Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

Glossary

Blue–yellow (tritan) defect – A color-vision deficiency in which colors along the blue–yellow axis are difficult to distinguish from one another and sensitivity to blue light is decreased. This is typically caused by a defect in the short-wavelength-sensitive cone photoreceptor pathway. The word tritanopia derives from the Greek tritos, meaning third, alluding to the defect being associated with the third of the three primary colors (blue) + anopia, meaning blindness.

Deuteranopia – A type of red–green defect in which the middle-wavelength-sensitive photopigment is nonfunctional, leading to decreased hue discrimination and a tendency to confuse reds and greens. Derives from the Greek deuteros, meaning second, alluding to the defect being associated with the second of the three primary colors (green) and anopia, meaning blindness.

Monochromacy – A complete lack of ability to distinguish colors.

Photopigment – A light-sensitive protein in the photoreceptors (rods and cones) that undergoes a conformational change when absorbing light and initiates the process of visual transduction. Protanopia – A type of red–green defect in which the long-wavelength-sensitive photopigment is nonfunctional, leading to a loss of sensitivity to red light and a tendency to confuse reds and greens. Derives from the Greek protos, meaning first, alluding to the defect being associated with the first of the three primary colors (red) and anopia, meaning blindness.

Trichromacy – The fundamental ability to see in full color, based on the possession of three types of cone photoreceptor. The formal proposal of this theory to explain human color vision is credited to Thomas Young.

Introduction

‘‘He knew the colors of everything, with an extraordinary exactness (he could give not only the names but the numbers of colors as these were listed in a Pantone

chart of hues he had used for many years). He could identify the green of Van Gogh’s billiard table in this way unhesitatingly. He knew all the colors in his favorite paintings, but could no longer see them, either when he looked or in his mind’s eye. Perhaps he knew them, now, only by verbal memory.’’ Oliver W. Sacks describes the ‘Case of the colorblind painter’ in his book An Anthropologist on Mars where after a car accident a painter tragically lost all ability to experience color.

While many color-vision deficiencies are inherited and present from birth (congenital), they may also be acquired, as in the case of the colorblind painter described above. Acquired defects, as the name implies, indicate a disruption in color discrimination as a consequence of a traumatic event, such as exposure to toxins, a cortical injury, or the defect may accompany an ocular disease. In most cases, the color-vision defect can be thought of as secondary because the causative event often has more serious consequences for the individual.

Classifying Acquired Color Blindness

Normal color vision relies on the presence of three spectrally distinct cone photoreceptor types in the retina, where the spectral sensitivity of the cone cell is determined by the photopigment it contains (short-, middle-, or longwavelength sensitive; S, M, or L, respectively). Inherited disruptions in color discrimination are normally classified according to which of the cone photopigment classes is functionally disrupted or absent altogether. A defect in the S photopigment produces a tritan defect, corresponding to a loss along the blue–yellow axis, whereas defects in the M and L pigments produce a deutan or protan defect, respectively, though both correspond to a loss along the red–green axis of color vision. Consequently, in inherited defects there is a 1:1 relationship between the affected cone type and the perceptual deficit. However, acquired defects are far more complex and thus must be categorized not by the type of photoreceptor affected, but rather as a variable loss along a particular color axis: blue–yellow axis, red–green axis, or a nonspecific loss of color vision. The dimensionality of these losses can be appreciated by looking at Figure 1 which illustrates the red–green and blue–yellow axes of color vision.

In addition to classifying the perceptual problems associated with acquired defects, they can be categorized based on the mechanism of the defect: absorption, alteration, and reduction. Absorption defects affect the absorption of a

Trichromacy

Green

Red

Blue

Black

particular hue due to deposits affecting the lens or cornea. For example, the normal aging process introduces a yellowing of the lens of the eye, causing a selective absorption defect in discrimination in the blue–yellow axis of color vision. An alteration defect is one that shifts normal color perception and normally reflects a destruction of the macular cones. A reduction defect occurs typically as a result of diseases of the optic nerve and causes perceptive reduction of saturation within colors along the red–green axis as well as a more mild blue–yellow reduction.

