- Clinical phenotype
- Key investigations
- Current research
- Further information and support
- Achromatopsia: for patients
|Genes involved (OMIM No.)||6 genes have been identified|
|Molecular diagnosis||Next generation sequencing|
|Therapies under research|
Achromatopsia is a predominantly stable/slowly progressive retinal dystrophy characterised by the lack of function in all three classes of cone photoreceptors (S-cones, M-cones and L-cones) from birth or early infancy.[2-5] Affected infants usually present with light sensitivity and nystagmus which may improve slightly over time. Other associated features include reduced visual acuity (VA), impaired or absent colour vision (in all three axes) and central scotoma. Parents may notice that their child have poor vision in bright daylight from birth and prefers to play in the dark. There are no specific refractive errors associated with achromatopsia apart from those harbouring PDE6C mutations who are typically high myopes.
Pathogenic mutations in 6 genes have been identified to cause achromatopsia, leading to significant intra- and interfamilial variability in clinical appearance and the severity of visual dysfunction, which can be broadly divided into “complete” and “incomplete” forms. Most patients are complete achromats and have little or no cone function, and vision is mainly mediated by rods (rod monochromatism). As a result, VA tends to be poor (6/60 [LogMAR 1.0] or worse) and there is total absence of colour vision. On the other hand, incomplete achromats (uncommon) usually display a milder phenotype due to residual cone function, with VA ranging between 6/24 (LogMAR 0.6) and 6/36 (LogMAR 0.78) and some degree of colour discrimination.
The fundal features are highly variable but patients usually have symmetrical ocular findings. Fundal examination tends to be unremarkable but some patients may display the following changes:
- Central retinal pigment epithelium (RPE) mottling
- Absent foveal reflex on fundoscopy
- Macular atrophy
- Foveal hypoplasia (seen in all ATF6 associated achromatopsia cases and a proportion of patients with CNGA3 and CNGB3 mutations but not reported in GNAT2 and PDE6C patients)[7-9]
Deep phenotyping studies utilising optical coherence tomography (OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO) have shown marked variability in cone mosaics among the associated genotypes. While there is no significant difference between CNGA3 and CNGB3 associated achromatopsia[10,11], patients harbouring GNAT2 mutations tend to have relatively well-preserved cone mosaics and stable disease course. On the other hand, there are very few (if any) remaining foveal cones in those with PDE6C and ATF6 mutations.[5,8] These findings can have implications on patient selection in future interventional trials.
Pathogenic mutation in 6 genes currently account for 90% of cases. The identified causative genes are:
- CNGA3 (together with CNGB3 account for approximately 70-80% of cases)
- GNAT2 (< 2% of cases)[3,14]
- PDE6C (<2% of cases)[5,15]
- PDE6H (<1% of cases)
- ATF6 (1-2% of cases)[7,8]
CNGA3 mutations account for about 30-40% of cases worldwide, predominantly in the Middle East and China where up to 80% of cases are due to variants in this gene.[17,18] It is less common among European populations (up to 30%).[19,20]
CNGB3 is the most the most common cause of achromatopsia, accounting for up to 50% of cases worldwide, and is particularly prevalent among individuals of European descent, mainly due to a single base pair deletion c.1148delC (found in over 70% of disease-causing alleles in CNGB3), which results in a frameshift mutation and a lack of normal protein production.
All of the implicated genes except ATF6 are involved in the cone-specific phototransduction cascade. ATF6 is expressed ubiquitously and has a role in endoplasmic reticulum stress homeostasis.[21,22] It is not entirely clear yet how mutations in this gene lead to isolated cone dysfunction and consistent foveal hypoplasia, although it has been suggested that ATF6 may be crucial in foveal and parafoveal cone development.
1) Optical coherence tomography (OCT)
Structural abnormalities associated with achromatopsia are mainly confined to the foveal and parafoveal regions. A variety of OCT phenotypes have been observed:
- Normal appearance with continuous ellipsoid zone (EZ)
- Disrupted or absent EZ
- Hyporeflective zone
- Outer retinal atrophy with RPE loss
- Foveal hypoplasia
Visual function (BCVA, retinal and contrast sensitivities) do not seem to correlate with OCT findings.
Although small longitudinal studies have shown that the structural changes observed in achromatopsia tend to remain stable or progress slowly over time[2,5,12,14], larger and longer-term prospective studies with molecularly diagnosed patients will better inform us about the rate of progression of different genotypes.
