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Leber Hereditary Optic Neuropathy: for patients

Overview

Leber Hereditary Optic Neuropathy (LHON) is an inherited condition involving the optic nerve. It occurs in about 1 in 31 000 people in the UK and mostly affects men.[1] Most patients (90%) have one of three specific mutations in mitochondrial DNA, which are m.11778G>A, m.14484T>C and m.3460G>A.[2] The mitochondrion (plural: mitochondria) is a structure found within cells and play an important role in the generation of energy. The mutations affect the normal functioning of the mitochondria, which subsequently cause selective 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.

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

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The condition

Symptoms

1) Visual

Symptoms usually start during teenage years to early adulthood with blurring of vision in one eye that tends to be painless.[1] Similar symptoms then start occurring in the second eye, usually within 3 months of the first eye being affected, but it may take longer in some cases.[3] In about 25% of patients, blurry vision can start simultaneously in both eyes. Affected individuals may also notice that they are not able to recognise colour easily.

Over time, the condition progresses and vision start deteriorating, leading to a severe loss of visual sharpness/clarity (visual acuity) and blind spots in the central vision.[4] This leads to severe visual impairment in most patients as we require out central vision for most daily tasks, such as reading, recognising faces or watching TV. However, the peripheral (side) vision tends to remain unaffected and this provides useful vision for navigation.

The rate of visual decline is highly variable (rapid to over 2 years), but most patients are severely visual impaired by 3 or 4 months after symptoms first started. Some patients may partially regain a small amount of central vision, and this seems to be dependent on the associated mutation in the mitochondrial DNA. Those having the m.14484T>C mutation are more likely to experience small degree of visual recovery compared to the more common m.11778G>A mutation.[5]

2) Systemic (other body systems)

In some patients, they may also experience neurological symptoms such as muscle weakness and poor co-ordination (ataxia).[2,6] When LHON is associated with symptoms affecting other parts of the body, it is known as “LHON plus”.

Cause

LHON results from mutations in the mitochondrial DNA. Most patients (90%) have one of these three changes, m.3460G>A (MTND1 gene), m.11778G>A (MTND4 gene), and m.14484T>C (MTND6 gene). Out of which, the m.11778G>A is the most prevalent, accounting for up to 70% of cases.

Not all patients having these mutations are affected by LHON, and those that do not display any symptoms are called “carriers”. While carriers may not be affected at a certain point in time, they may become affected (conversion) in the future due to a variety of triggers, such as smoking and drinking excessive amount of alcohol.[7] The conversion rate in males is about 50% while it is about 10% in females.[2]

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 the central vision loss. Patients are asked to 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 is required to identify one of the three changes in the mitochondrial DNA associated with LHON.

2) General medical assessment

As patients affected by LHON 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 may also be referred to other doctors (most likely a neurologist) to make sure that the visual loss is not caused by other conditions.

How is it inherited?

1) Mitochondrial inheritance

Mitochondrial or maternal inheritance is by far the most common inheritance pattern seen in LHON. This is because when we are still a developing embryo in the womb, the mitochondrial DNA is wholly contributed by the female egg cells, unlike any other cells in the body, which the DNA is made up of genetic materials from both parents. As a result, the faulty mitochondrial DNA gene copy is passed down from the mother, and can affect both female and male offspring equally. An affected male does not pass the faulty mitochondrial DNA copy to his children.

2) Other inheritance patterns

Rarely, the faulty mitochondrial DNA copy can also be passed in an autosomal dominant, autosomal recessive or X-linked recessive pattern.

If you are affected by LHON, 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) Idebenone (Raxone)

Idebenone is an antioxidant approved for the treatment of LHON in the UK and the European Union (EU). This is mainly based on the result of a clinical trial investigating the effect of daily idebenone consumption on visual function compared to placebo. The results suggested that treatment with idebenone most likely benefit patients with discordant visual acuity (different visual acuity in the two eyes of a patient), who are probably at the earlier stages in the course of the condition. The study also reported that in 20% of idebenone-treated patients who could not read the visual acuity chart at start of the study, they could read at least one line on the chart by the end of the study.[8]

A follow-up study of a sub-group of these patients showed that the treatment effect persisted despite idebenone has been stopped for a median of 2.5 years.[9] The authors hypothesised that idebenone can preserve or re-establish retinal ganglion cell (collection of these cells form the optic nerve) connection during the initial stages of the disease, protecting it from irreversible damage.