Discriminating Acquired from Inherited Color Blindness

There are a number of key differences between inherited and acquired defects. Acquired defects are often difficult to classify because combined, and sometimes subtle, defects often occur. While congenital color-vision deficiencies are typically stable throughout life and both eyes are equally affected, acquired deficits may change in severity over time, and they are more likely to be asymmetric. Furthermore, acquired defects are predominantly tritan, have an equal incidence in males and females, and are typically accompanied by a reduction in visual acuity. Erroneously, color-vision defects are often thought of as being exclusively inherited. However, acquired defects are even more common, with 5% of the population being

Table 1 General differences between acquired and inherited color-vision defects

affected. Table 1 provides a complete comparison of acquired and inherited defects.

Clinically, there are a number of tests used to diagnose color-vision defects (acquired or inherited). While genetic tests are obviously the definitive approach for characterizing inherited disorders, the diagnosis of acquired color-vision defects relies on the patients’ performance on psychophysical tests of color vision. Perhaps the most

widely used are pseudoisochromatic plate tests. These plates contain a field of dots that vary in luminance, and embedded within the dots is a number or other shapes differing in chromaticity from the background. For normal trichromats, this shape will be distinguishable from the background. However, depending on the design of the plate, the shape may blend into the background or a different shape may appear altogether for the colordeficient observer. Different plates are used to test for defects along the primary color axes (red–green and blue–yellow). Another type of test is an arrangement test in which the patient orders materials in a specific hue or saturation order. The stimulus is prearranged in a random order and subjects are instructed to arrange the stimuli according to color. Correct arrangement of the various color samples requires not only normal color vision, but also good discriminative ability. Finally, the gold standard in assessing color vision is color matching. By asking the patient to match either a monochromatic yellow test light to a mixture of red and green primaries (Rayleigh match) or a cyan/yellow test mixture to a blue/green primary mixture (Moreland match), one can detect even the most mild red/green or blue/yellow defect, respectively.

Conditions Resulting in an Acquired

Color-Vision Defect

Ocular Diseases

The most common acquired color-vision deficiencies arise from various diseases which can impact the eye in a number of ways. Such diseases include progressive cone dystrophies, retinal pigment epithelium (RPE) dystrophies, ocular media opacities, and impairments that affect the retinal neurons (ganglion cells). As a group, these deficiencies can be characterized by an abnormal cone electroretinogram (ERG), reduced visual acuity, central visual-field loss, and/or light sensitivity (photophobia). The age of onset, severity of color-vision defect, and rate of progression can vary widely among different diseases. A few of the most common diseases are discussed below. As an aside, the color-vision defect is often the least of these patients’ worries; nonetheless, it is affiliated with the disease (which itself may be an inherited condition) and can sometimes contribute to the diagnosis.

Age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. As such, it also represents the most prevalent form of acquired colorvision deficiency. Although this disease has two forms (wet and dry), both involve a degeneration of the photoreceptors in the central retina (macula). It is in this area where acuity and color vision are at their best, so it comes as no surprise that individuals with AMD suffer deficits in

both. In the slower-progressing dry form of AMD, yellow deposits called drusen develop underneath the macula. As these drusen negatively affect the health of the RPE, which is required for normal function of the photoreceptors, a loss of vision slowly results. In the fast-progressing wet AMD, tiny blood vessels begin to grow behind the retina toward the macula. Bleeding, leaking, and scarring occur from these fragile blood vessels, eventually causing irreversible damage to the retina and rapid vision loss. Color vision becomes progressively distorted as the disease progresses and more photoreceptors are functionally compromised, but this does not usually contribute to the differential diagnosis.

Glaucoma

The term glaucoma represents a group of diseases of the optic nerve characterized by a loss of retinal ganglion cells with a corresponding loss of some or most of the fibers of the optic nerve. In this disease, constriction of the visual field occurs slowly over time, and may not be recognized until the impairment is quite severe, with as many as 60% of the retinal ganglion cells degenerating before a perceptual consequence is detected. Worldwide, glaucoma is the second leading cause of blindness, and interestingly the deterioration in color vision of these patients has been proposed as a predictor of significant visual-field loss. Field loss arises from diffuse changes in the neural retina, supporting the idea that acquired color deficiency in glaucoma is caused by damage to the neural pathway rather than the retinal photoreceptors. Despite these patients having a normal S-cone ERG, acquired tritanopia (with severity paralleling the visual-field loss) is often found. This tritan deficiency is consistent with other optic nerve diseases, which suggests that the S-cones themselves remain intact, but that postreceptoral mechanisms involved in the transmission of blue–yellow color discrimination must be selectively disrupted.