2) Fundus autofluorescence imaging (FAF)
FAF enables assessment of photoreceptor and RPE integrity through visualisation of lipofuscin distribution. The FAF features that have been observed include:
- Normal appearance
- Increased central AF signal
- Reduced central AF signal +/- a surrounding hyper-AF ring
In full-field electroretinogram (ERG), the dark-adapted stimuli (DA 0.01, DA 3 and DA 10 flashes) predominantly measures rod function. The DA 0.01 dim flash elicits a rod-specific response while the stronger DA 3 and DA 10 flashes have some cone contribution. Cone function is selectively assessed with light-adapted stimuli (LA 3 flash and 30 Hz flicker).
Achromats typically have absent or markedly reduced cone-mediated responses while rod-specific responses (DA 0.01) are usually normal. The a-waves of strong scotopic flashes (DA3 and DA10) may be sub-normal due to loss of the dark-adapted cones. However, impairment of rod function (reduced b-wave amplitude on DA0.01 dim flash) has been reported despite the majority of associated genes are cone-specific. It is hypothesised that this may be due to smaller number of rods and/or altered rod outer circuitry.[17,25]
Achromatopsia can be diagnosed based on the unusual visual behaviour (poor daylight vision from birth and preference for the dark along with lifelong disability to discriminate colours) of the child. This is often offered by parents/patients themselves and clinical examination. Genetic testing should be undertaken to confirm the diagnosis molecularly. It can also facilitate genetic counselling, provide accurate advice on prognosis and future family planning, and aid in clinical trial participation.
This can be achieved through a variety of next generation sequencing (NGS) methods:
- Targeted gene panels (retinal)
- Whole exome sequencing
- Whole genome sequencing
- Genomics England PanelApp for inherited retinal dystrophies
- Clinical genetic testing: for professionals
Management of achromatopsia is mainly supportive:
- Correcting any refractive errors
- Referral to low vision services
- Tinted glasses/contact lens to optimise rod-mediated vision
- Directing patients to supporting organisations
- Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
- Encourage the use of assistive technology that may improve quality of life
- Smoking cessation
- UV protected sunglasses
- Blue light screen protectors on mobile devices or computer screens*
*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.
Optimising childhood development
Visual impairment from such an early age can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.
The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.
Family management and counselling
Mutations associated with achromatopsia are usually inherited in an autosomal recessive manner. However, cases of digenic and triallelic inheritance have been reported in patients harbouring homozygous or compound heterozygous c.1208G>A (p.Arg403Gln) mutations in CNGB3 with a concurrent mutant CNGA3 allele.26
Emotional and social support
Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.
Referral to a specialist centre
In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.
1) Gene therapy
Gene therapy works by introducing a normal gene into the appropriate cells (transgene) to compensate for the mutated gene that is not producing enough functional protein. The transgene is carried by a viral vector, usually adeno-associated virus (AAV) and delivered to the target cells through sub-retinal/intravitreal injections.
The main achromatopsia genes that are being investigated in translational studies are CNGA3 and CNGB3. A German phase 1/2 trial (NCT 02610582) of 9 adult patients with advanced CNGA3-associated achromatopsia has demonstrated that sub-retinal injection of AAV8-CNGA3 is not associated with any significant safety issues and improvements in visual outcomes (BCVA, contrast sensitivity and colour vision) were observed at 12 months post-treatment.
Other ongoing gene replacement trials for achromatopsia are:
- Sub-retinal injections of AAV2/8-hG1.7p.coCNGA3; MeiraGTx (NCT 03758404, phase 1/2)
- Sub-retinal injections of AAV2/8-hCARp.hCNGB3; MeiraGTx (NCT 03001310, phase 1/2)
- Sub-retinal injections of rAAV2tYF-PR1.7-hCNGA3 (AGTC-402); AGTC (NCT02935517, phase 1/2)
- Sub-retinal injections of rAAV2tYF-PR1.7-hCNGB3 (AGTC-401); AGTC (NCT 02599922, phase 1/2)
AAV-mediated gene therapy has also been shown to restore cone function in a GNAT2-achromatopsia mouse model. However due to its low prevalence, more detailed phenotyping and natural history studies of patients with GNAT2 variants are required to better understand the underlying disease mechanisms before clinical trials can begin.
