Achromatopsia
Summary
Clinical characteristics.
Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe.
Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography.
Diagnosis/testing.
The diagnosis of achromatopsia is established in a proband through clinical and family history, examination for nystagmus, visual acuity testing, color vision assessment, and fundoscopic examination. If achromatopsia is suspected, additional testing may include optical coherence tomography, fundus autofluorescence, visual fields, and electroretinogram. Identification of biallelic pathogenic variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis.
Management.
Treatment of manifestations: Dark or special filter glasses or red-tinted contact lenses to reduce photophobia and potentially improve visual acuity; low vision aids; preferential classroom seating for children; occupational aids.
Surveillance: Ophthalmologic examination every six to 12 months for children and every two to three years for adults.
Genetic counseling.
Achromatopsia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants have been identified in the family.
Diagnosis
Suggestive Findings
Achromatopsia should be suspected in individuals with the following typical clinical findings, additional testing, and family history.
Clinical findings
- Pendular nystagmus
- Increased sensitivity to light (photophobia)
- Eccentric fixation
- Reduced visual acuity
- Reduced or complete lack of color discrimination
- Small central scotoma
- Fundus appearance: normal in many affected individuals, but can show subtle bilateral macular changes such as absence of the foveal reflex, pigment mottling, or narrowing of the retinal vessels. Frank atrophy of the retinal pigment epithelium (RPE) in the fovea can occur in older individuals.
Additional testing
Color vision tests. The color perception of individuals with achromatopsia (achromats) is unreliable; many achromats learn to associate certain colors with objects and to recognize some colors by discerning differences in brightness [Sharpe et al 1999]. In general, all achromats have anomalous (impaired) color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). The following results are found on standard testing for color vision:
- Generally, no specific axis of color confusion is found on the Farnsworth Munsell 100-hue test.
- An achromat axis (in which the constituent color chips are arranged according to their rod-perceived lightness) is characteristic for complete achromatopsia on both the saturated and desaturated versions of the Panel D-15 test.
- The most important and diagnostic test is red-green color discrimination with the Rayleigh anomaloscope equation. Although a complete achromat can always fully color-match the spectral yellow primary to any mixture of the spectral red and green primaries, a brightness match is only possible to red primary-dominated mixtures.
Visual field testing. Small central scotomas can be demonstrated in some individuals by careful testing. However, unsteady fixation can make demonstration of a central scotoma difficult.
Electroretinogram (ERG)
- Full-field ERG. The photopic response (including the 30-Hz flicker response) is absent or markedly diminished; the scotopic response is normal or mildly abnormal.
- 15-Hz flicker ERG. A typical finding is absence of the cone-driven fast pathway response elicited by high flash intensities [Bijveld et al 2011].
Optical coherence tomography (OCT). A variable degree of foveal hypoplasia as well as disruption and/or loss of inner-/outer-segment junction of the photoreceptors and an attenuation of the RPE layer within the macular region can be observed at an early age [Genead et al 2011, Thomas et al 2011, Sundaram et al 2014, Lee et al 2015, Zobor et al 2017].
Fundus autofluorescence imaging shows missing or variable formation of foveal hypofluorescence or a larger lesion with a surrounding hyperautofluorescent ring and a central region of absent autofluorescence corresponding to the lesion area seen on OCT [Greenberg et al 2014, Kohl et al 2015].
Adaptive optics imaging shows remnant cone structure; however, the number and spatial distribution of the foveal cones are highly variable – the foveal cone mosaic ranges from a contiguously packed mosaic to a sparsely arranged collection of cones [Langlo et al 2016].
Family history is consistent with autosomal recessive inheritance.
Establishing the Diagnosis
The clinical diagnosis of achromatopsia is established in a proband with typical findings on clinical examination, additional testing, and family history (see Suggestive Findings). Identification of biallelic pathogenic variants in one of the six genes listed in Table 1 establishes the molecular diagnosis.
