Colour vision deficiency part 1--an introduction.
Course code: C-34398 | Deadline: January 10, 2014
To be able to explain to patients about the implications of colour vision defects (Group 1.2.4)
To appreciate the genetic significance of colour vision defects (Group 3.1.4)
To recognise the significance of acquired colour vision defects with respect to systemic disease and ocular abnormalities (Group 6.1.13)
To be able to explain to patients about the implications of colour vision defects (Group 1.2.4)
To understand the classification of colour vision defects (Group 3.1.4)
To understand the link between acquired colour vision defects and ocular abnormalities (Group 8.1.2)
Congenital red-green colour vision deficiency is the most common X-linked inherited abnormality in the population and affects about 8% of men and 0.4% of women. (1) Congenital tritan deficiency is rare and is inherited as an autosomal dominant trait. The characteristics of normal trichromatic vision and different types of congenital deficiency were established in the first half of the twentieth century. Developments in molecular genetic analysis have provided remarkable insight into the underlying mechanisms. (2-4) The central mosaic can also be visualised using adaptive optics and the identity of individual cones determined with selective chromatic bleaching (retinal densitometry). (5)
Normal colour vision
Trichromacy, in accordance with the Young-Helmholtz theory, is present at the receptor level and opponent processing, as proposed by Hering, is established in the inner retina. Opponency is maintained in the visual pathway but spatial organisation changes at different levels.
Trichromatic vision, often described inappropriately as 'red', 'green'and 'blue', is derived from three cone classes which contain photopigment with relatively long (L), medium (M) and short (S) wavelength spectral sensitivity. The L and M cones have peak sensitivity in the yellow-green part of the spectrum, at about 560nm and 530nm, respectively, and have overlapping spectral sensitivities; S cones have peak sensitivity in the spectral violet at about 420nm (see Figure 1). Colour vision is dichromatic for wavelengths greater than 540nm. Electrical signals from the three cone classes are segregated in the retinal bipolar layer and three structurally different pathways are established at the ganglion cell level. The parvocellular (P), or tonic, pathway is derived from L and M cones that input midget bipolars and ganglion cells with small receptor fields and transmits red/green opponent information. The magnocellular (M), or phasic, pathway is derived from diffuse bipolar cells that have large receptor fields and receive synergistic input from L and M cones. Information about luminance is transmitted to form the light/dark opponent pathway. Groups of S cones synapse with special blue-cone bipolars that access small bi-stratified ganglion cells that also receive input from diffuse bipolars. The S cone signal is, therefore, differenced with the sum of L and M signal to form the Koniocellular (K), or blue/yellow pathway, and contributes a small amount to the luminance channel.
Short wavelength sensitivity varies by a factor of 10 (1 log unit) due to individual differences in macular pigment density. Macular pigment consists of two carotenoids, lutein and zeaxanthin, which absorb wavelengths between 390nm and 530nm, with peak absorption at 460nm. Short wavelength sensitivity reduces progressively after about 55 years of age due to physiological changes in lens density.
Normal cone photopigments
Genes that specify L and M photopigments are positioned in a tandem head-to-tail array at Xq28. The two genes evolved about 35 million years ago from duplication of an ancestral mid-wavelength photopigment gene that was similar to the L gene. (6) The amino acid sequences have 96% identity. The opsin sequences have 364 amino acids divided into six exons separated by five 'neutral' segments or introns. Seven sites distributed between exons two, three, four and five, are in close proximity to the chromophore and collectively change the peak wavelength sensitivity of the M photopigment by about 30nm (exons two, three and four). A shift of about 17nm is produced at two sites on exon five. The shifts produced at other sites are relatively small. Polymorphism at site 180 on exon 3 of the L gene has a frequency of 40% and produces a marginal improvement in long wavelength sensitivity.
The array at Xq28 is headed by a locus control region (LCR) that regulates gene expression. The L gene is always first in the array and an M gene second. Proximity to the LCR is advantageous and there are usually more L cones than M cones that are randomly distributed in the cone mosaic. The mean L:M ratio is 2:1 but can vary between 1:1 and 1:9 without affecting hue discrimination ability (see Figure 2). (7) About 25% of men have two genes at Xq28, 50% have an additional M gene and 25% have several more M-like chimeras, or gene fragments in the array. Only the first two genes are expressed.
