Achromatopsia

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Achromatopsia is a rare inherited disorder of vision featured by a partial or total loss of color vision, accompanied by photophobia, nystagmus, and reduced visual acuity. This disorder is inherited in an autosomal recessive pattern and results from either poor functioning or lack of functioning of the cones. Several mutations have been identified, and the diagnosis is made based on clinical and diagnostic findings, while genetic testing is available to detect mutations. Current treatment includes supportive measures.

Achromatopsia arises due to the following process: hereditary.

Presentation

Patients with achromatopsia develop symptoms at birth, and the hallmark of this genetic disorder is a complete loss of color vision [9]. In some cases, color vision loss may be partial, while other symptoms include blurred vision, nystagmus, and photophobia, which may be particularly debilitating and can be accompanied by pain [10]. Frequent quivering or squinting may be signs of achromatopsia in infants and young children. Because of the non-progressive nature of the disease, symptoms are usually constant, they neither progress nor do they regress spontaneously.

Workup

In any patient with disturbances of vision, a detailed ophthalmoscopic workup is necessary to establish the cause of the complaints. In all patients except neonates and young infants, color vision tests may be performed, to confirm the absence of color vision [11], such as the Ishihara color plates.

Electroretinogram (ERG) is a diagnostic method which evaluates the function of retinal cells, including cones, and electrical stimuli are used to assess the status of the cones in the patients [12]. In virtually all cases, this test can detect loss of cone function. It is a procedure that can be performed in patients of all ages and can be useful for the diagnosis of achromatopsia in infants and young children.

Genetic testing can be performed in patients in whom the loss of cone function is confirmed through clinical findings and diagnostic procedures.

In addition to diagnostic techniques, family history of the patients should be obtained in detail, to identify other close relatives with similar symptoms, or those who have already been diagnosed with the disease.

Treatment

Current treatment of achromatopsia involves management of symptoms, through the use of tinted or filter lenses in different colors, which can effectively reduce photophobia and light sensitivity, while improving visual acuity [13]. By using different types of lenses, visual acuity can be partially or completely corrected, thus reducing the burden of this disease to a minimum. Occupational exposure to lighting can be adapted, depending on the occupation. With the help of optical aids, as well as aforementioned techniques, this disease may not be all that debilitating for the patient.

Identification of gene mutations in the majority of patients with achromatopsia has led to the development of gene therapy as a potential therapeutic strategy, and significant progress has been made in animal models [14]. Through injection of "normal" gene into an adeno-associated virus underneath the fovea centralis, into the retina, has led to improvement in visual function, and normal functioning of CNGB3, which presents as a major step in creating gene therapy as a definite measure for patients with this genetic disorder. Still, significant steps have to be made in order for this therapy to be used in everyday medical practice.

Prognosis

Achromatopsia is not a progressive disease. It does not affect any other system or organ and is not life-threatening. Several strategies have been developed to reduce the burden of photophobia and impaired visual acuity, especially in bright light.

Etiology

This disease is of genetic origin and is transmitted in an autosomal recessive manner. Several genes have been identified, which have been reported to be responsible for formation and function of ion channels in cones, as well as transmission of the light signal to the occipital cortex. Their mutations have been observed and confirmed as a cause in this genetic disease [2] [3]. Although achromatopsia is usually considered to be genetic in origin, acquired forms of achromatopsia, such as cerebral achromatopsia, which occurs as a result of extensive damage within the occipital lobe, where the primary visual cortex is located, have also been documented [4]. The cause is most likely trauma, but other causes may be considered as well.

Epidemiology

The prevalence rates of achromatopsia vary throughout different regions of the world, but it occurs in approximately 1 in 30,000 individuals [5], with the majority of patients developing complete achromatopsia rather than partial. This disorder has been established to occur more frequently in consanguineous marriages, and prevalence rates between 4% and 10% are observed among Pingelapese islanders living in Micronesia due to a high rate of consanguineous marriages. Neither racial nor gender predilection have been established.

Sex distribution
Age distribution

Pathophysiology

Under physiological conditions, the retina contains cells that are responsible for vision - rods which are the most numerous cells in the retina, and are responsible for formation of peripheral and light-sensitive vision; and cones, which are responsible for color and high-resolution vision, and are further divided into red, blue, and green cones. The concentration of the cones is highest in the central part of the retina, the fovea centralis. The signal from the cones is transmitted principally through glutamate, the main excitatory neurotransmitter in the central nervous system [6].

In patients who develop mutations in the genes responsible for the normal development of cones and proper color vision, which is the case in achromatopsia, the partial or total absence of functioning of cone cells in the retina lead to distorted color vision. Namely, mutations in genes responsible for normal ion channel functioning (cyclic nucleotide-gated ion channels, or CNGs), and concentrations in cyclic guanosine monophosphate (cGMP) have been established, and the pathogenesis of achromatopsia involves reduced levels of cGMP, resulting in hyperpolarization with no release of glutamate [7]. As a result, ion permeability and the efficacy of signal transduction is reduced, eventually leading to complete loss of cone function and color blindness. Specifically, mutations in CNGA3, CNGB3, or mutations in genes responsible for phosphodiesterase (PDE), e.g. PDE6C and PDE6H have been reported, and all are involved in the mediation of opening the ion channels [8].

Prevention

Currently, genetic forms of achromatopsia cannot be prevented, while the burden of acquired forms can be reduced through protection against brain damage, through various measures (wearing of protective equipment in contact sports or in other circumstances in which accidental head trauma may occur)

Summary

Achromatopsia is a rare genetic disease which results primarily in a loss of vision that may be either partial or total, depending on the severity of the disease [1]. Several gene mutations have been reported. This disease is transmitted in an autosomal recessive pattern. The disorder occurs either due to partial or total loss of cone function. The cones are located in the fovea centralis of the retina. This disorder is seen in about 1 in 30,000 individuals, but prevalence rates vary throughout the world. Complete achromatopsia is the most common variant observed. Additional symptoms include reduced visual acuity (since cones are also important mediators of fine-detail vision), nystagmus, pronounced photophobia. The diagnosis is made through clinical symptoms, while family history may reveal members with achromatopsia, and through the use of several ophthalmologic tests, such as ophthalmoscopy, visual acuity testing, and electroretinogram to evaluate the function of rods and cones. Genetic testing is available to confirm the diagnosis based on the history, signs, and symptoms. Current treatment strategies include management of symptoms, such as correction of visual acuity, wearing tinted lenses or glasses, to reduce photophobia and improve fine-detail vision. However, gene therapy has shown promising results in animal models and may serve as a potential therapeutic strategy in the near future.

Patient Information

Achromatopsia is an inherited genetic disorder that results in partial or total loss of color vision. This disorder is transmitted from parents to children in an autosomal recessive pattern, which implies that both parents need to have mutated copies of the genes responsible for this disease. In a majority of the cases, parents do not have signs of the disease, but each carries one copy of the mutated genes. Therefore, there is a 1 in 4 chance that their child will develop this disease.

Achromatopsia develops as a result of several established gene mutations, and in this disease, color vision loss occurs because of poor functioning of cells called cones, in the eyes. They are responsible for color vision . But since cones are also responsible for high-resolution vision, patients may often report blurred vision, accompanied with either farsightedness or nearsightedness, as well as increased sensitivity to light (termed photophobia) and involuntary eye movements (nystagmus). This disorder is considered to be rare, and approximately 1 in 30,000 individuals develop this condition.

Patients who report visual disturbances must undergo detailed inspection and examination of eyes, and ophthalmologic examination, usually accompanied with color vision tests that will confirm the absence of color vision. Electroretinogram is a technique which uses electric stimuli to evaluate the functions of the cells in the retina, and this test usually shows the absence of activity of the cells responsible for color vision. Since several gene mutations have been reported, genetic testing can confirm the diagnosis of achromatopsia.

Advances have been made in the field of gene therapy, but current therapeutic strategies include only symptomatic management, through the use of tinted or colored lenses, to aid patients with light sensitivity, and to improve visual acuity.

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References

  1. Pokorny J, Smith VC, Pinckers AJ, et al. Classification of complete and incomplete autosomal recessive achromatopsia. Graefes Arch Clin Exp Ophthalmol. 1982;219:121–30.
  2. Wissinger B, Jagle H, Kohl S, et al. Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2q11. Genomics. 1998;51:325–31.
  3. Wissinger B, Gamer D, Jägle H, et al. CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet. 2001;69:722–37.
  4. Meadows JC. Disturbed perception of colours associated with localized cerebral lesions. Brain. 1974;97:615–32.
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  7. Tränkner D, Jägle H, Kohl S et al. Molecular basis of an inherited form of incomplete achromatopsia. J Neurosci. 2004;24(1):138–47.
  8. Bright SR, Brown TE, Varnum MD. Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels. Mol Vis. 2005;11:1141–50.
  9. Zlotogora J. Hereditary disorders among Iranian Jews. Am J Med Genet. 1995;58:32-37.
  10. Kohl S, Marx T, Giddings I, et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nature Genet. 1998;19:257-259.
  11. Mollon JD, Reffin JP. A computer-controlled colour vision test that combines the principles of Chibret and of Stilling. J Physiol. 1989;414:5P.
  12. Marmor MF, Zrenner E. Standard for clinical electroretinography (1994 update). Doc Ophthalmol. 1995;89:199–210.
  13. Zeltzer HI. Use of modified X-chrom for relief of light dazzlement and color blindness of a rod monochromat. Journal of the American Optometric Association. 1979;50:813-816.
  14. Komáromy AM. Gene therapy rescues cone function in congenital achromatopsia. Human Molecular Genetics. 2010;19:2581-2593.

  • A quantitative scoring technique for panel tests of color vision. - AJ Vingrys, PE King-Smith - Investigative ophthalmology & visual science, 1988 - ARVO


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