Autosomal Dominant Optic Atrophy
Autosomal dominant optic atrophy is a rare eye condition that affects an estimated 1 in 25,000 individuals in the UK[1]. It causes progressive and irreversible sight loss in both eyes.
What is autosomal dominant optic atrophy?
Autosomal dominant optic atrophy (ADOA) is a rare genetic condition caused by the deterioration of the optic nerve, which transmits visual information from the eyes to the brain.
Damage to this nerve leads to vision loss.
How does autosomal dominant optic atrophy affect vision?
A child with autosomal dominant optic atrophy will usually experience sight loss in the first decade of life, and it will gradually worsen. However, the severity of vision loss varies widely from person to person, even among affected members of the same family – ranging from normal vision to complete blindness.
Around one in five individuals will have a more severe form, autosomal dominant optic atrophy ‘plus’ syndrome.
What is autosomal dominant optic atrophy plus syndrome?
As well as sight loss, other symptoms of ADOA plus include sensorineural hearing loss and symptoms affecting the peripheral nerves and muscles – such as numbness, weakness and problems with balance and coordination.[2] These symptoms usually appear in the second to fifth decades of life, after sight loss has become apparent.
Although a rare disease, autosomal dominant optic atrophy is the most common inherited optic nerve disorder seen in clinical practice. The condition is estimated to affect 1 in 25,000 individuals in the UK.
How is autosomal dominant optic atrophy inherited?
Autosomal dominant optic atrophy is an inherited condition, which means it is caused by genetic mutations (spelling mistakes) passed down through families.
Only one copy of the faulty gene (inherited from either parent) is required to cause the disease. So, each child of a person with a faulty gene has a 50% chance of inheriting it, regardless of their sex.
However, some individuals who inherit the faulty gene running in the family will not develop visual loss – a situation known as non-penetrance. In rare cases, the fault can also occur spontaneously in a child whose parents are unaffected[3].
Genetic causes of autosomal dominant optic atrophy?
Mutations in more than 20 genes[4] have so far been identified that cause autosomal dominant optic atrophy, with the most common one, by far, being OPA1.
The OPA1 gene causes around three-quarters of all cases of ADOA4. OPA1 contains the instructions for a protein made in many cells and tissues throughout the body. High levels of the OPA1 protein are present in a particular type of nerve cells, known as retinal ganglion cells, that make up the optic nerve.
The OPA1 protein plays a crucial role in the normal functioning of mitochondria, the energy-generating powerhouses of cells. When the OPA1 gene is faulty, the mitochondria become fragmented, and they have reduced energy-producing capabilities.
Cells containing these poorly functioning mitochondria appear to be more susceptible to premature death – particularly those with high energy demands, such as nerve cells.
Abnormal mitochondrial function and sight loss
The vision problems experienced by a person with autosomal dominant optic atrophy are caused by abnormal mitochondrial function, subsequently leading to the death of retinal ganglion cells and damage to the optic nerve.
An affected individual will experience progressive loss of retinal ganglion cells located in the inner retina, the light-sensitive layer at the back of the eye. Specialised extensions of retinal ganglion cells, called axons, form the optic nerve. The death of these cells leads to the degeneration of the optic nerve, which disrupts the transmission of visual information from the eyes to the brain, causing sight loss.
Nerve cells in other parts of the body are also likely to be similarly affected by poorly functioning mitochondria, causing other neurological symptoms associated with autosomal dominant optic atrophy ‘plus’ syndrome.
What are the symptoms of autosomal dominant optic atrophy?
A person with autosomal dominant optic atrophy will experience blurred vision in both eyes, which usually starts in early childhood, and gradually worsens over time.
They will usually experience visual difficulties before the age of ten, but earlier or later onset is also possible. For reasons that remain unclear, the extent of sight loss can vary considerably between individuals, even within the same family, ranging from mild to severe.
Visual symptoms of autosomal dominant optic atrophy include:
- Reduced visual sharpness (visual acuity),
- Difficulty in recognising colours (colour blindness),
Central (straight ahead) vision is usually more severely affected than peripheral (side) vision.
How does autosomal dominant optic atrophy affect hearing?
Autosomal dominant optic atrophy “plus” syndrome can be associated with hearing loss, typically occurring later in life after vision loss has begun. People with this “plus” syndrome may also experience other symptoms, including numbness, muscle weakness, muscle stiffness and balancing difficulties, leading to mobility problems.
{H2} How is autosomal dominant optic atrophy diagnosed?
A diagnosis of autosomal dominant optic atrophy is usually made based on a combination of the clinical features, the family history and the results of an eye examination.
A person may undergo the following tests as part of their assessment:
- Visual acuity test – to measure the sharpness of vision in each eye.
- Visual field testing – to measure the extent of vision loss in the central and peripheral fields.
- Colour vision testing – to find out how well a person can distinguish between different colours
- Optical coherence tomography (OCT) – taking a picture of the back of the eye to examine all the layers of the optic nerve and retina in detail
- Electroretinogram (ERG) – to test the electrical activity of the optic nerve and retina in response to light.
- Genetic testing – to confirm a diagnosis of autosomal dominant optic atrophy by identifying faults in one of the genes associated with the condition.
How is autosomal dominant optic atrophy treated?
Unfortunately, no treatment currently can prevent or reverse sight loss caused by autosomal dominant optic atrophy. Treatment mainly focuses on supporting people to manage some of the challenges of living with the condition.
These include:
- Wearing prescription glasses or contact lenses to optimise remaining vision.
- A low vision assessment to identify resources and support that could be helpful.
- Using visual aids and assistive technology to help improve quality of life.
- If present, hearing loss may be improved with hearing aids or cochlear implants (a small electronic device placed surgically under the skin and can help provide a sense of sound).
Individuals with autosomal dominant optic atrophy plus syndrome could also benefit from seeing a neurologist to help minimise some of their symptoms with the appropriate treatment.
What’s the latest research into autosomal dominant optic atrophy?
Clinical trials will soon be launched by Stoke Therapeutics and PYC Therapeutics to explore a proprietary antisense oligonucleotide (ASO) – a way of controlling or modifying how genes work. In this case, they will aim to alter the OPA1 gene, which could slow down or stop sight loss in people with ADOA[5].
Scientists are also searching for other genes that cause different types of inherited optic atrophy. Identifying these genes would mean more people could receive an accurate diagnosis, enabling access to better genetic counselling about how the condition might affect them and their families.
It will also help researchers improve their understanding of how faults in specific genes contribute to progressive optic nerve degeneration and vision loss, which could open new treatment avenues.
How can I support research into autosomal dominant optic atrophy?
The Cameron Family Fund is fundraising for pioneering research into autosomal dominant optic atrophy (ADOA) to help three family members – children Edward and Beth and Daniel (father) – and others diagnosed with the condition.
Find out more about the fund and support them if you can.
[1] https://pubmed.ncbi.nlm.nih.gov/23916084/
[2] https://pubmed.ncbi.nlm.nih.gov/20157015/
[3] https://pubmed.ncbi.nlm.nih.gov/11440989/
[4] https://pubmed.ncbi.nlm.nih.gov/36155660/
[5] https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-receives-authorization-initiate-phase-12
New content September 2023
Approved by Professor Patrick Yu-Wai-Man PhD, FRCPath, FRCOphth, Clinical Senior Lecturer University of Cambridge and Honorary Consultant Ophthalmologist and Dr Joshua Harvey, clinical research training fellow at the Institute of Ophthalmology, UCL