Congenital colour deficiency
There are three classes of deficiency with differences in severity. Types of deficiency are classified according to the number of variables needed to match all the spectral hues (see Table 1).
All people with colour deficiencies see fewer separate hues in the environment and confuse colours that are easily distinguished by normal trichromats (see Table 2). Colour confusions are specified in isochromatic zones in the reference system approved by the Commission Internationale d'Eclairage (CIE) in 1931. Colours with X, Y chromaticity co-ordinates within an isochromatic zone are confused if there is no perceived luminance contrast (see Figure 3).
Protan deficiency is characterised by a shift in relative luminous efficiency from 555nm to about 535nm and by reduced sensitivity to long wavelengths (shortening of the red end of the spectrum). S cones comprise about 7% of cells in the central mosaic and 'small field tritanopia' occurs for objects subtending less than half a degree.8
All types of red-green deficiency are caused by loss of a photopigment gene needed for normal trichromacy. (3) L and M genes are highly homologous and cross-over events readily occur during meiosis when paternal and maternal X chromosomes exchange part of their material. If the genes are misaligned, one chromosome may lose a gene and the other gain one (intergenic crossover). If the break occurs in an intron, complete exon sequences are exchanged and recombine to form a chimera consisting of conjoined sections of the normal L and M genes (intragenic crossover). (2) An L/M chimera consists of exons derived from the L gene joined to exons from the lower portion of the M gene and codes an M-like photopigment because the major wavelength tuning sites are derived from exon 5 of the M gene (see page 49). Similarly M/L chimeras have exons from the M gene joined to lower exons from the L gene and code L-like photopigments. Other structural changes are produced from a series of cross over events and result in a wide range of photopigments with peak wavelength sensitivities between 560nm and 530nm.
Different genotypes produce the same phenotype. Most dichromats have a single gene in the array. Protanopes have a normal M gene, whereas deuteranopes have a normal L gene. (9) The foveal mosaic is complete and all cones have the same photopigment. A minority of dichromats has two identical genes at the head of the array or two genes that code photopigments with the minimal peak wavelength separation of 3-4nm. (10) Some dichromats appear to have two normal genes but a mutation at site 203 on exon four, is present in one gene. In this case large gaps are seen in the foveal mosaic and microscotomas can be detected. Visual acuity is not affected although 30% of the receptors may be lost. (11) Deuteranopes with this genotype may have a normal M gene third in the array that is not expressed.
Most protanomalous trichromats have two L/M chimeras. It is less common to have a single L/M chimera followed by a normal M gene. Similarly, deuteranomalous trichromats have either two M/L chimeras or a normal L gene followed by an M/L chimera. Severity of deficiency varies according to the peak wavelengths of the photopigments and loss of hue discrimination ability is inversely proportional to the peak wavelength separation. Clusters of L/M photopigments have peak sensitivity within 8nm of the normal M photopigment, whereas M/L photopigments cluster within 12nm of the normal L photopigment. These pairings produce slight colour deficiency but protanomalous trichromats have a 40% reduction in hue discrimination ability compared with a 30% reduction in deuteranomalous trichromatism.
Red-Green deficiency in women
Women inherit two sets of genetic characteristics on paired X chromosomes and random inactivation (suppression) occurs at an early stage of development so that either the maternal or paternal gene is expressed in an individual cell (Lyonisation). Approximately 50% of women inherit genes for subtypes of the normal L photopigment and post mortem analysis shows that both photopigments are expressed in the cone mosaic. (12) A further 12% of women are heterozygous for a gene that produces anomalous trichromatism in men. Some women, therefore, have the potential for tetrachromatic vision if the visual pathway has the capacity to transmit and preserve information from four spectrally distinct cone types, although there is no evidence for this. (13) On the contrary, psychophysical measurements show that most heterozygous women have poorer red-green discrimination than normal trichromatic men suggesting that information from a fourth photopigment creates 'noise' that degrades chromatic signals in opponent pathways. (14)
The gene which specifies the S photopigment is located at 7q 31-32. The S opsin has 348 amino acids and has about 45% identity with X chromosome opsins. Single mutations at three separate sites produce tritan deficiency in different families--prevalence is about 0.02%.