Molecular genetic testing approaches can include targeted analysis for the common CNGB3 variant c.1148delC, use of a multigene panel, or comprehensive genomic testing (typically exome sequencing):
- Targeted analysis for the most common pathogenic variant c.1148delC in CNGB3 can be performed first in European populations or populations of European descent in the US, Canada, Australia, and New Zealand (see Molecular Genetics, CNGB3, Pathogenic variants).
- A multigene panel that includes ATF6, CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Comprehensive genomic testing does not require the clinician to determine which gene[s] are likely involved. Exome sequencing is most commonly used; genome sequencing can also be used.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Achromatopsia
| Gene 1 | Proportion of Achromatopsia Attributed to Pathogenic Variants in Gene 2 (Population) | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| ATF6 | 1.5% | 15/15 6 | None reported 7 |
| CNGA3 | 5%-33% (European) 84% (Israeli & Palestinian) 8 80% (Chinese) 9 | ~100% 10 | None reported 7 |
| CNGB3 | 60% (European) 16% (Israeli & Palestinian) 11 | ~95% 12 | 7 distinct deletions in 7 families; 3 duplications in 10 families 13 |
| GNAT2 | 1.8% | ~99% | 3 families 14 |
| PDE6C | 2.5% 15 | All reported 16 | None reported 7 |
| PDE6H | 0.1% | See footnote 17 | None reported 7 |
| Unknown | 10%-25% 18 | NA | |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
Mayer et al [2017] unless otherwise noted.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Ansar et al [2015], Kohl et al [2015], Xu et al [2015], Carss et al [2017], Skorczyk-Werner et al [2017]
- 7.
Larger deletions, insertions, or duplications have either not been reported or are confined to single reports or families [Rosenberg et al 2004]. Consequently, the prevalence and detection rate for such pathogenic variants cannot be estimated.
- 8.
Zelinger et al [2015]
- 9.
Kohl et al [1998], Wissinger et al [2001], Kohl et al [2005], Liang et al [2015], Zelinger et al [2015]
- 10.
Kohl et al [1998], Wissinger et al [2001], Johnson et al [2004], Tränkner et al [2004], Nishiguchi et al [2005], Varsányi et al [2005], Ahuja et al [2008], Koeppen et al [2008], Reuter et al [2008], Koeppen et al [2010], Thiadens et al [2010], Genead et al [2011], Vincent et al [2011]
- 11.
Kohl et al [2000], Kohl et al [2005], Thiadens et al [2009b], Zelinger et al [2015]
- 12.
Of 163 individuals with pathogenic variants in CNGB3, 105 (64%) were homozygotes for c.1148delC, 44 (27%) were compound heterozygotes, and in 14 (9%) only one pathogenic variant was identified [Mayer et al 2017].
- 13.
Kohl et al [2015], Mayer et al [2017]
- 14.
Rosenberg et al [2004]; S Kohl, unpublished data
- 15.
Chang et al [2009], Thiadens et al [2009a], Grau et al [2011], Huang et al [2013]
- 16.
Aligianis et al [2002], Kohl et al [2002], Michaelides et al [2003], Piña et al [2004], Rosenberg et al [2004], Ouechtati et al [2011], Langlo et al [2016], Bryant et al [2017], Carss et al [2017], Taylor et al [2017], Ueno et al [2017]
- 17.
A single nonsense variant has been reported in three families [Kohl et al 2012, Pedurupillay et al 2016].
- 18.
Kohl et al [2005], Thiadens et al [2009b]
Clinical Characteristics
Clinical Description
Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma (which is often difficult to demonstrate), eccentric fixation, and reduced or complete lack of color discrimination. Hyperopia is common. Nystagmus develops during the first few weeks after birth and is followed by increased sensitivity to bright light.
Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time, but both nystagmus and sensitivity to bright light may improve slightly. The fundus is usually normal, but macular changes and vessel narrowing may be present in some individuals, and optical coherence tomography (OCT) reveals macular changes that can progress with time [Thomas et al 2012].
