Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a rare genetic cause of visual loss. It is usually associated with variants in the mitochondrial genome, but can also be linked to nuclear-encoded mitochondrial genes. Loss of central vision is caused by the effect of variants within the retinal ganglion cells.

• LHON presents with progressive, painless sequential loss of vision in both eyes. Typically one eye is affected first, with the second eye becoming involved within months.
• Visual acuity is worse than 6/60, and often ‘off chart’ at what is known as ‘hand movements vision’ only.
• Colour vision is lost.
• The visual field shows a dense central anomaly.
• The pupil examination may be more brisk than expected for the amount of visual acuity and field loss.
• The optic nerve head may have subtle hyperaemia, peripapillary retinal telangiectasia and increased vascular tortuosity (this occurs early in the disease) and then optic pallor (which occurs late in the disease). Note that nearly one in five people at diagnosis appear to have no anomaly of the optic nerve.
• Neurological symptoms of LHON have been reported that overlap with other mitochondrial conditions. These include postural tremor, peripheral neuropathy, movement conditions, a multiple sclerosis-like illness, Leigh syndrome, nonspecific myopathy and cardiac arrhythmias.

It is likely that a combination of genetic and environmental influences play a role in symptomatic LHON. The three common primary point mitochondrial DNA variants are observed in approximately 90% of affected individuals (see Table 1).

Table 1: Three common point variants in mitochondrial gene responsible for LHON

Apart from the three common variants (Table 1), other variants in mitochondrial genes MT-ND1, MT-ND4, MT-ND6, MT-ND2, MT-ND4L and MT-ND5 have been found to cause LHON. Occasionally, variants in MT-ATP6, MT-CO3 and MT-CYB have also been reported. Recently, variants in a number of nuclear-encoded mitochondrial genes, including DNAJC30, have also been reported.

LHON is a mitochondrial condition and maternal inheritance is most common – this is known as mitochondrial LHON (mLHON). Rare autosomal recessive variants have been identified in those who do not have a mitochondrial variant – this is known as autosomal recessive LHON (arLHON).

Both mLHON and arLHON are associated with sex-dependent incomplete penetrance. Relatives of the affected individual may or may not have developed visual loss. Only in approximately 60% of families with mLHON is there a history of visual loss affecting the maternal relatives. In one nationwide cohort, the penetrance was reported to be 17.5% for males and 5.4% for females; the report concluded that the penetrance may be variant-specific. For patients with arLHON, transmission is the same as any other autosomal recessive condition. Gene-specific penetrance risks for arLHON are yet to be reported but are likely to be similar to mLHON. Incomplete penetrance can be a challenge when counselling people, because most individuals who have a genetic variant associated with LHON will remain asymptomatic.

Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are both possible; however, both require caution because inaccurate interpretation of a positive prenatal test can occur due to the difference of mutational load in the sample as compared to the rest of the fetus. The presence of a LHON-causing variant does not predict whether a person will become symptomatic through life, or what the age of disease onset, rate of progression or depth of visual loss will be if they do become symptomatic.

Management of people with LHON currently remains supportive, and includes provision of assistive aids, occupational rehabilitation and sight loss registration through the certificate of visual impairment.

Advice to the affected individuals should include not to smoke and to avoid moderate alcohol intake, and also to avoid binge-drinking of alcohol. In addition, it may be reasonable to suggest avoiding activities where head trauma could occur, as well as industrial toxins and drugs with mitochondrial toxic effects.

A referral should be made to cardiology for individuals with pre-excitation syndrome on electrocardiogram testing.

A referral should be made to neurology for affected individuals with extraocular neurologic features (such as ataxia, peripheral neuropathy, nonspecific myopathy and movement conditions).

Therapies and clinical trials

In the early 2010s, the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) evaluated a drug called idebenone in a randomised control trial. Idebenone is a synthetic hydrosoluble analogue of co-enzyme Q₁₀ (ubiquinone) and was found to be safe and well-tolerated. The European Medicine Agency granted idebenone orphan medicine status and authorised its use under exceptional circumstances to treat LHON in adolescents and adult patients at 900mg per day, divided into three doses.

Gene-directed therapies and clinical trials

Three Phase III multicentre, randomised, double-masked clinical trials of lenadogene nolparvovec have been conducted following an initial Phase I/IIa open-label, single-centre, dose-escalation clinical trial (Table 2). Lenadogene nolparvovec remains an experimental therapy that has not yet been recommended by major regulatory bodies; this is partly due to the unexpected observation of bilateral visual improvement with unilateral intravitreal injections and the lack of placebo-controlled arms in these trials.

Table 2: Gene-directed trials for LHON

Notes: LOESS is a nonparametric local regression model. rAAV2/2-ND4 means ‘recombinant adeno-associated virus vector 2, serotype 2’.

For clinicians

• European Medicines Agency: Summary of opinion: Raxone (idebenone) (PDF, two pages)
• NHS England: National Genomic Test Directory
• US National Library of Medicine ClinicalTrials database: Study to assess efficacy, safety and tolerability of idebenone in the treatment of Leber’s hereditary optic neuropathy (RHODOS)

References:

• Carbonelli M, de Coo IF, Valerio C and others. ‘International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy’. Journal of Neuro-Ophthalmology 2017: volume 37, issue 4, pages 371–381. DOI: 10.1097/WNO.0000000000000570
• Klopstock T, Konstantinos D, Yu-Wai-Man P and others. ‘A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy’. Brain 2011: volume 134, issue 9, pages 2,677–2,686. DOI: 10.1093/brain/awr170

For patients

• LHON
• LHON Society
• Royal National Institute for Blind People