Autosomal recessive incomplete achromatopsia with protan luminosity function.

A unique form of dichromatic color vision is described in a family with incomplete achromatopsia. In 1966, incomplete achromatopsia was diagnosed in 4 of 14 children of a consanguineous marriage. The 4 affected had best visual acuities of 6/60 or 6/180, pendular nystagmus, and aversion to bright lights. The ERG showed minimal photopic responses. No abnormality of rod function was present. There was a severe color vision defect. In 1976, one of the patients returned for further color testing. Color tests included measurement of the luminous efficiency function using heterochromatic flicker photometry and colorimetric evaluation. The luminous efficiency function resembled that of the protanope. From the colorimetric measurements, we conclude that the patient has a unique form of dichromatic color vision mediated by two visual photopigments: the normal MWS cone photopigment and a photopigment with the spectral characteristics of rhodopsin.     

A detailed phenotypic study of "cone dystrophy with supernormal rod ERG"

AIMS: To characterise the detailed phenotype of "cone dystrophy with supernormal rod ERG" in a case series of 10 patients. METHODS: 10 affected patients were examined clinically and underwent colour fundus photography, with nine undergoing detailed electrophysiological testing. Five patients were assessed further with fundus autofluorescence (AF) imaging, automated photopic and dark adapted perimetry, and dark adaptometry. Detailed colour vision assessment was performed in six subjects. Blood samples were taken from four patients for DNA extraction and mutation screening of NR2E3 was undertaken. RESULTS: The onset of symptoms was in the first and second decades of life. Subjects presented with reduced central vision and marked photophobia. All individuals were myopic and colour vision testing revealed severely reduced colour discrimination predominantly along the red-green axes; tritan colour vision was relatively well preserved. Nyctalopia is a later feature of the disorder. Funduscopy and AF imaging revealed a range of macular appearances. There was electrophysiological evidence of marked macular dysfunction, reduced and delayed cone responses, and supernormal and delayed rod responses. Photopic and dark adapted perimetry revealed central scotomata with widespread peripheral sensitivity loss. No disease causing sequence variants in NR2E3 were identified. CONCLUSIONS: The largest case series to date has been described of the clinical, psychophysical and electrophysiological characteristics of this unusual cone dystrophy with supernormal rod responses. Electrophysiological data were consistent with a post-phototransduction, but pre-inner nuclear layer, site of dysfunction. While the definitive diagnosis can only be made with electrophysiological testing, several characteristics that may increase suspicion of this diagnosis are presented.     

Color vision in the dog

The color vision of three domestic dogs was examined in a series of behavioral discrimination experiments. Measurements of increment-threshold spectral sensitivity functions and direct tests of color matching indicate that the dog retina contains two classes of cone photopigment. These two pigments are computed to have spectral peaks of about 429 nm and 555 nm. The results of the color vision tests are all consistent with the conclusion that dogs have dichromatic color vision.     

Color vision

Many visual disorders produce acquired color vision defects. Color vision theory emphasizes several stages of visual processing: prereceptoral filters (lens, macular pigment, pupil), cone photopigments (L-, M-, and S-cones), and postreceptoral processes (red-green, S-cone, and luminance channels). Congenital color defects, which affect 8% to 10% of males and 0.4% to 0.5% of females, result from alterations in the photopigment absorption spectra or the absence of one or more photopigments. The most common defects are color vision deficiencies (protan and deutan defects), which are milder than the rarer achromatopsias (complete loss of color vision). Acquired color vision defects can be attributed to a number of different causes: alteration of prereceptoral filters, reduced cone photopigment optical density, greater loss of one cone type than the others, and disruption of postreceptoral processes. Acquired color vision defects have been divided into three classes: type 1, red-green defect with scotopization; type 2, red-green defect without scotopization; and type 3, blue defects (with or without pseudoprotanomaly). Blue defects are usually type 3 acquired defects because congenital tritan defects have an incidence of one in several tens of thousands. Red-green defects can be acquired or congenital, and ruling out acquired defects can require a battery of tests (plates and arrangement tests, anomaloscopy, perhaps genetic analysis). Color vision tests must be administered carefully (with a standard illuminant and protocol), and pupillary miosis or high lens density should be noted and their possible effects considered when interpreting test results. Plate tests provide a simple screening method but do not provide a diagnosis. Arrangement tests and anomaloscope testing take more time and make greater demands on the tester, but they provide a more thorough evaluation. When standard protocols are followed and results are interpreted in terms of prereceptoral filters, photopigment optical density, cone loss, and disruption of postreceptoral processes, a battery of color vision tests can be useful in the differential diagnosis, after progression of the disease, and for evaluating the effectiveness of treatment.     