Most individuals have complete achromatopsia, in which the symptoms can be explained by a total lack of function of all three types of cone (i.e., photopic) photoreceptors of the eye, with all visual functions being mediated by the rod (i.e., scotopic) photoreceptors.
Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning along with the rods. The symptoms are similar to those of individuals with complete achromatopsia but generally less severe [Sharpe et al 1999]. Color discrimination ranges from well preserved to severely impaired; photophobia is usually absent; visual acuity is better preserved than in complete achromatopsia.
Phenotype Correlations by Gene
Complete achromatopsia. The majority of individuals with biallelic pathogenic variants in ATF6, CNGA3, CNGB3, GNAT2, and PDE6C have complete achromatopsia with similar clinical features. A significant genotype-phenotype correlation cannot be observed; however, individuals with ATF6-associated achromatopsia usually have a poorly formed or absent foveal pit.
Incomplete achromatopsia
- Certain CNGA3 and GNAT2 pathogenic variants are associated with a very mild phenotype of incomplete achromatopsia and oligo-cone trichromacy [Rosenberg et al 2004, Vincent et al 2011].
- Pathogenic variants in PDE6H lead to the incomplete form of achromatopsia [Kohl et al 2012].
- Cone-rod dystrophy and macular dystrophy have been reported for pathogenic variants in ATF6 [Carss et al 2017, Skorczyk-Werner et al 2017].
Nomenclature
The complete form of achromatopsia is also referred to as rod monochromacy (monochromatism), complete (or total) color blindness (OMIM 216900), day blindness (hemeralopia), or "Pingelapese blindness." Clinically, it is known as typical, complete achromatopsia or complete achromatopsia with reduced visual acuity.
The incomplete form of achromatopsia is also known clinically as atypical, incomplete achromatopsia or incomplete achromatopsia with reduced visual acuity.
Prevalence
Achromatopsia is a rare disorder with an estimated prevalence of fewer than 1:30,000 [Sharpe et al 1999].
Parental consanguinity is common in certain geographic regions. On the island of Pingelap in the eastern Caroline Islands in Micronesia, the prevalence of achromatopsia is between 4% and 10%, secondary to the founder variant p.Ser435Phe in CNGB3 [Sharpe et al 1999].
Differential Diagnosis
Achromatopsia is readily recognized by its characteristic features (see Suggestive Findings). Conditions to consider in the differential diagnosis are congenital nystagmus (as nystagmus is usually one of the first manifestations) and cerebral achromatopsia or dyschromatopsia, which is associated with severe or total color vision deficits and can arise adventitiously after brain fever, cortical trauma, or cerebral infarction, especially involving lesions to the ventral occipital cortex [Bouvier & Engel 2006].
Inherited retinal dystrophies that may be confused with achromatopsia are summarized in Table 3.
Table 3.
Inherited Retinal Dystrophies to Consider in the Differential Diagnosis of Achromatopsia
| Disorder | Gene(s) | MOI | Overlapping Clinical Features | Distinguishing Clinical Features | Comments |
|---|---|---|---|---|---|
| Blue-cone monochromatism 1 (OMIM 303700) | OPN1LW; OPN1MW 2 | XL 3 |
| In blue-cone monochromatism:
|
|
| Hereditary red-green color vision defects (OMIM 303800, 303900) | OPN1LW, OPN1MW | XL | Color vision defects 5 | In hereditary red-green color vision defects:
|
|
| Tritan and yellow-blue defects (OMIM 190900) | OPN1SW | AD | Color confusion | In tritan & yellow-blue defects: color confusion is limited to blues & greens. 6 | Other non-congenital yellow-blue deficits (similar in some ways to tritan defects) may result from aging or disorders of choroid, pigment epithelium, retina, or optic nerve (e.g., optic atrophy type 1); they are usually progressive & have other related signs; e.g. associated visual acuity defects. 7 |
| Cone / cone-rod dystrophies 8 | ABCA4, AIPL1, CABP4, CNNM4, CDHR1, GUCY2D, KCNV2, RAB28, RPGRIP1 | AD, AR |
| Disease progression occurs in cone dystrophy & typically not in achromatopsia. |
|
| Leber congenital amaurosis (LCA) | AIPL1 CABP4 CEP290 GUCY2D RPGRIP1 | AR |
| Night blindness & progression occur in LCA. | In very young individuals |
| Bradyopsia; delayed cone adaptation | RGS9 |
| |||
| Alström syndrome 11 | ALMS1 | AR |
| Possible additional findings in Alström syndrome: cardiomyopathy, kidney failure, obesity, sensorineural hearing loss, diabetes | In young individuals |
AD = autosomal dominant; AR = autosomal recessive; ERG = electroretinogram; MOI = mode of inheritance; XL = X-linked
- 1.
Blue-cone monochromacy may also be referred to as S-cone monochromacy or X-chromosome-linked achromatopsia.
- 2.
The dysfunction of the L (red) and M (green) cones is caused by pathogenic variants leading to the loss of the X-linked red (OPN1LW) and green (OPN1MW) opsin gene array, hybrid gene formation and/or inactivating variants, or by deletions affecting the locus control region, a critical region that regulates the expression of the red/green (OPN1LW/OPN1MW) gene array.
- 3.
Blue-cone monochromacy affects mostly males.
- 4.
Sharpe et al [1999]
- 5.
Some males with mildly defective red-green color vision may not be aware of it until they are tested. Among individuals of northern European origin, about 8% of males and 0.5% of females have red-green color vision defects; these defects are less frequent among males of African (3%-4%) or Asian (3%) origin.
- 6.
Often referred to as yellow-blue disorders, although the color confusion is typically between blues & greens, tritan defects affect the S (blue) cones.
- 7.
Sharpe et al [1999]
- 8.
See Glöckle et al [2014], Weisschuh et al [2016], Carss et al [2017] for genes identified in patients misdiagnosed as having achromatopsia.
- 9.
Holopigian et al [2004]
- 10.
Aboshiha et al [2014]
- 11.
Nasser et al [2018]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with achromatopsia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Standard clinical ophthalmologic evaluation and testing with attention to visual acuity and use of spectacles and/or contact lenses to achieve the best possible corrected visual acuity
- Color vision evaluation
- Consultation with a clinical geneticist and/or genetic counselor as treatment could be possible in the near future (see Therapies Under Investigation)
Treatment of Manifestations
Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity.
Low vision aids include high-powered magnifiers for reading as well as digital/electronic devices.
Children with achromatopsia should have preferential seating in the classroom (i.e., in the front to benefit maximally from magnifying devices and away from windows to reduce the effects of glare on vision).
Extensive information about learning and occupational aids is available from the Achromatopsia Network (www.achromat.org).
Surveillance
Ophthalmologic examination is indicated:
- Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity;
- Every two to three years in adults.
Agents/Circumstances to Avoid
To avoid additional light damage to the retina, it is recommended that individuals wear appropriate protective (dark) glasses in bright light.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
In July 2012 a Phase I/II clinical trial (NCT01846052) investigating the therapeutic effects and safety of an intraocular implant releasing ciliary neurotrophic factor (CNTF) in individuals with CNGB3-related achromatopsia was started. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, photopic electroretinogram, or color hue discrimination. Subjectively, individuals reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, but slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors [Zein et al 2014].
Several interventional Phase I/II clinical safety and efficacy trials for gene replacement therapy using viral AAV vectors for CNGA3-related achromatopsia (NCT02610582, NCT02935517) and CNGB3-related achromatopsia (NCT02599922, NCT03278873, NCT03001310) are currently running and recruiting patients.
In addition, clinical observational trials have been or are recruiting individuals for clinical assessment to establish the natural history of achromatopsia (NCT02435940, NCT01846052).
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.