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Leber Hereditary Optic Neuropathy: for professionals


Overview

Incidence
  • At least 1:31,000 in Northern UK[1]
  • Marked male preponderance
Inheritance
  • Mitochondrial inheritance mostly
Genes involved (OMIM No.)
Symptoms
  • Peak onset: 2nd to 3rd decade of life
  • Sequential, painless loss of vision
  • Second eye involvement occurs 3 months after the first eye on average
Signs
  • Severe reduction in visual acuity
  • Severe dyschromatopsia
  • Dense central/centrocaecal scotoma
  • Acute phase (hyperaemic disc, telangiectatic vessels, RNFL swelling); 40% of patients may have no fundal abnormalities
  • Normal pupillary response
  • Chronic phase (optic disc atrophy)
  • Spontaneous recovery in some patients
Systemic features
  • Mainly isolated ocular involvement
  • Ataxia
  • Dystonia
  • Peripheral neuropathy
  • Cardiac conduction abnormalities
Key investigations
  • Orthoptic assessment and refraction
  • Colour vision testing
  • Formal visual field testing (if possible)
  • Optic nerve head photographs
  • OCT of optic nerve head
  • Electrophysiology
  • MRI brain
  • Audiology
  • Systemic assessment with pediatricians, neurologists, and other relevant specialists if indicated
Molecular diagnosis
  • Targeted genetic sequencing of the mitochondrial DNA
ManagementOcular
  • Supportive management
  • Idebenone (900mg/day) can be initiated if disease onset is within 12 months
Systemic
  • Multidisciplinary approach if systemic features are present
Therapies under research
  • Gene therapy (phase 3)

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Clinical phenotype

Leber Hereditary Optic Neuropathy (LHON) is an inherited optic neuropathy with a male preponderance and peak onset in the second to third decades of life.[1] LHON is characterised classically by a sequential, painless loss of central vision. Symptom onset in the second eye usually occur on average three months after the first eye being symptomatic.[2] Simultaneous bilateral involvement is seen in about a quarter of patients.

Visual function is severely affected, with severe dyschromatopsia, dense central or centrocaecal scotoma and poor visual acuity (Snellen 6/60 or worse).[3] Pupillary response is often intact due to the relative sparing of melanopsin-containing retinal ganglion cells.

In the acute phase, disc hyperaemia, telengiectatic vessels around the disc, tortuosity of the posterior pole vessels and retinal nerve fibre layer (RNFL) swelling can be observed, though about 40% of patients do not display any significant fundal abnormalities during this stage.[4] Optical coherence tomography (OCT) imaging of the disc during the acute phase show an increase in peripapillary RNFL thickness, which is least marked in the temporal disc quadrant, indicating that the temporal nerve fibres are affected the earliest.[5] As the condition progresses, the optic disc becomes atrophic with global RNFL thinning, though the nasal quadrant can be relatively spared.

The vision in most patients tend to remain static, but spontaneous recovery is possible in some cases, which usually takes the form of fenestrations or ‘islands’ of vision within the central scotoma. Spontaneous recovery, if present, most often occur in the first year but it can occur years later as well. A genotype-phenotype relationship can be observed in this aspect, where patients harbouring the m.14484T>C mutation (37%) are more likely to experience partial visual recovery compared to those with m.11778G>A (5%) and m.3406G>A (22%) variants.[6] Other favourable factors include younger age of symptom onset and subacute presentation with a slower worsening of vision. On the other hand, environmental factors, particularly smoking and to a lesser degree heavy drinking, may contribute towards visual loss.[7]

Extraocular features

Most patients have isolated ocular involvement, but a range of systemic features have been reported in some case series.[8,9] These include:

  • Cardiac conduction defects
  • Ataxia
  • Myopathy
  • Dystonia
  • Peripheral neuropathy

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Genetics

The majority of cases (90%) are caused by three variants in the mitochondrial DNA, namely the m.11778G>A, m.14484T>C and m.3460G>A.[9] The m.1178G>A variant is the most common, accounting for up to 70% of all cases.