A novel cone visual cycle in the cone-dominated retina

The visual processing of humans is primarily reliant upon the sensitivity of cone photoreceptors to light during daylight conditions. This underscores the importance of understanding how cone photoreceptors maintain the ability to detect light. The vertebrate retina consists of a combination of both rod and cone photoreceptors. Subsequent to light exposure, both rod and cone photoreceptors are dependent upon the recycling of vitamin A to regenerate photopigments, the proteins responsible for detecting light. Metabolic processing of vitamin A in support of rod photopigment renewal, the so-called "rod visual cycle", is well established. However, the metabolic processing of vitamin A in support of cone photopigment renewal remains a challenge for characterization in the recently discovered "cone visual cycle". In this review we summarize the research that has defined the rod visual cycle and our current concept of the novel cone visual cycle. Here, we highlight the research that supports the existence of a functional cone-specific visual cycle: the identification of novel enzymatic activities that contribute to retinoid recycling, the observation of vitamin A recycling in cone-dominated retinas, and the localization of some of these activities to the Müller cell. In the opinions of the authors, additional research on the possible interactions between these two visual cycles in the duplex retina is needed to understand visual detection in the human retina.     

Influence of cone pigment coexpression on spectral sensitivity and color vision in the mouse

The mouse retina contains both middle-wavelength-sensitive (M) and ultraviolet-sensitive (UV) photopigments that are coexpressed in cones. To examine some potential visual consequences of cone pigment coexpression, spectral sensitivity functions were measured in mice (Mus musculus) using both the flicker electroretinogram (ERG) and behavioral discrimination tests. Discrimination tests were also employed to search for the presence of color vision in the mouse. Spectral sensitivity functions for the mouse obtained from ERG measurements and from psychophysical tests each reveal contributions from two classes of cone having peak sensitivities (lambda(max)) of approximately 360 and 509-512 nm. The relative contributions of the two pigment types to spectral sensitivity differ significantly in the two types of measurements with a relationship reversed from that often seen in mammals. Mice were capable of discriminating between some pairs of spectral stimuli under test conditions where luminance-related cues were irrelevant. Since mice can make dichromatic color discriminations, their visual systems must be able to exploit differences in the spectral absorption properties among the cones. Complete selective segregation of opsins into individual photoreceptors is apparently not a prerequisite for color vision.     

Why do mice have ultra-violet vision?

Murine vision has become a fascinating entity due to discoveries about the histology and physiology of its retina over the past decade. It has two varieties of cones, one serving the traditional green-yellow region of the vision spectrum and another serving the ultra-violet region, essentially invisible to man and many other mammal. This puts unusual constraints on the optical transmission of the murine eye, in particular its relatively large lens. Its ultra-violet vision appears to involve its upper much more than its lower visual field, providing a heuristic clue to its purpose. In addition behavioural evidence exists for colour vision in mice. On the other hand there is unequivocal evidence that many murine cones contain both cone photopigments, an unrealistic but not impossible arrangement for colour vision. A better understanding of how ultra-violet vision is interwoven into cone and rod vision and possible colour vision can be clarified by analysing the responses of single retinal neurons. This paper reviews the current information on this topic and provides new insights from single retinal ganglion cell recordings.     

Spectral sensitivity of monocularly deprived cats.

