the time delay; t, is the time after the flash onset; S, is the sensitivity; and Rm, is maximum response amplitude.

To minimize the intrusion from bipolar cell activity, only the first 10 ms of the leading edge of the a-wave responses was used in the analysis. This model yielded values for three parameters: log Rm, log S, and td. For all the fits, td was held constant at the average level of the control group (2.2 ms).

Rod ERG Responses after Prolonged Dark Adaptation
To determine whether the rod system is also altered in patients with FA, we recorded rod ERGs after prolonged dark adaptation. After 3 hours of dark adaptation, rod ERGs were elicited by dim blue-flash stimuli of 0.2 log scot td-s. Four responses were averaged.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Standard Cone ERGs
The standard cone ERGs, recorded from a representative normal subject (a 32-year-old man) and from 16 patients with FA with an RDH5 mutation, are shown in Figure 1 . The vertical and horizontal bars near the normal waveform indicate the range of the normal b-wave amplitude and implicit time obtained from the 55 normal subjects, respectively. The amplitudes of the b-wave of the cone ERG in the FA group ranged from within the normal range to severely decreased b-waves. As a group, the mean amplitude of cone b-wave in the FA group (73.6 ± 36.2 µV, mean ± SD) was significantly smaller than that in the normal group (128.6 ± 36.3 µV, P < 0.001, Mann-Whitney test). However, a more careful examination of the individual ERGs showed that the b-wave amplitude fell within the normal range in 10 patients (P1–P10), and was lower than the lowest limit of the normal subjects in 6 patients (P11–P16).



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  		FIGURE 1. Standard cone ERGs in a normal subject and 16 patients with FA. Vertical and horizontal bars near the normal waveform represent the normal ranges of the b-wave amplitude and implicit time, respectively, that were obtained from 55 normal subjects.

 
The b-wave amplitudes of cone ERGs were plotted as a function of the subjects’ age for the 55 normal controls and 16 patients with FA (Fig. 2A) . In the normal subjects, there was no significant correlation between the cone b-wave amplitude and age (r = –0.23, P = 0.14), although a significant correlation has been reported.19 In contrast, there was a weak, but significant inverse correlation between the cone b-wave amplitude and age for our FA group (r = –0.64, P = 0.007, solid line). In our oldest FA patient (P16, see also Fig. 1 ), the b-wave amplitude was severely reduced and essentially undetectable.



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  		FIGURE 2. (A) The amplitude of standard cone ERG b-wave as a function of age in 55 normal subjects and 16 patients with FA. Solid line: regression line between amplitude and age in the 16 patients (r = –0.64, P = 0.007). (B) The implicit time of the standard cone ERG b-wave as a function of age in 55 normal subjects and 16 patients with FA. There was no significant correlation between implicit time and age in normal subjects or the patients with FA.

 
We also found that the abnormality in the cone ERG b-wave was more severe in older patients than in younger patients. The difference in the b-wave amplitudes of the cone ERGs between control subjects and patients became larger with advancing age. For example, the mean amplitude of the cone ERG b-wave in patients with FA was reduced to 61% of that in the control subjects (control, 130.6 ± 37.0 µV; FA, 79.4 ± 32.4 µV) between ages 10 and 30 years, and it was further reduced to 34% of that in the control subjects at 50 and 70 years (control, 123.0 ± 32.0 µV; FA, 41.9 ± 24.9 µV).

We also compared the implicit times of the b-wave of the cone ERGs in the two groups (Fig. 2B) . There was no significant difference in the implicit time of the cone b-wave between the two groups (control, 30.9 ± 1.4 ms; FA, 31.8 ± 2.1 ms; P = 0.13, Mann-Whitney test). Three patients (P2, P15, and P16) had implicit times longer than the normal limits.

Cone a-Wave Analysis
We next examined whether the reduced standard cone ERG in patients with FA is due to a loss of cone photoreceptors. If this were the case, then the cone photoreceptor component of the ERG would be smaller in the reduced standard cone ERG group. Because it is known that the a-wave of cone ERGs elicited with conventional weak stimuli originates mainly from the activity of OFF-bipolar cells,20 a higher-intensity flash and a mathematical exponential decay model can be used to estimate the activity of cone photoreceptors. For this purpose, we recorded the cone a-wave elicited by a bright flash (3.9 log phot td-s) and analyzed the leading edge of the a-wave with the model proposed by Hood and Birch.17 To minimize the influence of the delayed photopigment regeneration in FA, the cone a-waves were recorded after a long (3-hour) dark-adaptation period and immediately (500 ms) after turning on the background illumination.