There is considerable clinical heterogeneity among families with LHON due to incomplete penetrance. The conversion rate for male carriers is approximately 50%, while for female carriers it is much lower at 10%.[9] Asymptomatic LHON carriers 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.[10]

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Key investigations

Ocular

1) Orthoptic assessment and refraction

This is to document baseline visual function and assess if vision can be optimised with correction of refractive error (if present).

2) Colour vision testing

Patients usually have severe dyschromatopsia.

3) Perimetry

A formal visual field test should be performed if the child is able to cooperate to document any central/centrocaecal scotoma. In the initial stages, 24-2 perimetry can assess for any central field but Goldmann visual field is usually required in more advanced cases where the scotoma extends beyond the central 20 degrees.

4) Optic nerve head imaging

A colour photograph of the optic disc should be obtained for future comparisons.  Optical coherence tomography of the optic disc and macula should also be undertaken. Measurements of the peripapillary retinal nerve fibre layer (RNFL) thickness, peripapillary and macular retinal ganglion cell thickness should be included. There is usually a global thinning of the peripapillary RNFL, although the nasal quadrant is often relatively spared.

5) Electrophysiology

A reduced N95:P50 ratio on pattern electroretinogram (ERG) in the presence of a normal pattern visual evoked potential (VEP) usually indicates retinal ganglion cell dysfunction in early cases of inherited optic neuropathies.

Systemic

Systemic input is usually not required for LHON unless there are specific concerns from history taking or clinical examination. However, a systemic assessment either by a paediatrician (in children) or a neurologist (in adults) may need to be undertaken initially when a patient first present with an optic neuropathy to exclude compressive, inflammatory, toxic, nutritional or metabolic causes for.

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Diagnosis

Optic neuropathy can be diagnosed clinically but a diagnosis of LHON can only be confirmed via genetic testing. A targeted sequencing of the mitochondrial DNA is usually performed to look for the three most common variants associated with LHON. In addition to diagnosis, genetic testing can also facilitate genetic counselling, provide accurate advice on prognosis and future family planning, and aid in clinical trial participation.

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Management

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 randomised placebo-controlled trial where patients were treated with either idebenone or placebo for 6 months. The results suggested that treatment with idebenone most likely benefit patients with discordant visual acuity, who are probably at the early stages of the disease course. 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.[11]

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.[12] The authors hypothesised that idebenone can preserve or re-establish retinal ganglion cell 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 visual recovery in patients who were continuously kept on idebenone treatment.[13,14] 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.[14] Therefore, the International Consensus Statement recommends idebenone (900mg/day) in LHON patients within twelve months of disease onset.[15]

2) Supportive management

Other than idebenone, the management of LHON is mainly supportive, which include:

  • Correcting any refractive errors
  • Referral to low vision services
  • Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
  • Smoking cessation
  • Avoid heavy consumption of alcohol
  • Encourage the use of assistive technology that may improve quality of life

Optimisation of development

As vision is important in normal childhood development and education, children with visual impairment due to 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.

Family management and counselling

LHON is mostly inherited in a mitochondrial (maternal) manner. The associated genetic variants can also be inherited in an autosomal dominantautosomal recessive or X-linked recessive manner.

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis. Counselling may be challenging due to incomplete penetrance of the associated genetic variants but it should not be an obstacle to support families in making informed medical and personal decisions.

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.

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Referral to a specialist service

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 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.[16-18] There are currently several ongoing phase 2/3 trials (REFLECT NCT 03293524NCT 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 clinically meaningful improvements in visual function.[19]

Related links

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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.  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
  3.  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
  4.  Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. Jul-Aug 2010;55(4):299-334. doi:10.1016/j.survophthal.2009.10.002
  5.  Barboni P, Savini G, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy. Ophthalmology. Jan 2005;112(1):120-6. doi:10.1016/j.ophtha.2004.06.034
  6.  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
  7.  Kirkman MA, Korsten A, Leonhardt M, et al. Quality of life in patients with leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. Jul 2009;50(7):3112-5. doi:10.1167/iovs.08-3166
  8.  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
  9.  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
  10.  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
  11.  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
  12.  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
  13.  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
  14.  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
  15.  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
  16.  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
  17.  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
  18.  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
  19.  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 18, 2021

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