Phenotypical variations are characteristic of autosomal inheritance and some family members are tritanopes while others are incomplete tritanopes that express some S photopigment. (15,16) There is no mechanism for changing peak wavelength sensitivity and the term 'tritanomalous trichromatism' is misleading. Mature expression of inherited tritan deficiency has been found, suggesting the onset of a cone dystrophy. (17)
Monochromatism (inherited achromatopsia)
Monochromats cannot distinguish wavelength differences in photopic illumination and are able to match all the spectral hues using a single variable. Typical, 'complete' or 'rod' monochromats are found to have structurally abnormal cones within a disrupted foveal mosaic. (18) Visual acuity is typically 6/36-6/60 in these individuals, with an absolute central scotoma, severe photophobia and nystagmus. Inheritance is autosomal recessive and consanguinity is a predisposing factor--prevalence is about one in 35,000. Single mis-sense mutations, on either chromosome 1, 2, 8 or 14, which prevent transcription of key enzymes in the cone transduction pathway, have been identified in different families.
Atypical, 'incomplete'or 'blue cone' monochromats (BCM) have S cones only--prevalence is about one in 100,000. (19) Some hue discrimination is possible in mesopic illumination when S cones and rods are active. Visual acuity is often about 6/18 with a relative central scotoma, moderate photophobia and low-grade nystagmus; the foveal mosaic is irregular and reduced in density. (20) Inheritance is X-linked with about 60% of cases caused by the mis-sense mutation at site 302 of exon 4, in both genes. An abnormality at the LCR at Xq28 that prevents all gene expression is found in 40% of cases. Some patients develop slowly progressive macular degeneration and visual acuity declines with age. (21)
Abnormal colour vision can be associated with disease or injury to any part of the visual pathway, from the retina to the cortex. Poor visual acuity and/or visual field defects are present and monocular differences in severity are common. Colour vision is very poor if macular oedema is present. Loss of hue discrimination is usually progressive. Colour vision remains abnormal following episodes of central serous chorio-retinopathy or retrobulbar neuritis and after successful treatment for wet AMD, even if visual acuity has recovered (see Figure 4). (22, 23) Acquired deficiencies differ qualitatively from congenital deficiency because opponent pathways are always compromised. Two classes, blue-yellow (tritan) or red-green, have been described but relative luminous efficiency and hue discrimination loss varies individually (see Table 3).
Detection of slight Type 3 (Tritan) deficiency is difficult with pseudoisochromatic tests due to poor specificity in older patients. The hues of the Farnsworth-Munsell 100 Hue test have smaller colour differences than in the rest of the test and errors are age-related and only significant acquired deficiency is identified. Short wavelength automatic perimetry (SWAP) is difficult for older patients and results lack consistency. New validated computerised examination techniques largely avoid these problems. The Colour Discrimination and Diagnosis (CAD) test is performed on a high-resolution colour calibrated display. Chromatic red/green (R/G) and blue/yellow (B/Y) thresholds are measured centrally and in different quadrants of the visual field, six degrees from the fovea, if required. The results show that both R/G and B/Y discrimination thresholds are raised in all types of pathology. Loss of short wavelength discrimination is found in the early stages of diabetic retinopathy, due to loss of S cones, but both R/G and B/Y thresholds are raised as the disease progresses. (23-24) Raised R/G thresholds are found in the early stages of glaucoma and both R/G and B/Y thresholds are raised symmetrically in later stages of the disease similar results are obtained in AMD. (25)
Lesions in the visual pathway result in abnormal colour vision in specific quadrants of the visual field or hemianopic loss of colour perception. (26) Cortical injury causes additional sensory deficits, including colour agnosia (the inability to remember colour names), coloured hallucinations (phosphenes), photopsia, migrainous 'fortification spectra' or episodes of chromatopsia in which the environment appears suffused in a single colour. Cortical centres dedicated to the perception of red, yellow, green and blue have been identified using functional magnetic resonance imaging and localised damage may result in the loss of perception of a single colour.