Retinitis pigmentosa

Retinitis pigmentosa (RP) is a hereditary retinal dystrophy in which abnormalities of the rods, or the RPE of the retina, lead to progressive visual loss. Affected individuals first experience night blindness and defective dark adaptation, followed by reduction in peripheral vision (tunnel vision), and often a loss of central vision late in the course of the disease. There is good evidence that the progressive degeneration of the rods leads to the secondary loss of cones, likely as a result of reduced rod-derived cone viability factors. Disruptions in color discrimination can occur as the cones degenerate, and these individuals can exhibit a severe tritan defect or occasionally pseudoprotanomaly (a mild red–green defect). Most RP sufferers eventually go blind, therefore again the color-vision defect is of relatively minor importance to the individual.

Cataract

An age-related cataract is an impairment of the crystalline lens of the eye in which the lens hardens, becomes opaque, and yellows. A normal lens selectively absorbs short-wavelength light, however, both normal aging and the development of cataracts enhance this effect and causes problems discriminating in the blue–green portion of the spectrum. This condition is known as xanthopsia and refers to an abundance of yellow which dominates the visual scene. Patients who have cataract surgery in which their natural lens is removed and replaced with a clear plastic lens often experience cyanopsia – or a bluedominated visual scene. This cyanopsia results because the brain compensates the perceptual yellow tint caused by the cataract by adding a blue tint to the visual scene, and when the yellow lens is removed it takes the brain time to renormalize to the new chromatic input. The mild-blue perception after cataract removal may persist for weeks or even months but normal color vision gradually returns, highlighting the significant chromatic plasticity of the adult visual system.

Diabetic retinopathy

Diabetic retinopathy is an ocular manifestation of the systemic disease, diabetes, occurring when the disease is left untreated. Elevated blood sugar levels present in diabetics can induce changes in the retinal blood vessels severe enough to impact patients’ vision. The swelling and growth of new vessels in the eye can cause these vessels to bleed, cloud vision, and destroy the retina by failing to supply adequate oxygen and meet the metabolic needs of the photoreceptors. Visual disturbances begin with a blur, but the pattern of vision loss in these patients is often diffuse, irregular, and achromatic, reducing visual perception to shades of gray interrupted by large blank patches.

Optic neuritis

Optic neuritis is an inflammation of the optic nerve which can cause partial or complete vision loss. These patients report sensitivity to light (photophobia), pain with eye movements, and a degradation of color vision. Direct axonal damage may also play a role in nerve destruction in many cases. The loss of color vision starts as an abnormal dimming, and apparent increased noise in the visual images, which then progresses to a general dimming or loss of color discrimination and blurring across the entire visual field. In many cases, only one eye is affected and patients are not aware of the loss of color vision until the doctor asks them to close or cover the healthy eye. Typically, these defects are similar to a deutan defect (a form of red–green defect), but with additional reduction in sensitivity to the shorter wavelengths. Nearly half of all patients with multiple sclerosis (MS) will develop an

episode of optic neuritis, and up to one-third of the time optic neuritis is the presenting sign of MS. This stems from inflammation of the optic nerve, as a result of the degeneration of the myelin sheath surrounding it. MS patients may suffer periodic attacks of optic neuritis, which increase in severity, leading to a permanent loss of color vision.

Cortical Defects

Another way in which one can acquire a color-vision deficiency is through a cortical insult. Cortical defects result from a head injury, stroke, or neurodegenerative disease. Unlike other forms of acquired color-vision deficiencies, those arising from cortical defects are often unilateral, impacting one-half of the brain, and in turn only one part of the visual field, although full-field defects can occur. Injuries impacting color vision typically result from damage to either V2 (prestriate cortex), or V4 – the areas of the brain responsible for processing color information; however, uncertainty remains about precisely which cortical loci (if any) are responsible. As cortical damage is rarely localized to a small section of the brain, there are often other behavioral deficits resulting from the injury, making it difficult to interpret individual cases and generalize about an individual’s symptoms.

Cerebral achromatopsia

One famous case of cerebral achromatopsia is that of the colorblind painter discussed in the introduction of this article. It is presumed that the painter’s acquired monochromacy was due to cortical injury caused either by damage to the visual cerebral cortex during an automobile accident, or by a stroke affecting one of the visual areas. As V2 and V4 are among the most metabolically active areas of the cerebral cortex, they are among the first to suffer from the effects of reduced oxygen delivery, and may therefore be affected in the case of a stroke. In this case, color disturbances occur very rapidly and may precede other symptoms. The resulting loss of color vision may occur as a total loss (complete achromatopsia), or as a partial loss affecting only one-half of the visual field (hemiachromatopsia). Unlike degenerative disorders with the same perceptual appearance, in central achromatopsia, the retina is not damaged so acuity typically remains unchanged. This finding illustrates how different cortical areas can serve discrete aspects of vision.

