Clinical Diagnosis

The clinical diagnosis of achromatopsia is based on the presence of typical clinical findings:

• Reduced visual acuity
• Pendular nystagmus
• Increased sensitivity to light
• Small central scotoma
• Eccentric fixation
• Reduced or complete loss of color discrimination

The following also contribute to the diagnosis:

• 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 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.
• Electrophysiology. In the single-flash electroretinogram (ERG), the photopic response (including the 30-Hz flicker response) is absent or markedly diminished while the scotopic response is normal or mildly abnormal.
• Fundus appearance. Many affected individuals have a normal-appearing fundus. Others 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 in the fovea can occur in older individuals.
• Visual fields. Small central scotomas can be demonstrated in some individuals by careful testing. However, unsteady fixation can make demonstration of a central scotoma difficult.
• Family history is consistent with autosomal recessive inheritance.
• Psychophysical tests, available in specialized centers but not necessary for diagnosis, include the following:
  • Absence of the Kohlrausch kink (cone-rod break) in the dark-adaptation curve in complete achromatopsia
  • Peaking of photopic luminosity or brightness measured as a function of spectral wavelength, whether by flicker photometry, incremental thresholds, or by side-by-side matching, at 507 nm (the peak wavelength of the rod or scotopic visual system) instead of at 555 nm (the peak wavelength of the cone or photopic visual system)

Molecular Genetic Testing

Genes. To date, mutations in the following four genes are known to be associated with autosomal recessive achromatopsia:

• CNGB3. ~50% of affected individuals [Kohl et al 2000, Kohl et al 2005]
• CNGA3. ~25% of affected individuals [Kohl et al 1998, Wissinger et al 2001]
• GNAT2. ~1% of affected individuals [Aligianis et al 2002, Kohl et al 2002]
• PDE6C. ~1% of affected individuals [Thiadens et al 2009, Chang et al 2009]

Other loci. An additional locus (ACHM1) had been assigned to chromosome 14 as a result of a single case of maternal uniparental isodisomy of chromosome 14. This locus had to be revised as the patient described in the original report was later shown to be homozygous for c.1148delC, the most common mutation in CNGB3 [Wiszniewski et al 2007].

Clinical testing

• Targeted mutation analysis. Targeted mutation analysis for the most common mutation in CNGB3 is available on a clinical basis. The 1-bp deletion, c.1148delC (p.Thr383IlefsX13), accounts for more than 70% of all mutant CNGB3 alleles [Kohl et al 2005].
• Sequence analysis. Sequence analysis of CNGA3, CNGB3, GNAT2, and PDE6C is available on a clinical basis.

Table 1. Summary of Molecular Genetic Testing Used in Achromatopsia

View in own window

Gene Symbol	Proportion of Achromatopsia Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
CNGB3	~50%	Targeted mutation analysis	c.1148delC 2	100% for the targeted variant	Clinical
		Sequence analysis	Sequence variants 3	>95% 4
CNGA3	~25%	Sequence analysis	Sequence variants 3	>95%	Clinical
GNAT2	<2%	Sequence analysis	Sequence variants 3	>95%	Clinical
PDE6C	<2%	Sequence analysis	Sequence variants 3	>95%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. This mutation accounts for 70%-75% of all CNGB3 mutant alleles and ~40% of all achromatopsia-related alleles.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Of 163 individuals with mutations in CNGB3, 105 (64%) were homozygotes, 44 (27%) were compound heterozygotes, and in 14 (9%) only one mutation was identified [Kohl et al 2005].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband, the order of molecular genetic testing is the following:

1.

Targeted mutation analysis for the most common mutation c.1148delC in CNGB3

2.

Sequence analysis of CNGA3

3.

Sequence analysis of CNGB3

4.

Sequence analysis of GNAT2

5.

Sequence analysis of PDE6C

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

CNGB3

• In a few individuals, progressive cone dystrophy has been associated with mutations in CNGB3 [Michaelides et al 2004].
• Macular degeneration has been described in some individuals [Nishiguchi et al 2005].

CNGA3. In a few individuals, progressive cone dystrophy has been associated with mutations in CNGA3 [Wissinger et al 2001, Nishiguchi et al 2005]. However, the differentiation from achromatopsia can be difficult and the diagnosis of cone dystrophy can often only be established by the observation of disease progression (see Differential Diagnosis).

CNGB3. In a comprehensive screen of individuals affected by progressive cone dystrophy, mutations in CNGB3 were identified [Thiadens et al 2010].

GNAT2. A mild phenotype best characterized as oligocone trichromacy has been described [Rosenberg et al 2004].