The reports of rod-dominated psychophysical spectral sensitivity from the deprived eye of monocularly lid-sutured (MD) monkeys are intriguing but difficult to reconcile with the absence of any reported deprivation effects in retina. As most studies of MD retina have been from cat, we have examined psychophysically the increment threshold spectral sensitivity of MD cats using both reaction time and simultaneous two-choice behavioral procedures. Although the deprived eyes exhibited an absolute increment threshold sensitivity deficit, both rod and cone spectral sensitivity functions were obtained on large white backgrounds. This normal transition from rod to cone vision, as background luminance increased, was also found in threshold vs. intensity functions. Using their deprived eye, some cats exhibited a rod spectral sensitivity function when a smaller, normally photopic, background was used providing some support for a hypothesis that the rod-dominated spectral sensitivity observed in monkey may represent detection of scattered stimulus light. Alternatively monocular deprivation may reveal a rod-dominated mechanism which exists in monkey but not in cat.     

Macular pigment, photopigments, and melanin: distributions in young subjects determined by four-wavelength reflectometry

We have developed an objective procedure, using a modified retinal camera, to determine macular pigment (MP) optical density distributions in the human retina. Using two multi-band filters, reflectance maps of the retinas of young subjects (<25 years old) were obtained at 460, 528, 610 and 670 nm, without pupil dilation. The log-transformed maps were combined linearly to yield optical density maps of MP, cone and rod photopigments, and melanin. MP optical density and heterochromatic flicker photometry results for 22 subjects were in reasonable agreement. Cone photopigments, like MP, showed similar, well-defined peaks at the fovea, whereas rod photopigment showed a minimum. Melanin was more broadly distributed.     

A study of unusual Rayleigh matches in deutan deficiency

Rayleigh match data were modeled with the aim of explaining the locations of match midpoints and matching ranges, both in normal trichromats and in subjects with congenital color deficiency. Model parameters included the wavelength of peak sensitivity of cone photopigments, the effective photopigment optical density, and the noise amplitude in the red-green color channel. In order to avoid the suprathreshold, perceptual effects of extreme L:M cone ratios on color vision, selective post-receptoral amplification of cone signals is needed. The associated noise is also amplified and this causes corresponding changes in red-green threshold sensitivity. We propose that the noise amplitude and hence the size of the matching range in normal trichromats relates to the known inter-subject variation in the relative numbers of L and M cones. If this hypothesis can be shown to account for the extremes of the red-green matching range measured in normal trichromats, it is of interest to establish the extent to which it also predicts the unexpected, small matching ranges that are observed in some subjects with red-green color deficiency. A subset of subjects with deutan deficiency that exhibited less common Nagel matches were selected for genetic analysis of their cone pigment genes in order to confirm the type of deficiency, and to predict the corresponding peak wavelength separation (delta lambda(max)) of their two, long-wavelength cone pigments. The Rayleigh match model predicted accurately the midpoint and the range for the spectral differences specified by the genes. The prediction also required plausible selection of effective optical density of the cone pigments and noise. The noise needed varied, but the estimates were confined to lie within the limits established from the matching ranges measured in normal trichromats. The model predicts correctly the small matching ranges measured in some deuteranomalous subjects, principally accounted for by a low estimate of noise level in the red-green channel. The model also predicts the "normal" matches made by some subjects that rely on two hybrid genes and therefore exhibit red-green thresholds outside the normal range, typical of mild deuteranomaly.     

Basic phenomena in acquired colour vision deficiency

Acquired colour vision defects are directly related to the fixation mode: blue-yellow defects in foveolar fixation, blue-yellow or red-green defects in eccentric fixation. The primary localization of a disease can be retraced from the degree of cone damage. Optic nerve diseases essentially lack signs of cone damage. Processes at the level of the choriocapillaris/retinal pigment epithelium induce a non-selective receptor impairment. There are minor signs of cone damage. In cone dystrophies there is selective cone damage. Scotopization indicates a relatively well-preserved rod function.     