Neurodegenerative diseases

Parkinson’s disease (PD) is a disease that impairs cognitive, motor, and sensory function through the progressive loss of dopaminergic neurons, and a few studies have reported abnormal color vision in these patients. Dopamine

deficiency is believed to alter retinal visual processing primarily by changing the receptive field properties of ganglion cells. The S-cone photoreceptors are sparse in the retina and are believed to have elevated susceptibility to retinal damage caused by progressive loss of the dopaminergic cells in the retina. This is certainly the case in retinal detachments where S-cone defects predominate. Consequently, those who have cited color-discrimination problems in patients with PD identified a tritan axis of confusion. There is debate on this, however, because most standard methods of testing color vision require the patient to make motor movements, which can provide an additional disadvantage and confounding variable for PD patients.

Another neurodegenerative disease, Alzheimer’s disease, also has implications for color vision. The cortical atrophy which causes the hallmark dementia associated with this disease causes not only degeneration of the visual areas of the brain (gray matter), but may also induce optic nerve degeneration. As the disease progresses, patients’ vision tends to decline from a mild tritan colorvision deficiency into complete achromatopsia.

Toxin-Induced Defects

In addition to the internal defects that cause color-vision abnormalities, there are numerous environmental factors that can alter color perception. Multiple therapeutic drugs have been reported to produce color-vision deficiencies in patients. While most of these occurrences have been documented as a result of toxic levels of the prescribed drugs, some can occur even at recommended dosages, though most side effects are transient. Many studies have found altered color perception in workers occupationally exposed to chemicals as well. A possible mechanism for these toxininduced defects may be related to the direct effect of the chemicals on cone function, and/or an interference with neurotransmitter signaling.

Digitalis

The digitalis family of drugs (digoxin and digitoxin) is typically prescribed to control congestive heart failure as well as certain cardiac arrhythmias. Several retinal cells (i.e., photoreceptors, Mu¨ller’s cells, and retinal pigment epithelial cells) express digitalis-sensitive isoforms of sodium–potassium adenosine triphosphate (ATP)ase, and inhibition of these pumps by digitalis is associated with alterations in electrical-response properties of the retina. Clinical ERG and in vitro cell studies have shown that toxic levels of digoxin lead to rod and cone dysfunction, with cones being affected to a greater extent. Patients experiencing disturbances of color vision while taking these drugs usually exhibit a red–green defect in which objects are covered with a reddish haze and sometimes exhibit symptoms similar to optic neuritis. Fortunately, color vision tends to recover after the drug is withdrawn. It has been

speculated that the prevalent use of yellow in Vincent Van Gogh’s work may be due to the use of digitalis, used at the time for its euphoric effects and as a treatment for epilepsy.

PDE5 inhibitors

Phosphodiesterase (PDE) inhibitors, including Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil), are used to treat erectile dysfunction by selectively inhibiting cyclic guanosine monophosphate (cGMP)- phosphodiesterase type 5 (PDE5), present in all vascular tissue, which leads to vasodilation. It also exerts an inhibitory action against PDE6, the phosphodiesterase isoform present in rod and cone photoreceptors, though the inhibition efficacy is only about 1/10 of that for PDE5. PDE6 is a key player in the phototransduction cascade, catalyzing the hydrolysis of cGMP in response to absorption of light by the photopigment molecule. This results in a reduction in cGMP, which results in a closing of the cyclic-nucleotide-gated ion channels and thus a hyperpolarization of the cell. As such, PDE5 inhibitors can interfere with this process and lead to transient changes in rod and cone outer segment function, and the retinal effects may include impaired blue–green color discrimination and decreased rodand cone-driven ERG amplitudes. At high doses of PDE5 inhibitors, patients have reported a blue tinge to vision, increased apparent brightness of lights, and blurred vision, although some studies report no effects on vision. Color-vision disruptions that were experienced were transient, and no consistent pattern has emerged to suggest any long-term effect of PDE5 inhibitors on the retina or other ocular structures.

