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Achromatopsia

What is Achromatopsia?

Achromatopsia, often referred to as rod monochromacy or total color blindness, is a rare autosomal recessive cone disorder with a prevalence estimated between 1 in 30,000 to 1 in 50,000 individuals. It is a genetic disease with symptoms that typically emerge within the first few weeks or months of life, presenting with severe light sensitivity (photophobia), nystagmus (involuntary eye movements), the absence of color vision, and reduced visual acuity.

This condition stems from the malfunction cone photoreceptor cells in the retina, responsible for daylight vision, for visual acuity and color perception. Specifically, achromatopsia in most instances occurs due to the deficiency of one of the proteins crucial for phototransduction, the process converting light into electrical signals in the retina.

The most prevalent mutations linked to achromatopsia affect the genes CNGB3 and CNGA3. Other genetic mutations can also contribute to the condition, albeit less frequently, involving the genes GNAT2, PDE6C, PDE6H, and ATF6. All these genes, except for ATF6, encode proteins involved in the cones phototransduction process. ATF6 encodes for a transcription factor involved in the unfolded protein response. Why mutations in this gene result in achromatopsia is to date unknown.

 

Symptoms

Achromatopsia presents with a range of clinical features, including:

  • Reduced visual acuity, often 20/200 or less in complete achromatopsia and up to 20/80 in incomplete cases;
  • Infantile nystagmus typically develops within the first few weeks after birth;
  • Severe photophobia (Increased sensitivity to bright light) is a common symptom;
  • Complete absence or severe impairment of color vision, leading individuals to perceive the world in shades of gray, black, and white. This colorblindness arises from dysfunctional cone photoreceptor cells in the retina, which are responsible for detecting various wavelengths of light and enabling color perception. As a consequence, those with achromatopsia lack the ability to distinguish colors and experience impaired color discrimination along all three axes of color vision: the long-wavelength-sensitive cone axis (red), the middle-wavelength-sensitive cone axis (green), and the short-wavelength-sensitive cone axis (blue);
  • A small central scotoma (blind spot), eccentric fixation, and macular changes may also be present.

 

 



Normal Vision

Vision with Achromatopsia


Inheritance and Causes

Achromatopsia follows an autosomal recessive pattern of inheritance, meaning it is passed down from both parents. A pathogenic variant in the very same gene needs to be inherited from father and mother.

Phototransduction is the process by which light signals are converted into electrical signals in the retina, initiating the visual perception cascade. In cone photoreceptor cells, this process starts with the activation of the visual pigments by photons of light. The visual pigment consists of the opsins and the chromophore 11-cis-retinal. It undergoes conformational changes upon light absorption, leading to the activation of G-proteins (G-Protein Transducin) that activates the Phosphodiesterase PDE. The phosphodiesterase then cleaves cGMP which is the ligand keeping the cGMP-gated cations channels open in the dark. Upon illumination, the intracellular cGMP level drops and the cGMP-gated cation channel of the cone photoreceptor closes resulting in hyperpolarization of the cone photoreceptor. This results in a change of glutamate release at the synapse,  creating a neural impulse, that reaches other retinal cells, named bipolar cells and finally the optical nerves and the brain.

Mutations in genes encoding these proteins can disrupt phototransduction and lead to the symptoms observed in achromatopsia. Six genes have been linked to achromatopsia: CNGB3 and CNGA3, which are responsible for approximately 90% of cases, along with GNAT2, PDE6C, PDE6H, and ATF6.

Phototransduction and genes:

A photoreceptor cones in light (left) and in the dark (right). The phototransduction process leads to a different activation of bipolar cells.

 

Molecular Genetics

GNAT2 (1p13) : cone a-subunit of transducin

PDE6C (10q24) : cone a’-subunit of cGMP-phosphodiesterase (PDE)

PDE6H (12p13) : cone h-subunit of PDE

CNGA3 (2q11) : cone a-subunit of the cGMP- gated (CNG) cation channel

CNGB3 (8q21-q22) : cone b-subunit of the CNG cation channel

ATF6 (1q23) : activating transcription factor 6

Types of Achromatopsia

There are two types of achromatopsia:

  • Complete Achromatopsia: Characterized by the absence of functional cones in the retina, resulting in severe visual symptoms due to the complete loss of proteins essential for phototransduction, such as those encoded by CNGB3 and CNGA3.
  • Incomplete Achromatopsia: Involves some functional cones, leading to less severe visual symptoms compared to the complete type. In incomplete achromatopsia, there may be a partial loss of proteins involved in phototransduction, resulting in a milder form of the condition.