The characteristics of a visual defect associated with abnormal responses to both colour and luminance

This paper deals with the visual response characteristics of a single male subject. Although members of his maternal family were found to be red-green defective, the subject's responses are not consistent with those of the recognized classes of colour vision defect. Thus his foveal colour matching is dichromatic: his foveal threshold spectral sensitivity is between 2.5 and 5.0 log units less than that of normal observers and his critical fusion frequency saturates at 15–18 Hz. Increment threshold measurements reveal the activity of only two spectral mechanisms and for long wavelength stimuli, the increment threshold level falls sharply as the illumination level of a superimposed background field is increased beyond a critical level. This last observation correlates with the observer's subjective report that objects which appear red to normal observers appear to him as “grey” or “black”, with no well-defined form. Experiments with stimuli located up to 11° off-axis on the temporal retina showed that the subject's visual responses are essentially invariant with respect to the stimulus location and that characteristic rod responses are entirely absent. We have proposed a functional model for the interpretation of the experimental data in which deuteranomalous colour vision is combined with malfunction of some of the central visual mechanisms.     

Signals from blue cones in "red-green" opponent-colour ganglion cells of the macaque retina.

Many opponent-colour ganglion cells of the macaque retina overt input from green and red-sensitive cones but often appear to lack input from blue-sensitive cones under usual test conditions. Comparisons of field and test action spectra of the responses of a selected group of such “red-green” ganglion cells, located in the perifovea and lacking rod input, indicate the presence of blue-sensitive cone signals having a suppressive influence upon the more direct and opponent signals from green- and red-sensitive cones to a fraction of these neurones, which seems to take place at a level distal to that of the ganglion cell. No cell excitation of inhibition mediated by blue-sensitive cone signals could be observed on intense yellow-adapting lights desensitizing the other two cone types. These neurones are characterized by a sharp fall-off in their short-wavelength test sensitivity and by a secondary shoulder in their short-wavelength field sensitivity. In addition, when cell responses overtly mediated by input from green-sensitive cones are depressed by the geometry of the stimuli, the suppressive signals from blue-sensitive cones also result in a large displacement towards the short wavelengths of the test peak sensitivity of such responses. This displacement can be described with acceptable accuracy by a two-stage model based on subtractive interactions between A₁-photopigments with λ_max at 445, 535 and 570 nm, which is qualitatively consistent with other spectral properties of these ganglion cells.     

Induced color blindness in goldfish: a behavioral and electrophysiological study.

To answer the question whether, like man, ethambutol treated fish would become color-blind, wavelength discrimination was measured behaviorally in goldfish, preceding, during and after ethambutol treatment. The results are that of the three high discrimination abilities at around 400, 500 and 600 nm, ethambutol affected the latter one. Red-green discrimination is lost reversibly leaving the discriminations in the blue-green and violet range unaffected. This red-green discrimination deficiency cannot be accounted for by a loss of long wavelength cones since the ERG and luminosity functions remain unaffected. Intracellular horizontal cell recordings in goldfish show that ethambutol hyperpolarizes all three types of cone driven horizontal cells and changes their color coding such that their spectral characteristics become cone-like as is the case in dark adapted retina. So, the initial effect induced by ethambutol seems to be an adaptation deficiency in color vision related tasks. Human wavelength discrimination and increment threshold spectral sensitivity functions obtained at low luminance levels are compared to behavioral functions in ethambutol treated goldfish. The high similarity between the ethambutol effects in man and goldfish, and the effects observed in the horizontal cell responses in goldfish are highly indicative that horizontal cells play a key role in color vision. So far their function has been puzzling.     

