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Dominant Optic Atrophy: for patients

Overview

Dominant optic atrophy is an inherited condition causing progressive degeneration of the optic nerve. Patients usually experience painless loss of vision in both eyes that comes on gradually in childhood or teenage years that progressively worsens over time. It is estimated to affect 1 in 25,000 individuals in the UK.[1] So far, two genes (OPA1 and OPA3) have been identified to be associated with this condition, where the majority of cases (roughly 75%) are caused by changes (mutations) in the OPA1 gene.[2] While mainly an isolated eye condition, about 20% of patients affected by dominant optic atrophy also experience hearing loss and other neurological symptoms including numbness, weakness and balancing difficulties (ataxia).[3] Genetic mutations causing dominant optic atrophy are predominantly inherited in an autosomal dominant pattern but cases of autosomal recessive inheritance have been reported in a small number of families.[3-6]

The normal optic nerve head is a circular structure with a yellow to orange appearance, with blood vessels overlying it. An atrophic optic nerve head is pale in colour.
The normal optic nerve head appears yellow to orange in appearance, while an atrophic optic nerve head appears pale in comparison.

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The condition

Symptoms

1) Visual loss

Patients usually experience blurry vision in both eyes which gradually worsen over time, subsequently forming a blind spot in the central vision. The onset and severity of visual symptoms are highly variable, even among family members, but patients typically notice visual disturbances from early childhood to teenage years, with a moderate reduction in visual sharpness (visual acuity) and difficulty in recognising colours (abnormal colour vision).[7,8] Visual impairment is usually more severe among patients that also have other associated systemic symptoms.[3]

2) Systemic (other body systems)

The condition can also manifest with symptoms affecting other parts of body, also known as dominant optic atrophy plus syndrome (DOA+), which can be seen in up to 20% of patients.[3] Hearing loss is the most common systemic symptom associated with dominant optic atrophy, and typically occurs later in life after vision loss has begun. If present, hearing can be improved with hearing aids or cochlear implants.[9] Other symptoms that patients affected by DOA+ may experience include numbness, muscle weakness, muscle stiffness (spasticity) and balancing difficulties (ataxia), which can lead to problems with mobility.[3]

In some patients with mutations in the OPA1 gene that are inherited in an autosomal recessive manner, several features have been consistently described which are collectively named as Behr syndrome.[3-5] Patients affected by Behr syndrome usually experience visual loss at an early age due to progressive degeneration of the optic nerve, ataxia, loss of sensation in the peripheral nerves and spasticity.

A similar type of condition known as Costeff syndrome is associated with autosomal recessive OPA3 mutations, which is predominantly observed in individuals of Iraqi Jewish descent.[6] Costeff syndrome is characterised by visual loss (usually noticed in the first 10 years of life) due to progressive optic nerve degeneration, subsequent development of movement problems such as spasticity, ataxia and involuntary jerking movements (chorea), and increased levels of a substance called 3-methylglutaconic acid in the urine.

Cause

Mutations in two genes have been identified so far to cause dominant optic atrophy, which are OPA1 and OPA3. Several other genes may also be implicated but the specific gene(s) have not been identified yet.

Most cases of dominant optic atrophy (about 75%) are caused by mutations in the OPA1 gene.[2] This gene provides instructions for the production of a protein called dynamin-related GTPase that are crucial to the normal functioning of the mitochondrion (plural: mitochondria).[10] The mitochondrion is a structure found within cells and play an important role in the generation of energy. Mutations causing abnormal or reduced production of the dynamin-related GTPase protein disrupt mitochondrial function, which subsequently cause degeneration of the retinal ganglion cells–a layer in the retina that sends electrical signals to the optic nerve and is crucial for normal visual function.[8,11]

A microscopic view of the cells in the retina. The cone-shaped and rod-shaped photoreceptors are situated deepest and supported by the RPE cells. Other cells above the photoreceptors are responsible for transmitting electrical signals to the brain to generate vision.
Microscopic view of the cells in the retina: The rod and cone photoreceptors are at the bottom supported by the retinal pigment epithelium. The other cell types above the photoreceptors relay electrical signals to the brain

How is it diagnosed?

1) Eye examination

Patients tend to undergo the following tests as part of their assessment:

  • Measurement of visual acuity by reading a chart and checking to see if glasses are needed to improve vision
  • Colour vision testing
  • Visual field testing to reveal the extent of central vision loss. There are different methods for testing this according to the age of the patient, but it can be performed from as young as 6 years of age, although the results become more accurate with increasing age and competency. Patients are asked to respond or press a button when they detect flashing lights and a map of their visual field is created.
  • Optical coherence tomography (OCT), a camera that allows detailed visualisation of all the layers of the optic nerve and retina
  • An electrodiagnostic test to assess the function of the optic nerve and the retina
A standard visual acuity measuring chart with letters arranged vertically in decreasing sizes.
A standard Snellen chart used to measure visual acuity

Genetic testing can help confirm the diagnosis by identifying mutations in one of the associated genes.

2) General medical assessment

As patients affected by dominant optic atrophy can present similarly to other conditions that affect the optic nerve (collectively termed optic neuropathies) such as inflammation or nutritional deficiency, the ophthalmologist may request an MRI (Magnetic Resonance Imaging) scan of the brain and some blood tests to be done. You or your child may also be referred to other doctors (usually a paediatrician and a neurologist) to make sure that the visual loss is not caused by other conditions and also to screen for other systemic features (if present). A hearing assessment would be useful to identify any associated hearing loss which can be addressed with hearing aids or cochlear implants.