PDE6C. In one family a clinical diagnosis of early-onset cone dystrophy associated with the homozygous mutation p.Arg29Trp in PDE6C was established [Thiadens et al 2009]

Natural History

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 loss 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.

Most individuals have complete achromatopsia, in which the symptoms can be explained by a total lack of function of all three types of cone (or photopic) photoreceptors of the eye, with all visual functions being mediated by the rod (or 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.

Genotype-Phenotype Correlations

In the majority of individuals affected by autosomal recessive achromatopsia, mutations in one of the four reported genes result in the complete form of the disorder. Yet CNGA3, CNGB3 and PDE6C mutations can also lead to autosomal recessive progressive cone dystrophy [Jägle et al 2001, Wissinger et al 2001, Michaelides et al 2004, Trankner et al 2004, Thiadens et al 2009, Thiadens et al 2010]. A splice mutation in GNAT2 is associated with the milder phenotype of incomplete achromatopsia (oligo cone trichromacy) [Rosenberg et al 2004].

Nomenclature

The complete form of autosomal recessive 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 autosomal recessive achromatopsia is also known clinically as atypical, incomplete achromatopsia or incomplete achromatopsia with reduced visual acuity.

Prevalence

Autosomal recessive achromatopsia is a rare disorder with an estimated prevalence of less than 1:30,000 [Sharpe et al 1999].

Parental consanguinity is common in certain geographical 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 mutation p.Ser435Phe in CNGB3 [Sharpe et al 1999].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with achromatopsia, the following evaluations are recommended:

• Standard clinical ophthalmologic evaluation and testing
• Electrophysiologic examination
• Color vision evaluation
• Dark adaptometry

Treatment of Manifestations

Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity [Park & Sunness 2004].

Low vision aids include high-powered magnifiers for reading. Children with achromatopsia should have preferential seating in the front of the class to benefit maximally from their magnifying devices.

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 and to achieve the best possible 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.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Achromatopsia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• 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.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with achromatopsia are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for family members at risk for CNGA3, CNGB3, or PDE6C mutations is possible if the disease-causing mutations in the family are known.

Carrier testing using molecular genetic techniques for GNAT2 is not offered because it is not clinically available.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for achromatopsia 2, 3, 4, or 5 (CNGA3, CNGB3, GNAT2, or PDE6C mutations) is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

CNGA3, CNGB3, GNAT2 and PDE6C are all expressed in the cone photoreceptor and are crucial for cone phototransduction: light-excited cone visual pigment molecules induce the exchange of GDP to GTP at the guanosine binding site of the transducin alpha subunit (GNAT2) and its subsequent release from the inhibitory beta/gamma subunits. The activated GTP-transducin then binds and activates the alpha’-subunit of the cone phosphodiesterase (PDE6C) by retracting the inhibitory gamma-subunit. PDE hydrolyzes cGMP and effectively reduces its intracellular concentration. This results in the closure of the hetero-tetrameric cGMP-gated cation channels (CNGA3/CNGB3) and, subsequently, membrane hyperpolarization [Lamb & Pugh 2006]. Transducin thus mediates the first step, PDE6C the intermediate, while the cGMP-gated channel represents the final component of the phototransduction cascade.

Functional analysis by heterologous expression of mutant CNG channels has shown that in many cases channel function is strongly impaired or completely absent (see CNGA3 Abnormal gene product, CNGB3 Abnormal gene product).

In addition, animal models may help to clarify the underlying pathogenic mechanisms. The analysis of the orthologous Cnga3 knockout mouse model shows complete absence of physiologically measurable cone function, a decrease in the number of cones in the retina, and morphologic abnormalities of the remaining cones. Cnga3^(-/-) cones fail to transport opsin into the outer segment and down-regulate various proteins of the phototransduction cascade. An apoptotic cell death is induced; however, loss of Cnga3 does not seem to affect the transcription of other cone-specific genes. Cone degeneration in the Cnga3 knockout animals is evident from the second postnatal week on and proceeds significantly faster in the ventral than in the dorsal part of the retina. In addition, Cnga3 appears to be essential for normal postnatal migration of cone somata [Biel et al 1999, Michalakis et al 2005].

Two naturally-occurring canine models for CNGB3 have been identified. It has been shown that autosomal recessive canine cone degeneration (cd) in the Alaskan malamute and the German shorthaired pointer breeds is caused by mutations in canine CNGB3 [Sidjanin et al 2002]. In the Alaskan malamute, cone-degenerate pups develop dayblindness and photophobia. Symptoms are present only in bright light; vision in dim light is normal. Affected dogs remain ophthalmoscopically normal throughout life. Cone function, detectable on electroretinogram in very young cd-affected pups, begins to fail at a few weeks' age and is undetectable in mature cd-affected dogs. Adult cd-affected retinas lack all cones. Cones degenerate by extrusion of the nucleus into the inner segment and later displacement of the cone nuclei in the interphotoreceptor space. Genetic analysis has shown that in the Alaskan malamute the disease is caused by deletion of the complete gene, while in the German shorthaired pointers, the disease is caused by a missense mutation.

