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Achromatopsia: for professionals

Overview

Prevalence
  • 1: 30,000 live births[1]
Inheritance
  • Autosomal recessive
Genes involved (OMIM No.)6 genes have been identified
Symptoms
  • Light sensitivity and nystagmus from birth/early infancy
  • Poor colour discrimination
  • Poor vision in bright setting, better vision in dim light from birth
  • Central scotoma
Ocular features
  • Reduced visual acuity
  • Impaired or absent colour vision
  • Divided into complete and incomplete achromatopsia based on severity of visual impairment
  • Variable fundal appearance (normal, central RPE changes, absent foveal reflex or macular atrophy)
  • Foveal hypoplasia can be seen in some genotypes (CNGA3, CNGB3 and ATF6)
Systemic features
  • No specific associated extraocular features
Key investigations
  • Full-field ERG: significantly reduced/absent cone responses with normal/sub-normal rod responses
  • OCT: Outer retinal attenuation mainly at the foveal and parafoveal areas (ellipsoid zone disruption/absence, hyporeflective zone, outer retinal and RPE atrophy, foveal hypoplasia)
  • FAF: Variable appearance; (Normal AF, central hyper-AF or reduced AF centrally +/- a surrounding hyper-AF ring)
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
  • Correct refractive errors
  • Low vision aids and assistive technologies
  • Tinted glasses/contact lens to optimise rod-mediated vision
  • Healthy diet consisting of fresh fruits and green leafy vegetables
  • Smoking cessation
Therapies under research
  • Gene therapy (phase 1/2)
  • Neuroprotection (phase 1/2)

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Clinical phenotype

Presenting features

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.[5]

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.[6]

Fundal appearance

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.[12] 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.

Multimodal imaging of a patient with biallelic CNGA3 mutations. The wide field colour fundus photograph (A) is unremarkable. Wide field FAF imaging (B) shows hyperautofluorescence in the central macula. OCT scan through the macula (C) demonstrates some disturbance at the foveal ellipsoid zone. The outer retinal layers are relatively preserved throughout.
Different images of the retina of a patient with achromatopsia due to mutations in the GNAT2 gene. No abnormalities in the retina was found in all imaging protocols.
Multimodal imaging of a patient with GNAT2-achromatopsia. Both wide field colour fundus photograph (A) and FAF imaging (B) are unremarkable. The OCT scan of the macula (C) looks normal.
Various retinal images of a patient with achromatopsia or cone dystrophy due to mutations in the PDE6C gene. The is a dark area in the centre of the retina, which demarcates the area of retinal degeneration.
Multimodal imaging of a patient with PDE6C-achromatopsia/cone dystrophy. Central macular atrophy can be appreciated clearly on FAF imaging (B), surrounded by a ring by hyperautofluorescence. OCT scan through the macula (C) shows foveal and parafoveal outer retinal and RPE atrophy, corresponding to the area of hypoautofluorescence. The outer retinal layers look relatively preserved beyond this area of hypoautofluorescence.

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Genetics

Pathogenic mutation in 6 genes currently account for 90% of cases. The identified causative genes are:

CNGA3 mutations account for about 30-40% of cases worldwide[6], 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.[20]

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.[8]

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

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[23]:

  • 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.[23]

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[9]:

  • Normal appearance
  • Increased central AF signal
  • Reduced central AF signal +/- a surrounding hyper-AF ring

3) Electrophysiology

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.[24] 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.[17] It is hypothesised that this may be due to smaller number of rods and/or altered rod outer circuitry.[17,25]

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Diagnosis

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

Related links

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Management

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

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

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.

Related links

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.

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Current research in achromatopsia

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.[9]

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.

Related links

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Further information and support

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References

  1.  Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004;88(2):291-297. doi:10.1136/bjo.2003.027102
  2.  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
  3.  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
  4.  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
  5.  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
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  8.  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
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  17.  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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  27.  Fortuny C, Flannery JG. Mutation-Independent Gene Therapies for Rod-Cone Dystrophies. Adv Exp Med Biol. 2018;1074:75-81. doi:10.1007/978-3-319-75402-4_10
  28.  Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci United States Am. 2011;108(15):6241-6245. doi:10.1073/pnas.1018987108
  29.  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

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Updated on December 16, 2020
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