Colour vision anomalies following experimental glaucoma in monkeys

Spectral sensitivity defects, associated with chronic elevated intraocular pressure (IOP) produced by Argon laser trabeculoplasty, were studied in monkeys. Increment-threshold spectral sensitivity (ITSS) and threshold versus intensity (TVI) functions were measured using a behavioural model. Elevated IOP resulted in slum wavelength (SW) sensitivity losses characteristic of many ocular diseases. The amount of SW sensitivity loss for ITSS functions depended upon the intensity level and chromatic composition of the background field. The optimum condition identifying the greatest SW sensitivity reduction was a yellow background of moderate intensity (100–100 Td). In the early stages of experimental glaucoma. The cone mechanisms and the rod mechanism typically showed decreased test and field sensitivities. The SW cone pathway has slightly greater threshold elevation (∼0.3 log unit) compared to the rod and cone pathways. On the other hand, in the advanced stages of experimental glaucoma, the largest sensitivity losses were in the longer-wavelength, red-green opponent mechanism, with the rod and SW cone pathways showing smaller losses. The similarities of the colour vision anomalies in this animal model with those of patients with glaucoma, provides support for its use as an experimental model for human glaucoma.     

Effects of prolonged dark adaptation in patients with retinitis pigmentosa of Bothnia type: an electrophysiological study

Bothnia dystrophy (BD) is a variant of recessive retinitis punctata albescens (RPA), caused by the missense mutation R233W in cellular retinaldehyde-binding protein (CRALBP), which is localized in the retinal pigment epithelium (RPE) and Müller cells of the retina. The purpose of this study was, by examining the electrophysiological responses of the retina, to evaluate the capacity of recovery of the whole retinal area and different cell types induced by extremely prolonged dark adaptation (DA) in BD disease and to gain further understanding of the pathogenesis of BD. Six young patients underwent bilateral full-field ERGs after 24 h of DA in one eye and standard DA in the fellow eye. The results were also compared with the effect of prolonged DA (10 h), previously studied in the same patients. After extremely prolonged DA (24 h) the rod b-wave and the mixed rod-cone a-wave responses reached normal though delayed amplitudes. An increase, up to normal level, in the oscillatory response was found. There was no obvious recovery of the cone response. We conclude that in young BD patients during extremely prolonged DA there is a significant additional capacity of recovery of rod function and also significant gain of activity in the inner retinal layer. A continuous but slow regeneration of rod photopigment seems to occur at least up to 24 h. The visual process in the RPE is retarded and CRALBP acts in this process; also, the Müller cells of the retina seem to be involved. The findings also support an extremely slow synthesis of photopigments and irreversibly disturbed cone function early in BD.     

Photopigment basis for dichromatic color vision in the horse

Horses, like other ungulates, are active in the day, at dusk, dawn, and night; and, they have eyes designed to have both high sensitivity for vision in dim light and good visual acuity under higher light levels (Walls, 1942). Typically, daytime activity is associated with the presence of multiple cone classes and color-vision capacity (Jacobs, 1993). Previous studies in other ungulates, such as pigs, goats, cows, sheep and deer, have shown that they have two spectrally different cone types, and hence, at least the photopigment basis for dichromatic color vision (Neitz & Jacobs, 1989; Jacobs, Deegan II, Neitz, Murphy, Miller, & Marchinton, 1994; Jacobs, Deegan II, & Neitz, 1998). Here, electroretinogram flicker photometry was used to measure the spectral sensitivities of the cones in the domestic horse (Equus caballus). Two distinct spectral mechanisms were identified and are consistent with the presence of a short-wavelength-sensitive (S) and a middle-to-long-wavelength-sensitive (M/L) cone. The spectral sensitivity of the S cone was estimated to have a peak of 428 nm, while the M/L cone had a peak of 539 nm. These two cone types would provide the basis for dichromatic color vision consistent with recent results from behavioral testing of horses (Macuda & Timney, 1999; Macuda & Timney, 2000; Timney & Macuda, 2001). The spectral peak of the M/L cone photopigment measured here, in vivo, is similar to that obtained when the gene was sequenced, cloned, and expressed in vitro (Yokoyama & Radlwimmer, 1999). Of the ungulates that have been studied to date, all have the photopigment basis for dichromatic color vision; however, they differ considerably from one another in the spectral tuning of their cone pigments. These differences may represent adaptations to the different visual requirements of different species.     

