Achromatopsia is a hereditary disease caused by mutations of various genes encoding retinal photoreceptor proteins and characterized by a complete (rod monochromasia) or partial absence of color perception. At the same time, black-and–white vision is preserved, although there are other disorders of the visual apparatus – day blindness (hemeralopia), nystagmus, decreased visual acuity, sometimes strabismus. For diagnosis, both methods of modern ophthalmology (Ishihar, Rabkin tests, electroretinography) and genetics are used – the study of hereditary anamnesis, sequencing of the sequence of genes associated with pathology. To date, there is no specific treatment, and gene therapy for some forms of achromatopsia is being developed.
Achromatopsia (rod monochromatism, color blindness) is a hereditary pathology in which the work of the cones – photoreceptors of the retina responsible for the perception of colors is disrupted. Complete achromatopsia is characterized by the loss of receptor function by all three types of cones – “blue”, “red” and “green”. The only photoreceptors of the retina are the rods that provide black-and-white vision. Traditionally, partial achromatopsia is isolated, in which only a certain type of cones is immune to light – “green” or “red”. Strictly speaking, partial achromatopsia is a monochromatism of “blue” cones, while some colors and shades fall out of perception, but in general color vision is preserved.
On average, the incidence of achromatopsia is approximately 1:300,000, with more than 70% of the total form of the disease. Complete rod monochromatism is inherited by autosomal recessive type, therefore it affects both men and women equally. Partial achromatopsia is a hereditary pathology linked to the X chromosome, because of this, the vast majority of patients are men. It is known that the famous scientist D. Dalton suffered from monochromatism of the “blue” cones, so in his honor such a violation is often called color blindness. Currently, color vision testing is a mandatory component of any preventive medical examination in ophthalmology, and persons with problems with color perception are limited in obtaining a driver’s license, working in some industries.
Causes of achromatopsia
Complete achromatopsia, or rod monochromatism, is a group of hereditary pathologies, each of which is caused by a mutation of a certain gene, all of them are inherited by an autosomal recessive type. These genes encode proteins that cause intracellular transmission of information from rhodopsin to the cell. A change in the conformation of rhodopsin under the influence of cells through a chain of proteins (G-protein – transducin – phosphodiesterase) leads to hyperpolarization of the photoreceptor membrane, this slows down the release of glutamate from it, causing the excitation of bipolar cells. The latter eventually transmit the action potential to the fibers of the optic nerve. Violation of the structure of the transmitter proteins in the cones due to mutation leads to the fact that in response to exposure to light and changes in the conformation of the photopigment protein, no cell reaction occurs and, as a consequence, a nerve impulse.
In this situation, the only active photoreceptors of the retina are rods, whose photopigment is not sensitive to a certain color, so these receptors perceive light waves of different lengths as different shades of gray. In addition to black-and–white vision, the absence of cones with complete achromatopsia leads to a central scotoma – there are practically no rods in the area of the macula. This, in turn, leads to impaired visual acuity, as it is provided by focusing light on the central part of the macula. Since the rods are generally more sensitive than cones (normally they provide night vision), with complete achromatopsia, photosensitivity sharply increases.
Partial achromatopsia, or color blindness, is caused by a mutation of genes localized on the X chromosome. These genes encode red (OPN1LW gene) or green (OPN1MW gene) cone photopigments. As a result of the violation of the structure, the pigment is no longer able to perceive light, which is why there is a violation of the perception of certain colors and shades. Since only about a third of the cones fall out of work with this disease, color vision is preserved, although somewhat changed. Visual acuity also suffers much less, not as with complete achromatopsia, photophobia is expressed.
Complete achromatopsia can be caused by mutations of several genes, it is on this basis that the classification of various forms of the disease is carried out. Taking into account the fact that clinically these forms have no differences, for a practicing geneticist and even more so, an ophthalmologist, such a separation, at first glance, is not essential. However, this is important for researchers searching for treatments for achromatopsia, as well as in the genetic diagnosis of the disease.
- ACHM2 type is caused by a mutation of the CNGA3 gene located on the 2nd chromosome and encoding the alpha-3 subunit of the G protein – the secondary messenger of cones.
- ACHM3 type is a mutation of the CNGB gene located on the 8th chromosome, it encodes the beta-3 subunit of the G protein.
- ACHM4 type is a mutation of the GNAT2 gene located on the 1st chromosome and encoding the alpha-3 subunit of the transducin protein.
- ACHM5 type is a mutation of the PDE6C gene located on the 10th chromosome, it encodes the alpha subunit of phosphodiesterase.
- ACHM6 type is a mutation of the PDE6H gene located on the 12th chromosome and encoding the gamma subunit of phosphodiesterase.
Thus, complete achromatopsia is caused by a violation of the transmission of information from rhodopsin to other structures of the photoreceptor due to a violation of the structure of intermediary proteins. Since these proteins are the same in all cones, all three types of these cells suffer. Unlike complete achromatopsia, with color blindness, the mutation occurs precisely in the gene of the photopigments themselves, the type of which divides the cones into three groups. The most common types of partial achromatopsia are:
- Protanopia is a red color immunity caused by a mutation of the OPN1LW gene located at the 28th locus of the X chromosome.
- Deuteranopia is a green color immunity, the mutation occurs in the OPN1MW gene located at the same 28th locus of the X chromosome.
Symptoms of achromatopsia
Most of the symptoms of achromatopsia are subjective, although there are a number of objective indicators of the disease. With complete achromatopsia, in addition to black-and-white vision, patients often have nystagmus and hyperopia. Due to the insensitivity to light of the photoreceptors of the macula (represented mainly by cones), visual acuity drops, often to the level of 0.1 and below. Achromatopsia also leads to increased sensitivity of the eyes to light and photophobia and daytime blindness (hemeralopia) developing against this background. Often the above symptoms are complicated by strabismus. Psychological factors also play an important role in complete achromatopsia – often a lowered look down (due to increased sensitivity to light), the need to wear dark glasses can depress the patient.
With incomplete achromatopsia, all of the above symptoms are observed, but in most cases they are much less pronounced. This is due to the fact that only a part of the photoreceptors (about a third of the cones) suffers, so visual acuity rarely drops below 0.3, photophobia and hemeralopia are less intense, farsightedness rarely develops. A subjective symptom will be a violation of color perception – for example, a patient with incomplete achromatopsia in the case of protanopia does not distinguish between green and red colors.
Diagnosis of achromatopsia
Diagnosis of achromatopsia is made on the basis of an examination by an ophthalmologist, as well as by studying the hereditary history and genetic studies. The main ophthalmological manifestation of the disease will be a violation of color perception, which is detected using Rabkin tables. In the presence of achromatopsia, patients become unable to distinguish numbers and other images in pictures made up of circles of a certain color. Using different types and colors of tables, an ophthalmologist can determine the form of achromatopsia – complete or incomplete (protanopia or deuteranopia). In addition, there will be changes in electroretinography – a decrease in the amplitude of cone peaks up to their complete disappearance with complete achromatopsia.
Genetic diagnostic methods are reduced to sequencing sequences of genes associated with achromatopsia in order to detect mutations. To help in the detection of the disease, a family history study can help to clarify the nature of the inheritance of pathology. Differential diagnosis should be carried out with some forms of retinal pigment abiotrophy – the initial manifestations of this disease may have symptoms similar to achromatopsia.
Treatment of achromatopsia
There is currently no specific treatment for any form of achromatopsia. Ongoing research in the field of gene therapy has partially restored the perception of colors in laboratory animals. To reduce other symptoms of achromatopsia (hyperopia, hemeralopia), corrective and sunglasses are used. Wearing glasses with neodymium glasses helps to slightly improve the perception of colors with incomplete achromatopsia – in some countries, patients with color blindness are even allowed to drive vehicles, provided they use such glasses.
In the presence of complete achromatopsia, the prognosis is more often unfavorable, since visual disturbances in such a disease tend to progress. However, the same glasses and other measures to improve the patient’s quality of life can slow down these processes. Supportive therapy based on vitamins A and E, vasodilators may also be prescribed. In the case of incomplete achromatopsia, a violation of color perception and a slight deterioration in vision do not lead to a serious condition of the patient.