Similarities between Blue Cone Monochromacy and Achromatopsia

The two forms have many elements in common:

  • intolerance to light;
  • weak central vision, low visual acuity;
  • poor ability to distinguish colors;
  • infantile nystagmus;
  • retina with a normal appearance.

Differences between Blue Cone Monochromacy and Achromatopsia

  • BCM is X-linked and affects mainly male individuals;
  • Achromatopsia is an autosomal recessive disease, and affects both males and females equally;
  • BCM causative mutations result in the lack of functional opsin photopigments in the red and green cones;
  • Achromatopsia results in the (function) loss of all cones (red, green and blue).

The Third European Meeting on Achromatopsia and Blue Cone Monochromacy – Tübingen, Germany, 2023

Diagnosis

Family medical history and observed symptoms like light sensitivity and diminished vision play key roles in identifying the condition.

Genetic testing is a very important step to confirm the diagnosis, by identification of biallelic pathogenic (or likely pathogenic) variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H.

Management, Treatment and Ongoing Gene Therapy Clinical Trials

Strategies to alleviate symptoms and improve quality of life may include:

  • Dark or special filter glasses, or red-tinted contact lenses, to reduce photophobia and potentially improve visual acuity.
  • Low vision aids and occupational aids to assist with daily tasks.
  • Preferential classroom seating for children to optimize learning environments.

Currently, there is no cure for achromatopsia. However, several clinical trials for gene therapy are underway, offering hope for future treatment options.

To find all clinical studies and trial please search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information inserting Achromatopsia in the disease name.

For example, on April 2024, these sites report the following studies:

  • MeiraGTx II UK Ltd trial on Achromatopsia human CNGB3 using a sub-retinal AAV8 injection
  • MeiraGTx II UK Ltd trial on Achromatopsia caused by mutations in the CNGA3 gene where study participants were administered a single dose in the worse-seeing eye at one of four dose levels.
  • Universitätsklinikum Tübingen – Safety and efficacy of a bilateral single subretinal injection of rAAV.hCNGA3 in adult and minor patients with CNGA3-linked achromatopsia investigated in a randomized, wait list controlled, observer-masked trial.
  • NCT02599922 by Applied Genetic Technologies Corp – Safety and Efficacy Trial of AAV Gene Therapy in Patients with CNGB3 Achromatopsia
  • NCT02935517 by Applied Genetic Technologies Corp – non-randomized, open-label, Phase 1/2 study of the safety and efficacy of AGTC-402, administered to one eye by subretinal injection in individuals with achromatopsia caused by mutations in the CNGA3 gene.

Achromatopsia support groups

There are several European Achromatopsia Support Groups:

Italy

Associazione Acromati Italiani Onlus

Email: info@acromatopsia.it

www.acromatopsia.it

https://www.facebook.com/groups/445196602262268

Germany

Achromatopsie Selbsthilfeverein e.V.

Email: info@achromatopsie.org

www.achromatopsie.org

Spain

Acròmates Spain – Marta Gonzalvo Gonzàles

Email: acromates@acromates.org

https://www.acromates.org

 Netherlands

https://www.facebook.com/groups/achromatopsie

 UK

https://www.facebook.com/groups/AchromatopsiaUK

 France

https://www.facebook.com/groups/468415927444308

https://www.facebook.com/unevieennoiretblanc

Moreover, there are patient associations in the USA and internationally:

USA

  1. The Achromatopsia Support Network https://www.facebook.com/groups/41648172586 – Private group 2,3K members on Apr 2024
  2. Achroma Corp achromacorp.org
  3. The Achromatopsia Support Group https://achromatopsia.org/
  4. https://www.facebook.com/groups/2267299643 – Private Group 1,7K members on Apr 2024

European Meetings on Achromatopsia and Blue Cone Monochromacy

Venice, Italy 2018 – First European Meeting

Venice, Italy 2022 – Second European Meeting

Tübingen, Germany 2023 – Third European Meeting

Third European Meeting on Achromatopsia and BCM – Tübingen, Germany, 2023

External Resources:

Publications of Gene Therapy results: