Color Vision - Clinical Tree

The ability to perceive color is a highly valued sensory capacity, and it has been a subject of experimental inquiry for over 200 years. Prior to the development of modern biological techniques, breakthroughs in color vision research stemmed from careful consideration of perceptual experiences. From color-mixing and matching experiments it was deduced that three different receptors in the eye, each maximally sensitive to a different region of the visible spectrum, were required to explain normal color vision. Thus, the three-component theories of Young and Helmholtz, as well as Hering's conflicting hypothesis of three paired, opponent color processes were developed in the 1800s, long before the three types of retinal cone photopigment were isolated and characterized. It is now understood that normal, or trichromatic, color vision is mediated by three types of cone photoreceptor – designated short- (S), middle- (M), and long- (L) wavelength-sensitive – the activities of which are, indeed, combined in later opponent organization to provide color perception. The first direct measurements of the absorption properties of primate cone photopigments occurred in the 1960s using a technique called microspectrophotometry. Since then, additional techniques including the electroretinogram and molecular genetics have allowed for refinement of the spectral sensitivity curves for the S, M, and L pigments, shown in Figure 34.1 .

The fact that most humans have trichromatic color vision explains why computer monitors and televisions mix just three primary colors, red, green, and blue, in order to produce colors that match almost all those seen in the real world. Likewise, if humans were tetrachromatic, having four cone photopigments, televisions with four primaries would be required. The presence of three classes of cone photoreceptor also explains color blindness. That is, loss of function of each individual cone class is associated with an inherited form of color vision deficiency: protan defects involve loss of L cone function, deutan defects with loss of M cone function, and tritan defects with loss of S cone function ( Box 34.1 ). Each type of color vision defect results from rearrangements, deletions, or mutations in the genes encoding the corresponding L, M, or S photopigment, and color vision tests have been developed which can detect changes in the cone complement. Observations that cannot be explained by the presence of three types of cone photoreceptor, however, involve the appearance of color. The neural circuitry for color vision extracts signals from only three cone types, and yet gives rise to six hue percepts arranged in opponent pairs: blue-yellow, red-green, and black-white. These topics, including the molecular genetics of color vision deficiencies, tests of color vision, and the neural circuitry of color perception, will be discussed in detail in the following sections.

Box 34.1

Nomenclature for inherited color vision deficiencies

Protan defects are the least common form of red-green color vision defects affecting about 2 percent of males in the US. There are two categories: dichromatic (protanopia), and anomalous trichromatic (protanomaly), each affecting about 1 percent of males. The severity of protan defects varies over a relatively narrow range. Protan comes from the Greek root for ‘the first.’ Protan color vision is mediated by S cones and M cones.

Deutan defects are the most common form of red-green color vision defects, affecting about 6 percent of males in the US. There are two categories: dichromatic (deuteranopia) and anomalous trichromatic (deuteranomaly). Deuteranomaly and deuteranopia affect ~5 percent and ~1 percent of males, respectively. The severity of deutan defects varies over a relatively broad range, from nearly normal to nearly dichromatic. Deutan comes from the Greek root for ‘the second.’ Deutan color vision is mediated by S cones and L cones.

Tritan defects are relatively rare and are characterized by impaired blue-yellow color vision. There is only one category, dichromatic (tritanopia). Tritan defects display incomplete penetrance, meaning there is variability in the degree to which color vision is impaired among individuals with the same underlying gene defect, even within a family. Tritan comes from the Greek root for ‘the third.’ Tritan color vision is mediated by M and L cones.

Molecular genetics of color vision and color deficiencies

Although the tendency for color vision defects to run in families and to be more prevalent among men had long been recognized, a major advancement in understanding the biological basis of color vision and its defects came in 1986 when Jeremy Nathans and colleagues cloned and sequenced the genes encoding the S, M, and L cone opsins and verified that the L and M opsin genes are in adjacent positions on the X-chromosome. Further breakthroughs in understanding differences in the quality of color vision among individuals with anomalous trichromacy followed, with identification of the amino acids involved in spectral tuning, which are responsible for the ~30 nm difference in peak sensitivity of the L and M pigments underlying normal color vision.

The majority of inherited red-green color vision defects are caused by rearrangement and deletions of the L and M opsin genes on the X-chromosome that come about by meiotic recombination during oogenesis in females. A dichromatic phenotype results in males who inherit an X-chromosome in which all but one of the opsin genes have been deleted. A protanopic type defect is characterized by the absence of L opsin genes, and a deuteranopic type defect is characterized by the absence of M opsin genes ( Box 34.2 ). Although humans often have more than just two opsin genes on the X-chromosome, only two are typically expressed, and these determine color vision phenotype. If meitoic recombination creates an array in which the first two genes encode pigments with identical spectral properties, a male who inherits the array will be dichromatic, either protanopic or deuteranopic. However, a male with an array in which the first two genes encode opsins of the same class (M or L), but differ slightly in spectral sensitivities, will be an anomalous trichromat. He will be protanomalous if the genes encode two M opsins, or deuteranomalous if they encode two L opsins. The extent of color vision loss in anomalous trichromats is determined by the degree of similarity in the spectral peaks of the two pigments.

Box 34.2

Visual pigments, cone opsins, and official gene designations

Visual pigments, also known as photopigments, are composed of an apoprotein and an 11- cis retinal chromophore. The genes, OPN1LW, OPN1MW, and OPN1SW, each encode an apoprotein (termed opsin). The chromophore is a vitamin A derivative that absorbs ultraviolet light; when covalently bound to an opsin, the chromophore absorption spectrum is shifted to longer wavelengths. Amino acid differences among the opsins are responsible for the differences in the absorption spectra of the three cone classes ( Fig. 34.1 ). Within the L and M classes, variations or polymorphisms in the amino acid sequences produce relatively small spectral shifts giving rise to variants of L and M photopigments.

OPN1MW: middle-wavelength sensitive cone opsin, expressed in M cones, commonly referred to as ‘green’ cones. OPN1MW is on the X-chromosome at location Xq28. Deutan defects are most commonly associated with the absence or lack of expression of the OPN1MW gene(s).
OPN1LW: long-wavelength sensitive cone opsin, expressed in L cones, commonly referred to as ‘red’ cones. OPN1LW is on the X-chromosome at location Xq28. Protan defects are most commonly associated with the absence or lack of expression of the OPN1LW gene(s).
OPN1SW: short-wavelength sensitive cone opsin, expressed in S cones, commonly referred to as ‘blue’ cones. OPN1SW is on chromosome 7 at 7q32.1. Tritan defects are caused by a missense mutation in one copy of the OPN1SW gene. A missense mutation is a change in the amino acid coding sequence of a gene that substitutes one amino acid for another in the encoded protein.

It has been assumed that the 30 nm spectral separation between the L and M pigments was optimized during evolution, and that there is also an optimal ratio of L and M cones. However, recent studies have shown that much smaller spectral separations between, and skewed proportions of, L and M cones still provide robust red-green color vision. For example, red-green chromatic sensitivity was recently demonstrated to exhibit a non-linear relationship with photopigment proximity, and observers did not show a reduction in color discrimination that could be reliably classified as just outside the normal range until the L/M separation was reduced to about 12 nm or less. Another surprising finding occurred with the development of adaptive optics, a technique that allows resolution of the cone photoreceptor mosaic in living humans. Selective bleaching allowed identification of the different cone types and revealed that individuals with normal color vision have roughly the same number and arrangement of S cones, but there is tremendous variation in the ratios of L and M cones. This was startling in light of the widely held belief that the quality of red-green color vision would be affected by extreme cone ratios, and it is a testament to the fact that the visual system is tuned for detecting very small differences.

Inherited blue-yellow color vision, or tritan, defects are considerably more rare than red-green defects. They are caused by mutations in the S opsin gene, and are inherited in an autosomal dominant fashion, meaning that an individual who is heterozygous for an S opsin gene mutation will often exhibit the phenotype. Recent evidence from adaptive optics imaging of tritan subjects suggests that the defect is an S-cone dystrophy, similar to rod dystrophy caused by heterozygous mutations in the rod pigment rhodopsin in retinitis pigmentosa. Tritan defects are said to be incompletely penetrant, meaning not everyone with an S opsin gene defect exhibits the phenotype, but this is perhaps due to a progressive loss of S cones which must reach a critical threshold before the phenotype is manifested.

Tests of color vision

As described above, color vision defects are the result of genetic changes that are responsible for either the alteration or loss of cone photopigments. Since color vision is based on neural comparisons between different classes of cone photoreceptor, both the loss of a photopigment type and changes in the peak sensitivity of a photopigment such that there is a reduction in the differential responses of the two cone classes, will result in a reduced ability to distinguish colors.

Pseudoisochromatic plate tests are perhaps the most familiar tool for diagnosing color vision deficiencies. Popular examples include Ishihara's test of color vision and the Hardy, Rand, and Rittler (HRR) pseudoisochromatic plates. The plates consist of printed pages with dots of various colors and shades of gray, each containing a colored symbol(s) that is visible to individuals with normal color vision, but invisible to those with certain color vision defects. Subjects are asked to identify the symbols, and the specific pattern of errors on a series of plates in a test allows for diagnosis of the likely presence or absence of a color vision defect, and for some tests, an indication of the type and severity.

A fundamentally different testing strategy is used with arrangement tests, in which subjects are asked to arrange a series of colored discs ‘in order’ so that each disk is placed adjacent to the discs that are most similar in color appearance. Misordering of the disks allows a diagnosis of the presence or absence of a color vision defect. Popular examples of arrangement tests are the Farnsworth-Munsell 100 Hue Test and its abridged version, the Farnsworth-Munsell Dichotomous D-15 Test.

The Rayleigh color match is often referred to as the ‘gold standard’ for color vision testing. It is performed on the anomaloscope, an instrument which contains an optical system that produces two side-by-side lighted fields. One field, the ‘test light,’ is a monochromatic amber color, and the other is a mixture of red and green light. The person being tested adjusts the ratio of red-to-green light in the mixture until it exactly matches the amber test light. Setting a match with a higher or lower ratio of red-to-green light compared to the match made by a person with normal color vision is diagnostic of an inherited color vision abnormality caused by a shift in the spectral peak of either the L or M pigment. This test is extraordinarily sensitive and can detect genetic alterations in the spectral sensitivities of the photopigments, even in subjects in whom the alteration in the photopigment has little or no effect on the person's ability to discriminate between different colors. Its extreme sensitivity in detecting the presence of anomalous photopigments is why the anomaloscope has been widely adopted as the ‘gold standard.’ However, it must be emphasized that mild photopigment abnormalities may be associated with little or no loss in color discrimination ability. Even with shifted pigments, the quality of color vision may still be quite good. Combining genetic analysis with the Rayleigh match can provide a more precise assessment of the likely quality of color vision.

Each of the widely used color vision tests has its separate advantages and is considered to be best under different circumstances. Because of this, for general diagnosis of color vision defects, the results from a battery of tests can provide the most complete picture from which to make a differential diagnosis. Ideally, for diagnosis of color vision defects, one should obtain information on the ‘type’ of problem. Is it a red-green or blue-yellow deficiency, or mixed? If it is red-green, is it a ‘protan’ or ‘deutan’ defect? Is it a genetic disorder or is it acquired? The test should also provide information about severity. Does the person have a severe dichromatic form, or a milder ‘anomalous’ form of deficiency? If it is an anomalous form, is it very mild, mild, moderate, or more severe? Under some conditions it is impractical to administer a battery of tests. Cole et al recently recommended the latest edition of the Richmond HRR Pseudoisochromatic test as the ‘one of choice for clinicians who wish to use a single test for color vision.’ It has plates for detecting protan, deutan, and tritan defects, and its classification of mild, medium, and strong categories for deutan and protan defects is useful. To absolutely distinguish dichromats from anomalous trichromats, the anomaloscope, the D15, or both should be used in conjunction with a pseudoisochromatic plate test.

Genetic testing is the most reliable means of distinguishing acquired color vision defects from inherited color vision defects. Presently, genetic tests are not commercially available; however, the technology exists to perform such tests because the molecular genetics of inherited color vision defects is well understood, as described in the previous section.

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