Congenital red–green color blindness

The only significant symptom of congenital red–green color blindness is deficient color vision (color blindness or discromatopsia). A red–green color blind subject will have decreased (or no) color discrimination along the red–green axis. This commonly includes the following colors of confusion: • Cyan and gray • Rose-pink and gray • Blue and purple • Yellow and neon green • Red, green, orange, brown • Black and red (protans) ==Classification==

Congenital red–green color blindness is classified into 1 of 4 groups: • Protanopia • Protanomaly • Deuteranopia • Deuteranomaly Each of these groups comprises a prefix and a suffix. The prefix indicates the cone (photopsin) that is affected, with lexemes from Greek, "first" (prot-) or "second" (deuter-) referring to the L- and M-opsins respectively. The suffix indicates the dimensionality of color vision: • Dichromacy gives the suffix -anopia (from the Greek for "no sight") • Anomalous trichromacy gives the suffix anomaly (from the Greek for "irregular"). Dimensionality in the fovea of an individual with normal color vision (left), and protanopia (right). The protanope is completely missing red cones and is therefore a dichromat. The dimensionality of normal color vision is trichromatic. This references that a visual system with three distinct cone classes and therefore a three dimensional gamut. Dichromatic color vision only has two distinct cone classes and therefore a two dimensional gamut. With red–green dichromacy, it is the dimension representing the red–green opponent channel that is lost. Anomalous trichromacy is also trichromatic, but the spectral sensitivity of at least one of the cone cells is altered, leading to a gamut that is a different size or shape. In the case of congenital red–green color blindness, the dynamic range of the red–green dimension is decreased when compared to normal color vision. The dimensionality of the defect is related to the strength/severity, but it is usually much easier clinically to define the severity empirically as mild, moderate and strong (or severe). Anomalous trichromacy can vary in severity from indistinguishable from normal color vision (mild) to indistinguishable from dichromacy (strong). Therefore, the differential diagnosis between anomalous trichromacy and dichromacy is difficult. An example clinical diagnosis would be strong deutan, which could correspond to either deuteranomaly or deuteranopia. Protan vs. deutan The two types of congenital red–green color blindness as based on the affected cone are: • Protan: (2% of males): lacking, or possessing anomalous L-opsins for long-wavelength-sensitive cone cells. • Deutan: (6% of males): lacking, or possessing anomalous M-opsins for medium-wavelength-sensitive cone cells. Despite often being called red-blind and green-blind respectively, protan and deutan varieties have very similar phenotypes (color vision), especially when compared to tritan color blindness. The condition is not called red–green color blindness because red and green are indicative colors of confusion, nor because the "red" and "green" cones are affected, but because the red–green opponent process channel is affected. In dichromacy, that channel is equally deactivated regardless of which cone (LWS or MWS) is missing. In anomalous trichromacy, that channel is equally affected regardless of which cone effectively moves towards the other. The starkest difference is the scoterythrous effect, where reds appear dimmer to protans. This is why protans often confuse red with black, while deutans do not. The protan luminous efficiency function is narrower at long wavelengths, which causes the reds to be darker. This is due to the red cones (which normally cover the red side of the spectrum) either shifting to shorter wavelengths or being missing. The two are difficult to differentiate with color vision tests, but is most reliably performed with an Anomaloscope. This device measures the proportion of red and green light that must be mixed to perceptually match a yellow reference. Protans add more red than color normals, and deutans add more green. ==Mechanism==

Genes The mechanism of congenital red–green color blindness relates to the functionality of cone cells, specifically to the expression of photopsins, the photopigments that 'catch' photons and thereby convert light into chemical signals. A typical human has three distinct photopsins: S-, M- and L-opsins expressed by distinct genes, respectively OPN1SW, OPN1MW or OPN1LW. OPN1MW and OPN1LW are located in a gene cluster (along with a locus control region gene) at position Xq28, at the end of the q arm of the X chromosome in a tandem array. OPN1SW is unrelated to the condition and located on a different chromosome. The genes in the cluster are summarized in the following table: Differentiating from a duplication event 30-40 MYA, and are therefore 96% similar. While the two genes share 19 dimorphic sites (amino acids that differ), only 7 of them lead to a functional difference between the genes, i.e. tune the opsin's spectral sensitivity. The duplicate genes are sometimes referred to with numerical suffixes, where the OPN1MW gene in the second position is called OPN1MW2. The duplicated genes are always in sequence and can consist of different alleles of the gene, but only the first gene of a duplicate series is ever expressed. Blue-cone monochromacy While blue-cone monochromacy exhibits much stronger symptoms than the congenital red–green color blindness (including total color blindness), it follows a very similar mechanism. In most cases, unequal homologous combination must first occur to generate a genotype with a single L/M-opsin gene. Then that gene must experience a nonsense mutation to entirely deactivate it. ==Genetics==