Chloroquine

This drug is used in the treatment and prevention of malaria and more recently has gained use as an immune system suppressant prescribed in autoimmune disorders such as rheumatoid arthritis and lupus erythematosus. The color-vision impairment from chloroquine is a consequence of the fact that it is a melanotropic compound with an affinity for pigmented, melanin-containing structures; this naturally results in accumulation of the drug in the highly pigmented RPE. Both the dose and duration of chloroquine treatment impact the level of toxicity because the compound remains in the retina for several years, even after treatment has been discontinued. A tritan defect is most common, but as toxicity increases, a protanlike red–green defect can also manifest. Unfortunately, this is one of the few cases in which withdrawal of the drug is typically insufficient to prevent further damage.

Ethambutol

Ethambutol is a drug prescribed in combination as a treatment for tuberculosis. It has been found to induce a secondary color-discrimination disturbance which shifts the threshold for wavelength discrimination without a change

in absolute sensitivity, resulting in color-discrimination errors along the red–green axis. There is evidence that it may disrupt the morphology of the cone pedicle – disturbing the transmission of signals from the cone photoreceptors to their postreceptoral contacts (horizontal and bipolar cells). This disturbance is most profound for low-intensity stimuli. These effects can occur after either a lengthy therapy at a low dosage, or a short therapy at high doses. The color defect is similar to a deutan-like red–green defect, but with a reduction in sensitivity to the shorter wavelengths as well. Unlike many other acquired defects, in this case, impairments in color discrimination can be useful for detection of toxicity, thus color vision should be monitored in patients undergoing regular treatment for tuberculosis. Generally, color vision improves gradually after withdrawal of the drug; yet, in some cases color vision is permanently impaired.

Vitamin A deficiency

Common in developing countries, and associated with alcoholism and metabolic storage diseases in developed countries, vitamin A deficiency is a very preventable cause of acquired color-vision deficiency. This essential vitamin is required for regeneration of the visual pigments of both rods and cones in the retina. A deficit in vitamin A initially causes night blindness and, if left untreated, will contribute to complete blindness by making the cornea very dry and damaging the retina and cornea. In the more mild forms, tritan deficiencies occur, and transition to a general loss of hue discrimination. Approximately 400 000 children in developing countries go blind each year due to a deficiency in vitamin A. If reached before the onset of blindness, recovery can be shown following oral or injectable doses of the vitamin.

Exposure to metals and chemicals

Multiple studies have examined the color perception in groups of workers exposed to high levels of metallic mercury. Surprisingly, a dose-related loss of color vision is demonstrated even at presumed safe levels of mercury exposure. Although the mechanism of mercury’s impact on the visual system is not fully understood, it seems to be localized to the retina because traces of mercury have been reported in the optic nerve, RPE, inner plexiform layer, vessel walls, and ganglion cells. Color-vision deficiencies revolve mainly around the blue–yellow axis, but may show some nonspecific losses. As with most of the other toxins, this effect seems to be reversible if individuals are removed from toxic exposure.

An additional collection of chemicals used in plastic, rubber, and viscose rayon manufacturing plants, rotogravure printing industries, as well as dry-cleaning facilities have similarly been implicated in reversible color-vision deficiencies. These chemicals include styrene, perchloroethylene (PCE), toluene, carbon disulfide, and n-hexane.

Conclusion

The range of acquired color-vision deficiencies is broad in both type and severity; some affect ocular structure directly while others perturb the neural pathways responsible for color vision, some are preventable and/or reversible while others are merely an indicator of a more serious condition. Despite their diverse etiology and manifestation, these defects can have a significant impact on the individual, for unlike those born with a colorvision deficiency, acquired sufferers know, and in most cases can remember, what they are lacking perceptually. Returning to the case of the colorblind painter gives those of us who are color normal a small taste of the devastating psychological effect of an acquired colorvision deficiency: ‘‘The wrongness of everything was disturbing, even disgusting, and applied to every circumstance of daily life.’’

See also: Color Blindness: Inherited; The Colorful Visual World of Butterflies; Cone Photoreceptor Cells: Soma and Synapse; Phototransduction: Adaptation in Cones; Phototransduction: Inactivation in Cones; Phototransduction: Phototransduction in Cones; Polarized-Light Vision in Land and Aquatic Animals; Primary Photoreceptor Degenerations: Retinitis Pigmentosa; Primary Photoreceptor Degenerations: Terminology; Rod and Cone Photoreceptor Cells: Outer Segment Membrane Renewal; Secondary Photoreceptor Degenerations: AgeRelated Macular Degeneration.