Other studies observed that it can take an average of 17 months for some visual recovery in patients who were continuously kept on idebenone treatment.[10,11] This means that prolonged treatment may result in some degree of visual recovery even in patients with established disease. Current data also suggest that idebenone treatment has the most visual impact if initiated early in the disease course.[11] Therefore, the International Consensus Statement recommends idebenone (900mg/day) in LHON patients within twelve months of disease onset.[12]

2) Supportive visual measures

Apart from idabenone, there are no other approved treatment options that can reverse vision loss in LHON. 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

LHON carriers who do not have symptoms should be advised not to smoke and to avoid excessive consumption of alcohol, which can interfere with mitochondrial function increasing the risk of disease conversion and visual loss.[6]

2) Optimisation of development and educational support

If the onset of visual impairment occurs in early childhood, it can have a negative impact on a child’s early general development and education. Hence, children affected by LHON 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 Leber Hereditary Optic Neuropathy

1) Gene therapy

Mitochondrial replacement gene therapy is a promising therapeutic approach for LHON. The safety and efficacy of intravitreal mitochondrial gene delivery have been demonstrated in earlier clinical trials.[13-15] There are currently several ongoing phase 2/3 trials (REFLECT NCT 03293524; NCT 03153293) and one phase 1 trial (NCT 02161380). 96-week data of both the RESCUE and REVERSE phase 3 trials demonstrated that single intravitreal injection of the rAAV2/2-ND4 (GS010) gene therapy product in patients carrying the most common m.11778G>A mitochondrial DNA mutation resulted in improvements in visual function.[16]

Injection of a drug into the clear jelly (vitreous) of the eye.
Intravitreal injection

Related links

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Practical advice

Living with LHON

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, Griffiths PG, Hudson G, Chinnery PF. Inherited mitochondrial optic neuropathies. J Med Genet. Mar 2009;46(3):145-58. doi:10.1136/jmg.2007.054270
  2.  Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). May 2014;28(5):521-37. doi:10.1038/eye.2014.37
  3.  Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. Apr 1995;118 ( Pt 2):319-37. doi:10.1093/brain/118.2.319
  4.  Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol. Jun 15 1991;111(6):750-62. doi:10.1016/s0002-9394(14)76784-4
  5.  Johns DR, Heher KL, Miller NR, Smith KH. Leber’s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthalmol. Apr 1993;111(4):495-8. doi:10.1001/archopht.1993.01090040087038
  6.  Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol. Dec 2016;132(6):789-806. doi:10.1007/s00401-016-1625-2
  7.  Cui S, Jiang H, Peng J, Wang J, Zhang X. Evaluation of Vision-Related Quality of Life in Chinese Patients With Leber Hereditary Optic Neuropathy and the G11778A Mutation. J Neuroophthalmol. Mar 2019;39(1):56-59. doi:10.1097/wno.0000000000000644
  8.  Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. Sep 2011;134(Pt 9):2677-86. doi:10.1093/brain/awr170
  9.  Klopstock T, Metz G, Yu-Wai-Man P, et al. Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain. 2013;136(2):e230-e230. doi:10.1093/brain/aws279
  10.  Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. Sep 2000;20(3):166-70. doi:10.1097/00041327-200020030-00006
  11.  Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain. Sep 2011;134(Pt 9):e188. doi:10.1093/brain/awr180
  12.  Carelli V, Carbonelli M, de Coo IF, et al. International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy. J Neuroophthalmol. Dec 2017;37(4):371-381. doi:10.1097/wno.0000000000000570
  13.  Wan X, Pei H, Zhao MJ, et al. Efficacy and Safety of rAAV2-ND4 Treatment for Leber’s Hereditary Optic Neuropathy. Sci Rep. Feb 19 2016;6:21587. doi:10.1038/srep21587
  14.  Guy J, Feuer WJ, Davis JL, et al. Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results. Ophthalmology. Nov 2017;124(11):1621-1634. doi:10.1016/j.ophtha.2017.05.016
  15.  Vignal C, Uretsky S, Fitoussi S, et al. Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy. Ophthalmology. Jun 2018;125(6):945-947. doi:10.1016/j.ophtha.2017.12.036
  16.  Moster M, Sadun A, Klopstock T, et al. rAAV2/2-ND4 for the Treatment of Leber Hereditary Optic Neuropathy (LHON): Final Results from the RESCUE and REVERSE Phase III Clinical Trials and Experimental Data in Nonhuman Primates to Support a Bilateral Effect (2339). Neurology. 2020;94(15 Supplement):2339

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Updated on January 29, 2021
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