References Visit www.optometry.co.uk/clinical, click on the article title and then on 'references' to download.
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Jennifer Birch was formerly a senior lecturer in Clinical Optometry at City University London. She is now a senior research fellow in the Henry Wellcome Research Laboratory in the Department of Optometry. She was a founder member of the International Research Group on Colour Vision Deficiencies and has written extensively on clinical aspects of defective colour deficiency and on occupational colour vision requirements. She was appointed to an Honorary Life Fellowship of the College of Optometrists in 2012.
Table 1 Prevalence of congenital colour deficiency types classified according to the number of colour matching variables needed to obtain all the spectral hues Type of colour deficiency Prevalence Class Denomination Men Women Protan Altered Protanopia Severe 1% 0.01% relative deficiency luminous Protanomalous 1% 0.03% efficiency trichromat Varies individually: slight, moderate or severe deficiency Deutan Deuteranopia Severe 1% 0.01% deficiency Deuteranomalous 5% 0.35% trichromat Varies individually: slight, moderate or severe deficiency Tritan Tritanopia About 1 in 10,000 Incomplete Unknown, Tritanopia possibly about 1 in 500 Type of colour deficiency Classification from colour matching variables Class Denomination Protan Altered Protanopia Severe Dichromat Two relative deficiency matching variables luminous Protanomalous efficiency trichromat Varies individually: Anomalous trichromat slight, moderate Three matching or severe variables deficiency Deutan Deuteranopia Severe Dichromat Two matching deficiency variables Deuteranomalous Anomalous trichromat trichromat Varies Three matching individually: variables slight, moderate or severe deficiency Tritan Tritanopia Dichromat Two matching variables Incomplete Abnormal trichromat Tritanopia Three matching variables Table 2 Typical colour confusions in protan, deutan and tritan congenital colour deficiency. Typical confusions in Protan Deutan Typical confusions Red-Green deficiency in Tritan deficiency Green-Yellow/Yellow/ * * Green/Blue-Green Yellow-Red Green/Orange (Amber)/ * * Purple/Red Brown/Green * * Yellow/White Red-Purple/GREY/Blue- * Violet/GREY/Yellow- Green (#) Green (#) Blue-Purple/GREY/ * Green (#) Red/Black * Navy-Blue/Black Green/Black * Threshold Red/White * * Threshold Blue/White discrimination Discrimination Threshold Green/White * * discrimination (#) Neutral or complementary colours Table 3 Outline classification and characteristics of different types of acquired colour deficiency obtained from pigment tests and measurement of relative luminous efficiency Class Characteristics Association Type 1 Red-Green * Maximum relative * Cone and RPE luminous efficiency dystrophies Eg is changed towards Stargardt's disease shorter wavelengths Chloroquine toxicity and there is reduced sensitivity to short and long wavelengths * Reduced VA and central field defects Type 2 Red-Green * Relative luminous * Retinal ganglion efficiency is normal cell disease Eg but there is reduced Ethambutol toxicity sensitivity to short wavelengths * Reduced VA and * Optic neuropathy central field Eg Retrobulbar defects neuritis Type 3 Blue- a) Similar to * Rod dystrophies Eg Yellow Tritan congenital tritan RP complex deficiency but with peripheral field defects * Retinal vascular disorders Eg Proliferative diabetic eye disease * Peripheral retinal lesions Eg Retinal detachment * Retinal nerve fibre defects/ lesions in the visual pathway Eg Glaucoma b) Similar to * Macular oedema Eg congenital tritan AMD, Diabetic deficiency but with maculopathy Central reduced sensitivity serous to long wavelengths chorioretinopathy and central field defects
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|Title Annotation:||1 CET POINT|
|Date:||Dec 13, 2013|
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