Further Reading

Birch, J. (1993). Diagnosis of Defective Colour Vision. New York: Oxford University Press.

Cowey, A. and Heywood, C. A. (1995). There’s more to colour than meets the eye. Behavioural Brain Research 71: 89–100.

Gegenfurtner, K. R. and Sharpe, L. T. (1999). Color Vision: From Genes to Perception. New York: Cambridge University Press.

Heywood, C. A. and Kentridge, R. W. (2003). Achromatopsia, color vision, and cortex. Neurological Clinics of North America 21: 483–500.

Iregren, A., Andersson, M., and Nylen, P. (2002). Color vision and occupational chemical exposures: I. An overview of tests and effects.

NeuroToxicology 23: 719–733.

Jackson, G. R. and Owsley, C. (2003). Visual dysfunction, neurodegenerative diseases, and aging. Neurologic Clinics of North America 21: 709–728.

Lamb, T. D. and Pugh, E. N., Jr. (2006). Phototransduction, dark adaptation, and rhodopsin regeneration: The proctor lecture.

Investigative Ophthalmology and Visual Science 47(12): 5137–5152. Pokorny, J. (1979). Congenital and Acquired Color Vision Defects.

New York: Grune and Stratton.

Pokorny, J. and Smith, V. C. (1986). Eye disease and color vision defects. Vision Research 26: 1573–1584.

Sacks, O. W. (1995). An Anthropologist on Mars. New York: Random House.

Zeki, S. (1990). A century of cerebral achromatopsia. Brain 113: 1721–1777.

Glossary

Blue–yellow defect – A color-vision deficiency in which blue and yellow are difficult to distinguish from one another. In inherited defects, this is typically caused by a defect in the short-wavelength-sensitive photoreceptor.

Dichromacy – A color-vision deficiency in

which only two primaries are required to perfectly match a monochromatic light. In this deficiency, one of the three types of photopigments is functionally absent so color vision is reduced to only two dimensions.

Monochromacy – A complete lack of ability to distinguish colors caused by defects in the morphology or function of the cones. Photopigment – A light-sensitive protein in the photoreceptors (rods and cones) that undergoes a conformational change when absorbing

light and initiates the process of visual transduction.

Red–green defect – A color-vision deficiency in which red and green are difficult to

distinguish from one another. There are two inherited forms of this defect: Deutan, which is caused by a defect in the medium-wavelength-sensitive photoreceptor, and protan, which is caused by a defect in the long-wavelength-sensitive photoreceptor.

Trichromacy – The fundamental ability to see in full color, based on the ability to match a monochromatic light by using a mixture of any three primaries. This ability requires the possession of three distinct classes of photoreceptors.

Introduction

Beyond the occasional spousal argument over the color of a shirt or tie, a significant number of people are born with a defect in their ability to perceive and discriminate colors. While the existence of deficiencies in color discrimination had been appreciated for some time, it was the famous chemist John Dalton who gave the most wellknown analytical description of the condition in 1798. This was due to the fact that he himself suffered from a

color-vision defect: ‘‘Reflecting on these facts, I was led to conjecture that one of the humors of my eye must be a transparent, but colored, medium, so constituted as to absorb red and green rays principally, because I obtain no proper ideas of these in the solar spectrum; and to transmit blue and other colours more perfectly.’’ While Dalton did not accurately identify the biological basis of his color-vision deficiency, he articulately described it, and thus the term Daltonism is now synonymous with color-vision deficiencies.

Photoreceptor Basis of Human

Color Vision

Humans with normal color vision can discriminate some 2 million hues. The retinal substrate for this exquisite color vision is the cone photoreceptor mosaic. While the highly sensitive rods outnumber cones nearly 20:1 and subserve vision at low (scotopic) light levels, it is the cones that underlie the majority of our visual experience at high light levels (photopic), including high spatial acuity and color vision.