2) Ciliary neurotrophic factor (CNTF)
CNTF is a type of protein that have been shown to have neuroprotective effects on cone photoreceptors.[28,29] Although intravitreal injections of CNTF in a CNGB3-achromatopsia canine model resulted in a small and transient improvement in cone-mediated function, similar outcome was not replicated in a phase 1/2 trial. However, the participants reported subjective improvements in light sensitivity and increased sharpness in vision but this may be due to pupillary constriction that was observed in all treated eyes. No further CNTF trials involving achromatopsia patients have been reported since.
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
- Retina UK
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
- Look UK
- Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004;88(2):291-297. doi:10.1136/bjo.2003.027102
- Aboshiha J, Dubis AM, Cowing J, et al. A prospective longitudinal study of retinal structure and function in achromatopsia. Investig Ophthalmol Vis Sci. 2014;55(9):5733-5743. doi:10.1167/iovs.14-14937
- 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
- Georgiou M, Litts KM, Kalitzeos A, et al. Adaptive Optics Retinal Imaging in CNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability. Investig Ophthalmol Vis Sci. 2019;60(1):383-396. doi:10.1167/iovs.18-25880
- Georgiou M, Robson AG, Singh N, et al. Deep Phenotyping of PDE6C-Associated Achromatopsia. Investig Ophthalmol Vis Sci. 2019;60(15):5112-5123. doi:10.1167/iovs.19-27761
- Hirji N, Aboshiha J, Georgiou M, Bainbridge J, Michaelides M. Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options. Ophthalmic Genet. 2018;39(2):149-157. doi:10.1080/13816810.2017.1418389
- Kohl S, Zobor D, Chiang W-C, et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015;47(7):757-765. doi:10.1038/ng.3319
- Mastey RR, Georgiou M, Langlo CS, et al. Characterization of Retinal Structure in ATF6-Associated Achromatopsia. Investig Ophthalmol Vis Sci. 2019;60(7):2631-2640. doi:10.1167/iovs.19-27047
- Georgiou M, Fujinami K, Michaelides M. Retinal imaging in inherited retinal diseases. Ann Eye Sci Vol 5 (September 2020) Ann Eye Sci. Published online 2020. http://aes.amegroups.com/article/view/5540
- Genead MA, Fishman GA, Rha J, et al. Photoreceptor structure and function in patients with congenital achromatopsia. Investig Ophthalmol Vis Sci. 2011;52(10):7298-7308. doi:10.1167/iovs.11-7762
- Dubis AM, Cooper RF, Aboshiha J, et al. Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health. Investig Ophthalmol Vis Sci. 2014;55(11):7303-7311. doi:10.1167/iovs.14-14225
- Georgiou M, Singh N, Kane T, et al. Photoreceptor Structure in GNAT2-Associated Achromatopsia. Investig Ophthalmol Vis Sci. 2020;61(3):40. doi:10.1167/iovs.61.3.40
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- Kohl S, Baumann B, Rosenberg T, et al. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002;71(2):422-425. doi:10.1086/341835
- Thiadens AAHJ, den Hollander AI, Roosing S, et al. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009;85(2):240-247. doi:10.1016/j.ajhg.2009.06.016
- Kohl S, Coppieters F, Meire F, et al. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia. Am J Hum Genet. 2012;91(3):527-532. doi:10.1016/j.ajhg.2012.07.006
- Zelinger L, Cideciyan A V, Kohl S, et al. Genetics and Disease Expression in the CNGA3 Form of Achromatopsia: Steps on the Path to Gene Therapy. Ophthalmology. 2015;122(5):997-1007. doi:10.1016/j.ophtha.2014.11.025
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- Sundaram V, Wilde C, Aboshiha J, et al. Retinal structure and function in achromatopsia: implications for gene therapy. Ophthalmol J Am Acad Ophthalmol. 2014;121(1):234-245. doi:10.1016/j.ophtha.2013.08.017
- 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. Investig Ophthalmol Vis Sci. 2017;58(2):821-832. doi:10.1167/iovs.16-20427
- Haverkamp S, Michalakis S, Claes E, et al. Synaptic plasticity in CNGA3(-/-) mice: cone bipolar cells react on the missing cone input and form ectopic synapses with rods. J Neurosci Off J Soc Neurosci. 2006;26(19):5248-5255. doi:10.1523/JNEUROSCI.4483-05.2006
- Burkard M, Kohl S, Krätzig T, et al. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Investig. 2018;128(12):5663-5675. doi:10.1172/JCI96098
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- Talcott KE, Ratnam K, Sundquist SM, et al. Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment. Investig Ophthalmol Vis Sci. 2011;52(5):2219-2226. doi:10.1167/iovs.10-6479