Congenital means that the condition is present from birth, but is usually used to represent the genetic, inherited basis of the condition. This is in contrast to acquired color blindness that is not present at birth and may be caused by aging, accidents, medication, etc. Heredity Since the affected opsin genes (OPN1LW and OPN1MW) are on the X chromosome, they are sex-linked, and therefore affect males and females disproportionately. Because the colorblind alleles are recessive, colorblindness follows X-linked recessive inheritance. Males have only one X chromosome (karyotype XY), and females have two (karyotype XX); Because the male only has one allele of each gene, if it is missing or chimeric, the male will be color blind. Because a female has two alleles of each gene (one on each chromosome), if only one allele is mutated, the dominant normal alleles will "override" the mutated, recessive allele and the female will have normal color vision. However, if the female has two mutated alleles, she will still be colorblind. This is why there is a disproportionate prevalence of colorblindness, with ~8% of males exhibiting colorblindness and ~0.5% of females Some conclusions from the table include: • A male cannot inherit colorblindness from his father. • A colorblind female must have a colorblind father. • A female must inherit colorblindness alleles from both parents to be colorblind. • Colorblind females can only produce colorblind males. • Because carrier females often have a colorblind father, colorblind males often will have a colorblind maternal grandfather (or great-grandfather). In this way, colorblindness is often said to 'skip a generation'. The Punnett square and this section assume each chromosome only has one affected gene. It also assumes females with two affected chromosomes are affected in the same way. Genotypes The table to the right shows the possible allele/chromosome combinations and how their interactions will manifest in an individual. The exact phenotype of some of the combinations depend on whether the affected gene represents an anomalous allele or is missing. For example, the XY male may have blue-cone monochromacy if the genes are both missing/non-functional, or near-normal color vision if both genes are anomalous. • Y : male-only chromosome (no effect on colorblindness) • X : X chromosome will have two subscripts indicating the alleles present: • M : normal M opsin allele • L : normal L opsin allele • M*: chimeric (or missing) M opsin allele • L*: chimeric (or missing) L opsin allele Tetrachromacy in carriers of CVD Females that are heterozygous for anomalous trichromacy (i.e. carriers) may be tetrachromats. have shown that with appropriate and sufficiently sensitive equipment it can be demonstrated that any female carrier of red–green color blindness (i.e. heterozygous protanomaly, or heterozygous deuteranomaly) is a tetrachromat to a greater or lesser extent. Since the incidence of anomalous trichromacy in males is ~6%, which should equal the incidence of anomalous M opsin or L opsin alleles, it follows that the prevalence of unaffected female carriers of colorblindness (and therefore of potential tetrachromats) is 11.3% (i.e. 94% × 6% × 2), based on the Hardy–Weinberg principle. One such woman has been widely reported to be a true or functional tetrachromat, as she can discriminate colors most other people can't. == Diagnosis ==

Color vision test The diagnosis of congenital red–green color blindness is usually inferred through psychophysical testing. These color vision tests detect the color vision phenotype, and not the subject genotype, so are unable to differentiate acquired from congenital red–green color blindness. However, color vision and genotype are highly correlated, especially when acquired color blindness is ruled out. Electroretinography When psychophysical testing is undesired, an electroretinogram (ERG) can be used instead. An ERG measures the electrical response from the retina as a function of wavelength of light. Due to the shape of spectral sensitivity of cone cells, the peak wavelengths of cone sensitivity can be assumed from an ERG. The peak wavelengths are highly correlated to genotype. Genetic testing The genotype can be directly evaluated by sequencing the OPN1MW and OPN1LW genes. The correlation between genotype and phenotype (color vision) are well known, so genetic testing can be a useful supplement to psychophysical color vision tests that may provide incomplete information. ==Treatment==

Despite much recent improvement in Gene therapy for color blindness, there is currently no FDA approved treatment for congenital red–green color blindness, and otherwise no cure exists. Management of the condition through the use of color blind glasses to alleviate symptoms or smartphone apps to aid with daily tasks is possible. ==Epidemiology==

Congenital red–green color blindness affects a large number of individuals, especially individuals of European ancestry, where 8% of men and 0.4% of women exhibit congenital red–green color deficiency. The lower prevalence in females is related to the X-linked inheritance of congenital red–green color blindness, as explained above. Interestingly, even Dalton's very first paper already arrived upon this 8% number: Other ethnicities will generally have a lower prevalence of congenital red–green color blindness. The following table summarizes a number of studies performed in different regions. == See also ==