There are three subclasses of cone photoreceptor, each having a distinct spectral sensitivity (Figure 1). The spectral sensitivity of the photopigment simply reflects the probability of it absorbing a photon of light, and is determined by the particular photopigment present in the cone cell. Photopigments (and their associated cones) are classified according to the region of the visible spectrum they are most sensitive to – either short-, middleor long-wavelength sensitive (abbreviated S, M, and L). All humans with normal color vision have the same S-cone pigment, with peak absorption around 417 nm. The M-cone pigment varies slightly among individuals, with an average peak of about 530 nm. There is widespread variation in the peak sensitivity of the L-cone pigment among humans with normal color vision, though there are two main variants that peak at 555 and 559 nm, respectively. Trichromatic color vision is afforded by the presence of one cone type from each of these three spectral classes, and these cone types appear to be randomly arranged within the cone mosaic (Figure 1). While the human retina contains nearly 100 million photoreceptors, only about 5 million of them are cones, and of the cones, about 95% are of the L/M type. If the function of one or more of the cone classes is disrupted or absent, the result is a compromised ability to make chromatic discriminations, that is, a color-vision deficiency.

log relative spectral sensitivity

(a)

2.5

S Rod M L

2

1.5

1

0.5

0

Genetic Basis of Human Color Vision

All inherited color-vision defects are associated with disruptions in the expression of normal cone photopigments. Human photopigments differ only in their opsin (protein) component, though they share the same chromophore, 11-cis-retinal. At the protein level the L and M pigments are about 96% homologous, though they show only 43% identity with the S pigment, while human rhodopsin (the opsin found in rods) is about 41% homologous with any of the cone opsins. Each of the human cone opsins is encoded by a different gene. The gene encoding rhodopsin is 5.0-kb long and found on chromosome 3, while the gene encoding the S opsin is located on chromosome 7 and is 3.2-kb long. The rhodopsin and S-opsin genes each have four introns and five exons, and as a result of their autosomal location, humans normally have two copies of each of these genes. In contrast, the L/M gene(s) are located on the X chromosome. While most mammals have only a single L/M gene on the X chromosome, most Old World primates (including humans) possess both L and M genes. In primates that have both the L and M genes on a single X chromosome, they are located in a tandem array near the end of the long arm of the X chromosome (Xq28), and a locus-control region (LCR) enables exclusive expression of one gene from the array in a given cone photoreceptor cell.

The location of the L/M gene array and their high homology allow for frequent unequal homologous crossovers (intermixing of the genes). During meiosis, this can occur between the genes (intergenic crossover) or within the genes (intragenic crossover) between two parental X chromosomes. Such recombination events are responsible for the observed variation in L/M gene number on the X chromosome (humans with normal color vision can

have between two and nine genes in this array). In addition, genes with hybrid L and M sequences are produced from intragenic crossover events. These hybrid genes encode photopigments that have spectral sensitivities intermediate of the normal L- and normal M-cone photopigments. The combined variability in gene number and gene sequence means that in a group of 100 males, the probability that any two will have identical L/M arrays is less than 2%. Interestingly, there is no normal variation in the S-pigment gene.

As mentioned previously, there is a great deal of variability in the L and M photopigments. In fact, of the 364 amino acids there are 18 residues where differences have been identified between and among the L and M photopigments (positions 65, 111, 116, 153, 171, 174, 178, 180, 230, 233, 236, 274, 275, 277, 279, 285, 298, and 309; see Figure 2(a)). Positions 274, 275, 277, 279, 285, 298, and 309 co-segregate and can be used to identify a pigment as either L or M. This is because these amino acids, in particular the substitutions at positions 277 and 285, are responsible for generating the majority of the spectral separation between the L and M pigment classes. L genes specify tyrosine and threonine at positions 277 and 285, respectively, whereas M genes specify phenylalanine and alanine at these same positions, resulting in a shift in peak sensitivity toward shorter wavelengths of approximately 24 nm. Substitutions at the other amino acid positions can produce more subtle spectral shifts, driving the spectral variations within the L and M classes. The most common, a serine/alanine dimorphism at position 180, shifts the maximum absorption (lmax) by about 3–7 nm, though the amino acid identity at other polymorphic positions can influence the magnitude of this shift.

This genetic variation can have a measurable impact on color vision. For example, among normal trichromats, the

C-lI

E-lI

(a)

C-lI

E-lI

(b)

C-terminal

C-lII

E-IIl

N-terminal

C-terminal

C-lII

E-IIl

N-terminal

variation in spectral sensitivity within the L and M pigment classes can be readily observed on color-matching performance. In the Rayleigh match, an individual is asked to determine the mixture of a red and green primary needed to exactly match a monochromatic yellow light. Variability in color-matching behavior had long been recognized, but only in the last 20 years has it been directly linked to the variability in the L and M photopigments, and thus the L/M gene array.