The actual and fitted waveforms in a normal subject (32-year-old man, black trace), a patient with FA with normal standard cone ERGs (P10, blue trace), and a patient with FA with reduced standard cone ERGs (P15, red trace) are shown in Figure 3A . The values of log Rm (maximum response amplitude) and log S (sensitivity) in 10 normal subjects (age, 27–68 years), three patients with FA with normal standard cone ERGs (P7, P8, P10), and four patients with reduced standard cone ERGs (P12–P15) are plotted in Figure 3B .



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  		FIGURE 3. Results of the cone a-wave analysis. (A) Examples of the cone a-wave data and the fitted model in a normal subject (black trace) and patients with FA with normal (blue trace, P10) or reduced (red trace, P15) standard cone ERG. (B) Log Rm and log S derived from the fitted model of the cone a-wave in 10 normal subjects and in 3 patients with FA with normal standard cone ERG and 4 with reduced standard cone ERG.

 
Rm was normal in all three patients with FA who had normal standard cone ERGs. In contrast, Rm was lower than the normal range or at the lower border in all four patients with FA with reduced standard cone ERG. The value of S was also reduced in three of the four patients with FA with reduced standard cone ERGs.

Rod ERGs after Prolonged Dark Adaptation
Finally, we determined whether there was also an alternation of the rod system in patients with FA. To assess this, we recorded rod ERGs after 3 hours of dark adaptation. The rod ERGs obtained from a representative normal subject (32-year-old man) and 14 patients with FA (P1–P8, P10, P12–P16) are shown in Figure 4A . A plot of the b-wave amplitude of rod ERGs as a function of the subjects’ age for the 55 normal control subjects and 14 FA are shown in Figure 4B . There were four patients with FA whose rod ERGs were lower than the lowest limit in the normal subjects (P13–P16), and all these patients had reduced standard cone ERGs (Figs. 1 2) . These results indicate that not only the cone system but also the rod system was affected in some patients with FA.



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  		FIGURE 4. Recordings of rod ERG. (A) The rod ERGs were elicited by dim blue flashes after 3 hours of dark adaptation in 14 patients with FA, and after 30 minutes of dark adaptation for normal subjects. Vertical bar near the normal waveform represents the normal range of the b-wave amplitude, which was obtained from 55 normal subjects. (B) The amplitude of the rod ERG b-wave as a function of age in 55 normal subjects and 14 patients with FA.

 
To compare the relative degree of dysfunction in the cone and rod systems in patients with FA, we plotted the ratio of the amplitude of the cone ERG to the rod ERG as a function of the subjects’ age (Fig. 5) . As expected, the ratio of cone-rod amplitude was significantly lower in the FA group (0.56 ± 0.25) than in the control group (0.79 ± 0.21; P < 0.001, Mann-Whitney test). Eight of 14 patients with FA had lower cone–rod amplitude ratios than the lowest limit in the normal group (P3–P6, P8, P13, P15, P16).



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  		FIGURE 5. The relative amplitude ratio of the cone ERG b-wave to the rod ERG b-wave as a function of the subject’s age.

 
Gene Analysis
DNA analysis revealed either a homozygous or a compound heterozygous mutation in the RDH5 gene in all 16 patients (Table 1) . They included Gly35ser (c.103 G->A), Arg42Cys (c.124C->T), Val132Met (c.394 G->A), a c.719 G insertion, Arg280His (c.839 G->A), Try281His (c.841 T->C), and Leu310GluVal (c.928 C->GAAG) mutations. The Gly35ser,13 21 Val132Met,13 22 c.719 G insertion,13 Arg280His,6 13 22 23 Try281His,13 24 and Leu310GluVal,13 24 25 26 27 mutations have been reported. The Arg42Cys mutation in patient 8 was novel. These nucleotide changes were not present in 100 alleles in normal individuals. The sequences of the healthy parents of patients 1 to 9, 11, 12, 14, and 15 showed a heterozygous pattern, including both the wild-type and mutant alleles. The Leu310GluVal mutation has been frequently detected, and was found homozygously in six and heterozygously in 12 of our 16 patients with FA. We could not find any significant correlation between nucleotide changes and phenotype in the 16 patients.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
There are several studies reporting that patients with FA are often found to have severely reduced cone ERGs.12 13 21 22 There is also evidence that there is no apparent ERG progression over 13 to 14 years in a patient with FA.28 However, the exact prevalence of extensive cone system dysfunction in FA, as found in our study, has not been reported.