The mouse model Gnat2(cpfl3) (cpfl3 = cone photoreceptor function loss, 3) for achromatopsia related to GNAT2 mutations carries a homozygous missense mutation c.598G>A (p.Asp200Asn) in exon 6 of murine Gnat2 [Chang et al 2006]. Homozygous cpfl3 mice have poor cone-mediated responses on ERG at three weeks that become undetectable by nine months. Rod-mediated waveforms are normal, but decline with age in Gnat2(cpfl3) mice but also wild type litter mates. Microscopy of the retina reveals progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers show progressive loss of labeling for Gnat2 protein, but the cone outer segments in the oldest mice examined remain intact and positive for peanut agglutinin (PNA) [Chang et al 2006].

The cone photoreceptor function loss 1 (cpfl1) mouse mutant is a model for achromatopsia related to mutations in Pde6c [Chang et al 2009], due to the presence of a 116-bp insertion between exon 4 and 5 (c.864_865ins116) and an additional 1-bp deletion in exon 7 (c.1042delT) in cis (on the same allele) in the cpfl1 mouse. The mutations result in a frame-shift introducing a premature termination codon (p.Glu289fsX297). The phenotype can be easily typed by electroretinography (ERG) as early as age three weeks. While dark-adapted ERG responses are normal, light-adapted responses representing cone function are virtually absent. Histology of cpfl1 mouse retinae revealed grossly normal morphology and layering. However, as early as age three weeks, there was vacuolization of a small subset of cells in the photoreceptor layer with subsequent rapid, progressive depletion of cone photoreceptors. In addition, some swollen and pyknotic nuclei were observed in the inner nuclear layer. Loss of cones further proceeds so that only very few could be detected in retinal sections of five-month-old animals [Chang et al 2009].

