Achromatopsia is recognized by the codes per the International Classification of Diseases (ICD) nomenclature.
Achromatopsia is a rare, bilateral inherited retinal degeneration affecting all three types of cone photoreceptor cells that results in reduced visual acuity, photophobia, hemeralopia, and severe loss of color discrimination. The disease can be complete with total lack of cone function, also known as rod monochromacy, or incomplete with reduced cone function. Retinal achromatopsia is distinct from cerebral achromatopsia, the latter of which consists of poor color discrimination due to cerebral pathology. Achromatopsia is also distinguished from more common forms of color blindness by the fact that all three types of cones are defective.
Achromatopsia is estimated to affect approximately 1 in 30,000 individuals worldwide.
The island of Pingelap in the country of Micronesia has a uniquely high achromatopsia prevalence, an observation popularized by the late author Oliver Sacks’ book ‘The Island of the Colorblind.’ After a typhoon in the late 1700s that dramatically reduced the population, the prevalence of achromatopsia rose to almost 10% due to a founder effect and high homozygosity of a mutation in CNGA3.
This autosomal recessive disease affects all three types of retinal cones. The most common mutations affect genes that code for or regulate cone cyclic nucleotide-gated (CNG) cation channel subunits, including CNGB3 in 50% of cases and CNGA3 in 25% of cases. To date, nearly 100 mutations in CNGA3 and CNGB3 have been linked to achromatopsia in humans.  The CNG channels are located on photoreceptor outer segment cell membranes and are involved in signal transduction. These mutations result in a significant decline in cone function. Other implicated genes accounting for a smaller fraction of achromatopsia cases include GNAT2, PDE6C, PDE6H and ATF6.
Patients typically present at a young age with hemeralopia, glare, decreased visual acuity, absent or diminished color vision and pendular nystagmus. Nystagmus often develops within the first several weeks of life and is commonly the first symptom noted by parents or pediatricians. Patients with achromatopsia also have a high rate of hyperopia requiring spectacle correction.
There are no systemic abnormalities associated with achromatopsia and patients can expect a normal life expectancy.
Visual acuity ranges from 20/200 or worse in complete achromatopsia to 20/80 in incomplete achromatopsia. Color vision testing is severely or completely diminished and pupillary exam in children can demonstrate a paradoxical pupil, where the pupil initially constricts on dimming of light. Fundus exam can appear normal early in the disease course. Later on, patients may develop retinal pigment epithelial mottling and atrophy. 
Electroretinography (ERG) is the gold standard for the diagnosis of achromatopsia. Cone function is severely or completely diminished while rod function is normal.
Optical coherence tomography (OCT) can provide diagnostic assistance as well as insight into the structure of dysfunctional cone cells. A hyporeflective “optical gap” can be found at the fovea that corresponds to foveal loss of photoreceptor outer segments. This finding is not specific to achromatopsia and can be seen in other retinal degenerations such as Stargardt’s disease, occult macular dystrophy and cone dystrophies. Eventually the hyporeflective area involutes as seen in Figure 1. The disease has been described to go through sequential stages that can be followed on OCT (Table 1). However, a functional decline association with this proposed sequence has not been found. The cones may be nonfunctional at birth but still physically present - degradation over time may result in these structural changes without a corresponding change in function. The OCT stages may also not be sequential for all patients and could represent the end-stages of different degrees of cone dysfunction.
Table 1. OCT stages of Achromatopsia
|1||Intact outer retina|
|2||Ellipsoid zone disruption|
|3||Optically empty space|
|4||Optically empty space with partial retinal pigment epithelium disruption|
|5||Outer nuclear layer loss and/or complete retinal pigment epithelial disruption|
Patients often have some degree of foveal hypoplasia. On ERG, cone function is completely or almost completely extinguished with a normal or mostly normal rod function.
Currently there is no approved treatment for achromatopsia. Children should be monitored for associated high hyperopia that can be corrected with spectacles or contacts; howeveer, a wide range of refractive errors have been reported, with myopia occurring in some patients. Any underlying amblyopia can be managed with occlusion or atropine therapy. Clinical research trials, low vision and genetic counseling should be considered for patients and their families.
Genetic testing can help confirm the diagnosis and provide parents with information regarding the risk to other children. A molecular diagnosis is also typically required for consideration of ongoing clinical research trials.
Several phase I/II clinical trails assessing the effectiveness of gene therapy for achromatopsia are currently ongoing. A list can can be found through clinicaltrials.gov: Achromatopsia trials.
Gene therapy is emerging as a promising therapeutic tool across medicine and particularly in the field of inherited retinal diseases. Achromatopsia may be a particularly suitable condition for gene therapy as the structural loss of dysfunctional cone photoreceptors occurs relatively late in the disease course. Cone photoreceptors are therefore available for transduction over a longer time period, in contrast to other inherited retinal dystrophies with earlier outer retinal degeneration. A series of 9 patients, published in April of 2020, was found to have promising results following subretinal adenoviral gene therapy targeting CNGA3, with cone photoreceptor activation and improved vision in some adult patients. Some remaining challenges for gene therapy include genetic heterogeneity, surgical challenges in young eyes, development of amblyopia prior to treatment, and need for long-term efficacy.
For patients with the ATF6 mutation, a small trial at Columbia will be investigating gylcerol phenylbutyrate (PBA).
Referral to a low vision specialist can be considered, where tinted glasses or contacts can help with debilitating hemeralopia and individualized training can help patients function with low vision. Glasses that are reported to help with color discrimination are currently under investigation, but primarily in red-green color deficiencies. Electronic devices that aid with color discrimination are also being investigated. The use of filters of light to reduce photophobia is also being tested and may involve reducing the stimulation of photoreceptors.
The disease is autosomal recessive and referral to a genetic counselor should be considered for patients and family members.
Patients typically maintain the vision that develops during childhood. Although symptomatically patients often remain stable, several studies have suggested that age-related development of foveal structural changes may indicate a slowly progressive degeneration and loss of cone photoreceptor cells in affected patients.  A longitudinal study of 17 patients in Italy found a slow deterioration of the macular structure in the years following diagnosis.
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