Red–Green Color-Vision Deficiencies

Besides inducing subtle alterations in performance on laboratory color-vision tests, the genetic mechanisms that give rise to variability in the L/M-gene array can induce significant defects in color discrimination. Disruptions in normal L/M-photopigment expression result in an inherited form of color-vision deficiency that affects the red–green (L/M cone) system. Among individuals of Western European ancestry, about 8% of males have a red–green color-vision defect. The incidence is significantly lower among Africans and Asians, as well as smaller isolated populations such as Fijian Islanders and the Inuit. These defects are associated with the L/M array on the X chromosome and are inherited as X-linked recessive traits, so the incidence in females is much lower (approximately 0.4%). Nonetheless, approximately 15% of females are heterozygous carriers of a red–green colorvision defect. It has been suggested that there may be a heterozygous advantage for female carriers, as given the variability with the L and M spectral classes, these women can have four spectrally distinct cone types, providing the photoreceptor basis for tetrachromatic color vision.

The genetic causes of inherited red–green color-vision deficiency fall into two main categories. The most common cause is a rearrangement of the L/M genes resulting either in the deletion of all but one L or M pigment gene, or in the production of a gene array in which the first two genes encode a pigment of the same spectral class (i.e., L/L or M/M). Even though the L/M array can contain more than two genes, it is believed that only the first two genes in the array are expressed. The second general cause involves the introduction of a mutation in either the first or the second gene in the array, rendering the expressed pigment nonfunctional. The most prevalent inactivating mutation, accounting for nearly 10% of red–green dichromacy, results in the substitution of arginine for cysteine at position 203 (C203R) in the L/M opsin molecule. Mutating the corresponding cysteine residue in human rhodopsin (position 187) causes autosomal dominant retinitis pigmentosa (RP). This cysteine residue forms an essential disulfide bond and is highly conserved among all G-protein-coupled receptors. Mutant photopigments do not fold properly, and are retained in the endoplasmic

reticulum and not targeted to the cone outer segment membrane. As such, L/M cones expressing this mutant pigment are nonfunctional, and individuals harboring this mutation base their color vision on an S cone and a single L- or M-cone type (rendering them dichromatic).

In the case where the first two genes encode pigments from the same spectral class, they can have either the same spectral sensitivity or slightly different spectral sensitivity (owing to the fact that there is variation within the L and M pigment classes). If the first two genes encode pigments with identical spectral sensitivities, the individual again bases their color vision on an S cone and a single L- or M-cone type and will be dichromatic. However, if the first two genes encode pigments with different spectral sensitivities (though from the same spectral class, L or M), the individual is technically trichromatic, in that they have three different cone types. However, since the spectral separation between their two types of L (or M) pigment is not as great as the separation between L and M, their discrimination is not normal. Thus, these individuals are known as anomalous trichromats. The standard L and M photopigments differ in their peak spectral sensitivity by nearly 30 nm. In anomalous trichromats with multiple L (or M) pigments, the lmax may be separated by as few as 2 nm or as many as 10–12 nm, where the degree of spectral separation depends on the identity of the amino acids at sites 65, 111, 116, 153, 171, 174, 178, 180, 230, 233, and 236 within the L/M pigment (Figure 2(a)). In general, the further apart the pigments, the better the discrimination; in some cases, the deficiency is so mild that the individual is unaware of it until genetic and/or behavioral testing. Likewise, as the lmax of the pigments gets closer together, the discrimination worsens, with the most severe individuals behaving nearly like dichromats.

The red/green defects can be separated based on the

(1) dimensionality of the residual color vision (dichromat or anomalous trichromat) and (2) spectral subtype of the remaining cone (protan or deutan). Figure 3 shows the different spectral sensitivity curves that underlie the different forms of red/green color-vision deficiency.

Individuals with an absence of L-cone function are said to have a protan defect. Protanopes are dichromats who possess an S pigment and an M pigment. Protanomalous trichromats possess a normal S pigment and two spectrally distinct M pigments. Perceptually, the absence of a cone type can have differing effects. Individuals with a protan defect are less sensitive to light in the long-wave- length (red) portion of the spectrum. Therefore, the brightness of red, orange, and yellow are reduced compared with a normal observer. Furthermore, they may have problems in distinguishing red from green, as well as difficulties differentiating a red hue from black.

Individuals with an absence of M-cone function are said to have a deutan defect. A deuteranope possesses an