Literature Cited

1. Ahuja Y, Kohl S, Traboulsi EI. CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis. 2008;14:1293–7. [PMC free article: PMC2464613] [PubMed: 18636117]
2. Alexander KR, Fishman GA. Br J Ophthalmol. 1984;68:69–78. [PMC free article: PMC1040261] [PubMed: 6607068]
3. Aligianis IA, Forshew T, Johnson S, Michaelides M, Johnson CA, Trembath RC, Hunt DM, Moore AT, Maher ER. Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2). J Med Genet. 2002;39:656–60. [PMC free article: PMC1735242] [PubMed: 12205108]
4. Ben Salah S, Kamei S, Sénéćhal A, Lopez S, Bazalgette C, Bazalgette C, Eliaou CM, Zanlonghi X, Hamel CP. Novel KCNV2 mutations in cone dystrophy with supernormal rod electroretinogram. Am J Ophthalmol. 2008;145:1099–106. [PubMed: 18400204]
5. Biel M, Seeliger M, Pfeifer A, Kohler K, Gerstner A, Ludwig A, Jaissle G, Fauser S, Zrenner E, Hofmann F. Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. Proc Natl Acad Sci U S A. 1999;96:7553–7. [PMC free article: PMC22124] [PubMed: 10377453]
6. Bouvier SE, Engel SA. Behavioral deficits and cortical damage loci in cerebral achromatopsia. Cereb Cortex. 2006;16:183–91. [PubMed: 15858161]
7. 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. [PubMed: 16379026]
8. Cai K, Itoh Y, Khorana HG. Mapping of contact sites in complex formation between transducin and light-activated rhodopsin by covalent crosslinking: use of a photoactivatable reagent. Proc Natl Acad Sci U S A. 2001;98:4877–82. [PMC free article: PMC33131] [PubMed: 11320237]
9. Chang B, Dacey MS, Hawes NL, Hitchcock PF, Milam AH, Atmaca-Sonmez P, Nusinowitz S, Heckenlively JR. Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci. 2006;47:5017–21. [PubMed: 17065522]
10. Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, Wissinger B. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A. 2009;106:19581–6. [PMC free article: PMC2780790] [PubMed: 19887631]
11. Faillace MP, Bernabeu RO, Korenbrot JI. Cellular processing of cone photoreceptor cyclic GMP-gated ion channels: a role for the S4 structural motif. J Biol Chem. 2004;279:22643–53. [PubMed: 15024024]
12. Gouras P, Eggers HM, MacKay CJ. Cone dystrophy, nyctalopia, and supernormal rod responses. A new retinal degeneration. Arch Ophthalmol. 1983;101:718–24. [PubMed: 6601944]
13. Grau T, Artemyev NO, Rosenberg T, Dollfus H, Haugen OH, Cumhur Sener E, Jurklies B, Andreasson S, Kernstock C, Larsen M, Zrenner E, Wissinger B, Kohl S. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia. Hum Mol Genet. 2010 Dec 13. [Epub ahead of print] [PMC free article: PMC3269206] [PubMed: 21127010]
14. Holopigian K, Greenstein VC, Seiple W, Hood DC, Carr RE. Rod and cone photoreceptor function in patients with cone dystrophy. Invest Ophthalmol Vis Sci. 2004;45:275–81. [PubMed: 14691184]
15. Jägle H, Kohl S, Apfelstedt-Sylla E, Wissinger B, Sharpe LT. Manifestations of rod monochromacy. Col Res Appl. 2001;26:S96–9.
16. Johnson S, Michaelides M, Aligianis IA, Ainsworth JR, Mollon JD, Maher ER, Moore AT, Hunt DM. Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet. 2004;41:e20. [PMC free article: PMC1735666] [PubMed: 14757870]
17. Khan NW, Wissinger B, Kohl S, Sieving PA. CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function. Invest Ophthalmol Vis Sci. 2007;48:3864–71. [PubMed: 17652762]
18. Koeppen K, Reuter P, Kohl S, Baumann B, Ladewig T, Wissinger B. Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). Eur J Neurosci. 2008;27:2391–401. [PubMed: 18445228]
19. Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet. 2000;9:2107–16. [PubMed: 10958649]
20. Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002;71:422–5. [PMC free article: PMC379175] [PubMed: 12077706]
21. Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet. 1998;19:257–9. [PubMed: 9662398]
22. Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jagle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet. 2005;13:302–8. [PubMed: 15657609]
23. Lamb TD, Pugh EN. Phototransduction, dark adaptation, and rhodopsin regeneration the proctor lecture. Invest Ophthalmol Vis Sci. 2006;47:5137–52. [PubMed: 17122096]
24. Liu C, Varnum MD. Functional consequences of progressive cone dystrophy-associated mutations in the human cone photoreceptor cyclic nucleotide-gated channel CNGA3 subunit. Am J Physiol Cell Physiol. 2005;289:C187–98. [PubMed: 15743887]
25. Michaelides M, Aligianis IA, Ainsworth JR, Good P, Mollon JD, Maher ER, Moore AT, Hunt DM. Progressive cone dystrophy associated with mutation in CNGB3. Invest Ophthalmol Vis Sci. 2004;45:1975–82. [PubMed: 15161866]
26. Michaelides M, Aligianis IA, Holder GE, Simunovic M, Mollon JD, Maher ER, Hunt DM, Moore AT. Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2). Br J Ophthalmol. 2003;87:1317–20. [PMC free article: PMC1771876] [PubMed: 14609822]
27. Michalakis S, Geiger H, Haverkamp S, Hofmann F, Gerstner A, Biel M. Impaired opsin targeting and cone photoreceptor migration in the retina of mice lacking the cyclic nucleotide-gated channel CNGA3. Invest Ophthalmol Vis Sci. 2005;46:1516–24. [PubMed: 15790924]
28. Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat. 2005;25:248–58. [PubMed: 15712225]
29. Okada A, Ueyama H, Toyoda F, Oda S, Ding WG, Tanabe S, Yamade S, Matsuura H, Ohkubo I, Kani K. Functional role of hCngb3 in regulation of human cone cng channel: effect of rod monochromacy-associated mutations in hCNGB3 on channel function. Invest Ophthalmol Vis Sci. 2004;45:2324–32. [PubMed: 15223812]
30. Park WL, Sunness JS. Red contact lenses for alleviation of photophobia in patients with cone disorders. Am J Ophthalmol. 2004;137:774–5. [PubMed: 15059731]
31. Patel KA, Bartoli KM, Fandino RA, Ngatchou AN, Woch G, Carey J, Tanaka JC. Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel. Invest Ophthalmol Vis Sci. 2005;46:2282–90. [PubMed: 15980212]
32. Peng C, Rich ED, Varnum MD. Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels. J Biol Chem. 2003;278:34533–40. [PubMed: 12815043]
33. Piriev NI, Viczian AS, Ye J, Kerner B, Korenberg JR, Farber DB. Gene structure and amino acid sequence of the human cone photoreceptor cGMP-phosphodiesterase alpha' subunit (PDEA2) and its chromosomal localization to 10q24. Genomics. 1995;28:429–35. [PubMed: 7490077]
34. Reuter P, Koeppen K, Ladewig T, Kohl S, Baumann B, Wissinger B. Achromatopsia Clinical Study Group; Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia. Hum Mutat. 2008;29:1228–36. [PubMed: 18521937]
35. Rojas CV, Maria LS, Santos JL, Cortes F, Alliende MA. A frameshift insertion in the cone cyclic nucleotide gated cation channel causes complete achromatopsia in a consanguineous family from a rural isolate. Eur J Hum Genet. 2002;10:638–42. [PubMed: 12357335]
36. Rosenberg T, Baumann B, Kohl S, Zrenner E, Jorgensen AL, Wissinger B. Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest Ophthalmol Vis Sci. 2004;45:4256–62. [PubMed: 15557429]
37. Sharpe LT, Stockman A, Jagle H, Nathans . Opsin genes, cone photopigments, color vision, and color blindness. In: Gegenfurtner K, Sharpe LT, eds. Color Vision: from Genes to Perception. Cambridge: Cambridge University Press; 1999:3-52.
38. Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet. 2002;11:1823–33. [PubMed: 12140185]
39. Sundin OH, Yang JM, Li Y, Zhu D, Hurd JN, Mitchell TN, Silva ED, Maumenee IH. Genetic basis of total colourblindness among the Pingelapese islanders. Nat Genet. 2000;25:289–93. [PubMed: 10888875]
40. Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009;85:240–7. [PMC free article: PMC2725240] [PubMed: 19615668]
41. Thiadens AA, Roosing S, Collin RW, van Moll-Ramirez N, van Lith-Verhoeven JJ, van Schooneveld MJ, den Hollander AI, van den Born LI, Hoyng CB, Cremers FP, Klaver CC (2010) Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. Ophthalmology. 117:825-30.e1. [PubMed: 20079539]
42. Thiagalingam S MT, Weleber RG, Sandberg MA, Trzupek KM, Berson EL, Dryja TP. Novel mutations in the KCNV2 gene in patients with cone dystrophy and a supernormal rod electroretinogram. Ophthalmic Genet. 2007;28:135–142. [PubMed: 17896311]
43. Trankner D, Jagle H, Kohl S, Apfelstedt-Sylla E, Sharpe LT, Kaupp UB, Zrenner E, Seifert R, Wissinger B. Molecular basis of an inherited form of incomplete achromatopsia. J Neurosci. 2004;24:138–47. [PubMed: 14715947]
44. Varsanyi B, Wissinger B, Kohl S, Koeppen K, Farkas A. Clinical and genetic features of Hungarian achromatopsia patients. Mol Vis. 2005;11:996–1001. [PubMed: 16319819]
45. Wissinger B, Dangel S, Jägle H, Hansen L, Baumann B, Rudolph G, Wolf C, Bonin M, Koeppen K, Ladewig T, Kohl S, Zrenner E, Rosenberg T. Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2. Invest Ophthalmol Vis Sci. 2008;49:751–757. [PubMed: 18235024]
46. Wissinger B, Gamer D, Jagle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S. CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet. 2001;69:722–37. [PMC free article: PMC1226059] [PubMed: 11536077]
47. Wiszniewski W, Lewis RA, Lupski JR. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14. Hum Genet. 2007;121:433–9. [PubMed: 17265047]
48. Wu H, Cowing JA, Michaelides M, Wilkie SE, Jeffery G, Jenkins SA, Mester V, Bird AC, Robson AG, Holder GE, Moore AT, Hunt DM, Webster AR. Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause "cone dystrophy with supernormal rod electroretinogram" in humans. Am J Hum Genet. 2006;79:574–579. [PMC free article: PMC1559534] [PubMed: 16909397]

Suggested Reading

1. Deeb SS. Molecular genetics of colour vision deficiencies. Clin Exp Optom. 2004;87:224–9. [PubMed: 15312026]
2. Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004;88:291–7. [PMC free article: PMC1771989] [PubMed: 14736794]

Revision History

• 23 December 2010 (cd) Revision: sequence analysis available clinically for mutations in GNAT2
• 23 September 2010 (cd) Revision: prenatal testing available for achromatopsia 2 and 3; achromatopsia 5 (caused by mutations in PDE6C) added; clinical testing and prenatal testing available for PDE6C mutations.
• 25 June 2009 (me) Comprehensive update posted live
• 23 October 2006 (me) Comprehensive update posted to live Web site
• 24 June 2004 (me) Review posted to live Web site
• 17 February 2004 (sk, bw) Original submission