Our results demonstrated that 6 of 16 of patients with FA with an RDH5 mutation had significantly reduced full-field cone ERG amplitudes, suggesting that approximately 38% of patients with FA have extensive dysfunction of the cone system throughout the retina. This frequency is higher than we had expected, and indicates that cone dysfunction should be recognized as a major phenotypic finding in FA. Another new finding was that even patients with FA without macular lesions can be associated with cone dysfunction. In our six patients with FA with cone dysfunction, three had completely normal maculae ophthalmoscopically.

Although it is still not known whether the cone dysfunction in FA is stationary or slowly progressive, we assume that it must be progressive because of the following reasons: First, the difference in the cone ERG amplitudes between controls and patients with FA was larger at older ages (50–70 years) than at younger ages (10–30 years). Second, there was a steep regression line between age and the cone b-wave amplitude in the FA group (Fig. 2A) . And third, the three older patients with FA (P12, P13, P16) actually stated that the visual disturbance in their day vision was slowly progressive. To prove this hypothesis, it is necessary to observe more patients with FA for a longer time.

The results of our cone a-wave analysis demonstrated that the maximum amplitude of cone photoreceptor response (Rm) was lower than the normal range or at the lower limit in all four patients with FA with reduced standard cone ERG. This suggests that an extensive loss of cone photoreceptors (i.e., the decreased number of cone photoreceptors or shortening of cone outer segments is the primary cause of the cone system dysfunction in FA). Cideciyan et al.11 also studied the rod and cone photoreceptor function in a patient with FA with a null mutation of RDH5 and reported that the maximum amplitude of cone photoresponse was reduced to 60% of normal, supporting our conclusion.

The results of our cone a-wave analysis also demonstrated that S was reduced in three of four patients with FA with reduced standard cone ERGs. However, this result disagrees with those in a previous study. Cideciyan et al.11 demonstrated that S remained within the normal range in a patient with FA in whom the Rm was approximately 60% of normal. One possible explanation for this discrepancy is that the cone sensitivity may remain relatively normal at the early stage of cone degeneration and may gradually become abnormal with progression of retinal degeneration. Figure 3B shows that S became smaller with progression of retinal degeneration, supporting this idea.

Data have not been published to indicate whether the cone system degenerates specifically or together with the rod system in patients with FA. Our analysis of rod ERGs after prolonged dark adaptation demonstrated clearly that not only the cone system, but also the rod system is impaired in these patients. As shown in Figure 4 , patients with FA with reduced cone ERGs tended to have smaller rod ERGs. However, the degree of degeneration in the rod system was found to be less than in the cone system, because the cone–rod amplitude ratio was significantly lower than the control in patients with FA.

One question that should be clarified is why the cone system is more affected than the rod system in patients with FA with RDH5 mutations. It is known that the 11-cis RDH, the product of the RDH5 gene, is involved in the regeneration of both the rod and cone photopigments in the retinal pigment epithelium.5 11 But then, why do the cone photoreceptors predominantly degenerate from an inactivation of 11-cis RDH enzyme in older patients? It has been suggested that cone degeneration may be due to nonspecific effects on the function of retinal pigment epithelium or a direct consequence of the decreased supply of 11-cis retinal to the cones.29 Analysis of cone function in older RDH5-deficient mice30 may provide some useful information regarding the exact mechanism of cone degeneration.

In conclusion, in our study, approximately 38% of patients with FA with the RDH5 mutation had extensive cone dysfunction. The degree of cone dysfunction tended to be more severe in older patients. The reduction of the standard cone ERGs in FA was found to be mainly due to the extensive loss of cone photoreceptors. Not only the cone system, but also the rod system was found to be affected in patients with FA. Further studies are needed to clarify the exact mechanism of cone–rod photoreceptor degeneration caused by the RDH5 mutations.


   Footnotes
 
Supported by Grants-in-Aid 13307048 (YM), 14370557 (HT), 14770952 (MK), and 14370556 (MN) from the Ministry of Education, Science, Sports and Culture, Japan.

Submitted for publication June 2, 2004; revised October 23, 2004; accepted November 20, 2004.

Disclosure: Y. Niwa, None; M. Kondo, None; S. Ueno, None; M. Nakamura, None; H. Terasaki, None; Y. Miyake, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Mineo Kondo, Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; kondomi{at}med.nagoya-u.ac.jp.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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S. Ueno, M. Kondo, C.-H. Piao, K. Ikenoya, Y. Miyake, and H. Terasaki
Selective Amplitude Reduction of the PhNR after Macular Hole Surgery: Ganglion Cell Damage Related to ICG-Assisted ILM Peeling and Gas Tamponade.
Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3545 - 3549.
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