Scanning laser densitometry and color perimetry demonstrate reduced photopigment density and sensitivity in two patients with retinal degeneration

PURPOSE: To test the feasibility of scanning laser densitometry with a modified Rodenstock scanning laser ophthalmoscope (SLO) to measure the rod and cone photopigment distribution in patients with retinal diseases. METHODS: Scanning laser densitometry was performed using a modified Rodenstock scanning laser ophthalmoscope. The distribution of the photopigments was calculated from dark adapted and bleached images taken with the 514 nm laser of the SLO. This wavelength is absorbed by rod and cone photopigments. Discrimination is possible due to their different spatial distribution. Additionally, to measure retinal sensitivity profiles, dark adapted two color static perimetry with a Tübinger manual perimeter was performed along the horizontal meridian with 1 degree spacing. RESULTS: A patient with retinitis pigmentosa had slightly reduced photopigment density within the central +/- 5 degrees but no detectable photopigment for eccentricities beyond 5 degrees. A patient with cone dystrophy had nearly normal pigment density beyond +/- 5 degrees, but considerably reduced photopigment density within the central +/- 5 degrees. Within the central +/- 5 degrees, the patient with retinitis pigmentosa had normal sensitivity for the red stimulus and reduced sensitivity for the green stimulus. There was no measurable function beyond 7 degrees. The patient with cone dystrophy had normal sensitivity for the green stimulus outside the foveal center and reduced sensitivity for the red stimulus at the foveal center. The results of color perimetry for this patient with a central scotoma were probably influenced by eccentric fixation. CONCLUSION: Scanning laser densitometry with a modified Rodenstock SLO is a useful method to assess the human photopigment distribution. Densitometry results were confirmed by dark adapted two color static perimetry. Photopigment distribution and retinal sensitivity profiles can be measured with high spatial resolution. This may help to measure exactly the temporal development of retinal diseases and to test the success of different therapeutic treatments. Both methods have limitations at the present state of development. However, some of these limitations can be overcome by further improving the instruments.     

Limits of colour vision in dim light

Humans and most vertebrates have duplex retinae with multiple cone types for colour vision in bright light, and one single rod type for achromatic vision in dim light. Instead of comparing signals from multiple spectral types of photoreceptors, such species use one highly sensitive receptor type thus improving the signal‐to‐noise ratio at night. However, the nocturnal hawkmoth Deilephila elpenor, the nocturnal bee Xylocopa tranquebarica and the nocturnal gecko Tarentola chazaliae can discriminate colours at extremely dim light intensities. To be able to do so, they sacrifice spatial and temporal resolution in favour of colour vision. We review what is known about colour vision in dim light, and compare colour vision thresholds with the optical sensitivity of the photoreceptors in selected animal species with lens and compound eyes.     

The neural retina in retinopathy of prematurity

Retinopathy of prematurity (ROP) is a neurovascular disease that affects prematurely born infants and is known to have significant long term effects on vision. We conducted the studies described herein not only to learn more about vision but also about the pathogenesis of ROP. The coincidence of ROP onset and rapid developmental elongation of the rod photoreceptor outer segments motivated us to consider the role of the rods in this disease. We used noninvasive electroretinographic (ERG), psychophysical, and retinal imaging procedures to study the function and structure of the neurosensory retina. Rod photoreceptor and post-receptor responses are significantly altered years after the preterm days during which ROP is an active disease. The alterations include persistent rod dysfunction, and evidence of compensatory remodeling of the post-receptor retina is found in ERG responses to full-field stimuli and in psychophysical thresholds that probe small retinal regions. In the central retina, both Mild and Severe ROP delay maturation of parafoveal scotopic thresholds and are associated with attenuation of cone mediated multifocal ERG responses, significant thickening of post-receptor retinal laminae, and dysmorphic cone photoreceptors. These results have implications for vision and control of eye growth and refractive development and suggest future research directions. These results also lead to a proposal for noninvasive management using light that may add to the currently invasive therapeutic armamentarium against ROP.