How is it inherited?

1) Autosomal dominant inheritance

Changes in the genes associated with dominant optic atrophy are mostly inherited in this manner. Only one faulty gene copy (inherited from either parent) is required to cause disease. This means that each newborn of the patient has a 50% chance of inheriting the condition regardless of gender.

The faulty gene copy is present in the father while the mother is not affected. Each newborn of this couple has a 50% chance to be affected by the condition.
Autosomal dominant inheritance

2) Autosomal recessive inheritance

The genetic changes in a small number of patients, usually with other associated systemic symptoms in addition to visual loss, are inherited in this manner. In contrast to AD inheritance, two faulty copies of a gene are required to cause disease. Both parents are usually unaffected carriers (who only carry one faulty copy of the gene) while the patient has two faulty gene copies (inherited one faulty copy from each parent). This means that every newborn of the patient has the following risks regardless of gender:

  • 25% chance of being affected
  • 25% chance of being unaffected and not a carrier
  • 50% chance of being a carrier with no symptoms
If the mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
Autosomal recessive inheritance

If you or your child is affected by this condition, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

1) Supportive visual measures

There is currently no available treatment that can prevent or reverse vision loss associated with dominant optic atrophy. Research is ongoing and there may be potential treatment options in the future. In the meantime, Treatment is mainly focused on optimising and preserving remaining sight. These include: 

  • Regular monitoring of visual function and prescribing glasses (if required) to optimise remaining vision
  • Referral to low vision services
  • Utilising visual aids and assistive technology to improve quality of life
  • Having a healthy diet consisting of fresh fruits and green leafy vegetables
  • Stop smoking
  • Avoid excessive alcohol consumption

2) Optimisation of development and educational support

Patients affected by DOA+ often require input from a number of healthcare professionals, such as paediatricians, neurologists, hearing specialists, physiotherapists and occupational therapists.

In addition, if the onset of visual impairment occurs in early childhood, it can have a negative impact on their early general development and education. Hence, children affected by dominant optic atrophy should be referred to developmental paediatricians and advisory teaching services for children/adolescents with visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence. Children with visual impairment can be referred to developmental services such as the developmental vision clinic in the Great Ormond Street Hospital for Children for further management.

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Current research in dominant optic atrophy

Much work is being done to improve the genetic diagnosis of inherited optic neuropathies (inherited causes of progressive optic nerve degeneration) through the incorporation of genomic medicine into clinical practice and expanding genetic testing services in the UK.[12] As a result, it is hoped that patients’ quality of life can be improved as they are able to access the appropriate care at an earlier stage and given the opportunity to participate in research and clinical trials. Furthermore, it can expand our understanding of how mutations in specific genes contribute to progressive optic nerve degeneration and visual loss by using stem cell-based or animal models.

In terms of potential therapies, the antioxidant idebenone (Raxone) is a promising option. Idebenone is an approved treatment in the UK and European Union (EU) for Leber Hereditary Optic Neuropathy (LHON), a type of inherited optic neuropathy also caused by dysfunction of the mitochondria. Treatment of dominant optic atrophy caused by mutations in the OPA1 gene has been investigated in a small number of patients, which showed visual stabilisation or recovery after taking the medication daily for at least 7 months.[13] Unlike the standard idebenone dose recommended for the treatment of LHON (900mg/day), the dosages taken among the patients in this small study ranged from 135mg/day to 675mg/day but most were on 540mg/day. While the results are promising, a well-designed standardised clinical trial is required to confirm this finding.

Related links

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Practical advice

Living with dominant optic atrophy

Patients are still able to lead independent lives through maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Utilising assistive technology to improve quality of life and aid independence
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
  • Registering as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page.

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Further information and support

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References

  1.  Yu-Wai-Man P, Chinnery PF. Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. Ophthalmology. Aug 2013;120(8):1712-1712.e1
  2.  Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy. Orphanet J Rare Dis. Jul 9 2012;7:46
  3.  Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. Mar 2010;133(Pt 3):771-86
  4.  Bonneau D, Colin E, Oca F, et al. Early-onset Behr syndrome due to compound heterozygous mutations in OPA1. Brain. Oct 2014;137(Pt 10):e301
  5.  Schaaf CP, Blazo M, Lewis RA, et al. Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations. Mol Genet Metab. Aug 2011;103(4):383-7
  6.  Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet. Dec 2001;69(6):1218-24
  7.  Yu-Wai-Man P, Griffiths PG, Burke A, et al. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. Aug 2010;117(8):1538-46, 1546.e1
  8.  Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res. Mar 2011;30(2):81-114
  9.  Santarelli R, Rossi R, Scimemi P, et al. OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. Brain. Mar 2015;138(Pt 3):563-76
  10.  Lenaers G, Reynier P, Elachouri G, et al. OPA1 functions in mitochondria and dysfunctions in optic nerve. Int J Biochem Cell Biol. Oct 2009;41(10):1866-74
  11.  Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. Jan 2004;23(1):53-89
  12.  Black GC, MacEwen C, Lotery AJ. The integration of genomics into clinical ophthalmic services in the UK. Eye. 2020/06/01 2020;34(6):993-996
  13.  Romagnoli M, La Morgia C, Carbonelli M, et al. Idebenone increases chance of stabilization/recovery of visual acuity in OPA1-dominant optic atrophy. Ann Clin Transl Neurol. Apr 2020;7(4):590-594

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Updated on March 14, 2021
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