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 has a uniquely high achromatopsia prevalence, an observation popularized by the late author Oliver Sacks’ book ‘The Island of the Colorblind.’ Since a typhoon in the late 1700s that dramatically reduced the population, the prevalence of achromatopsia has risen 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. 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 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 course and later patients can 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, and eventually degrade with time resulting in these structural changes without a 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 and any underlying amblyopia can be managed with occlusion or atropine therapy. Clinical research trials, low vision and genetic counselling should be considered for the appropriate patient and 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 clinical research trials are underway and a list 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 good candidate 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. 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 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. Use of filters of light to reduce photophobia is also being tried 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.
Fortunately, the disease is very slowly progressive, if at all, and patients can typically maintain the vision that develops during childhood.
- ↑ Aboshiha J, Dubis AM, Carroll J, Hardcastle AJ, Michaelides M. The cone dysfunction syndromes. Br J Ophthalmol. 2016;100(1):115-121.
- ↑ Sheffield VC. The vision of typhoon lengkieki. Nat Med. 2000 Jul;6(7):746-7.
- ↑ Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jägle H, et al. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet. 2005 Mar;13(3):302-8.
- ↑ Kohl S, Marx T, Giddings I, Jägle H, Jacobson SG, Apfelstedt-Sylla E, et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet. 1998 Jul;19(3):257-9.
- ↑ Felden J, Baumann B, Ali M, et al. Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene. Hum Mutat. 2019;40(8):1145-1155. doi:10.1002/humu.23768
- ↑ Weisschuh N, Stingl K, Audo I, et al. Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Hum Mutat. 2018;39(10):1366-1371. doi:10.1002/humu.23606
- ↑ Ritter M, Arno G, Ba-Abbad R, Holder GE, Webster AR. Macular maldevelopment in ATF6-mediated retinal dysfunction. Ophthalmic Genet. 2019;40(6):564-569. doi:10.1080/13816810.2019.1706749
- ↑ Flynn JT, Kazarian E, Barricks M. Paradoxical pupil in congenital achromatopsia. Int Ophthalmol. 1981 Mar;3(2):91-6.
- ↑ Oh JK, Ryu J, Lima de Carvalho JR,Jr, Levi SR, Lee W, Tsamis E, et al. Optical Gap Biomarker in Cone-Dominant Retinal Dystrophy. Am J Ophthalmol. 2020 May 20.
- ↑ Greenberg JP, Sherman J, Zweifel SA, et al. Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia. JAMA Ophthalmol. 2014;132(4):437-445. doi:10.1001/jamaophthalmol.2013.7987
- ↑ Zobor D, Werner A, Stanzial F, et al. The Clinical Phenotype of CNGA3-Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial. Invest Ophthalmol Vis Sci. 2017;58(2):821-832. doi:10.1167/iovs.16-20427
- ↑ Aboshiha J, Dubis AM, Cowing J, et al. A prospective longitudinal study of retinal structure and function in achromatopsia. Invest Ophthalmol Vis Sci. 2014;55(9):5733-5743. Published 2014 Aug 7. doi:10.1167/iovs.14-14937
- ↑ Fischer MD, Michalakis S, Wilhelm B, Zobor D, Muehlfriedel R, Kohl S, et al. Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol. 2020 Apr 30;138(6):1-9.
- ↑ “Use of modified X-Chrom for relief of light dazzlement and color blindness of a rod monochromat.” JAOA 1979;50(7)
- ↑ Schornack MM, Brown WL, Siemsen DW. The use of tinted contact lenses in the management of achromatopsia. Optometry. 2007;78(1):17-22. doi:10.1016/j.optm.2006.07.012
- ↑ Gómez-Robledo L, Valero EM, Huertas R, Martínez-Domingo MA, Hernández-Andrés J. Do EnChroma glasses improve color vision for colorblind subjects?. Opt Express. 2018;26(22):28693-28703. doi:10.1364/OE.26.028693