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.
• Vision in most patients tends to remain static, but spontaneous recovery is possible in some cases, which usually takes the form of ‘islands’ of vision within a central scotoma. A genotype-phenotype relationship has been reported for visual prognosis, as outlined in Table 1 below.

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 the 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). In those who do not have a mitochondrial variant, rare autosomal recessive nuclear DNA variants have been identified – 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 about 60% of families with mLHON is there a history of visual loss affecting the maternal relatives.

Genetic counselling can be further complicated by the fact that penetrance can vary markedly in different branches of the same family, as well as between families with the same LHON causing variant.

The two most important risk factors for vision loss are biological sex and age. About 50% of males and 90% of females with primary LHON-causing mtDNA variants do not develop blindness. Therefore, the majority of people with LHON-causing mtDNA variants remain asymptomatic.

With regards to age, the median age of onset for most LHON-causing mtDNA variants is between 20–30 years. For those with such variants who remain asymptomatic after this age, their risk of visual loss falls with every year they remain symptom free. While vision loss can occur at any age, over 90% of carriers who will experience visual loss do so before 50 years of age. In addition, smoking and excessive alcohol intake, particularly binge-drinking, have been associated with an increased risk of vision loss in LHON.

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.

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. In addition, 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

RESCUE, REVERSE and REFLECT are three phase III multicentre, randomised, double-masked clinical trials of lenadogene nolparvovec, which were conducted following REVEAL. At present, Lenadogene nolparvovec – a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4) – 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.

Gene-directed trials for LHON have mainly focused on the m.11778G>A variant in MT-ND4, all using lenadogene nolparvovec (rAAV2/2-ND4) delivered by intravitreal injection. The studies are described below. Further information about current trials, including those actively recruiting patients, can be found at the LHON society research website as well as at ClinicalTrials.gov – see Resources below.

REVEAL

This was a phase I/IIa open-label, single-centre, dose-escalation study. Participants with visual loss lasting between six months and 23 years received a unilateral intravitreal injection. The treatment was well tolerated and showed a good safety profile during five years of follow-up.

RESCUE

This phase III study’s recruited participants with up to six months of visual loss. The same agent and route of administration produced comparable visual outcomes in the injected and non-injected eyes.

REVERSE

This was a phase III study that recruited participants with visual loss of between six and 12 months. Bilateral improvements in visual acuity, contrast sensitivity and visual fields were seen.

REFLECT

Also a phase III study, participant recruitment criteria was 12 months of visual loss. In this study, one affected eye received an intravitreal injection and the other affected eye received either a second intravitreal injection or a placebo. There was a trend towards slightly better visual improvement with bilateral treatment.

RESTORE

This was a long-term follow-up study of RESCUE and REVERSE. It reported outcomes five years after unilateral intravitreal injection and showed, using a ‘locally estimated scatterplot smoothing’ (LOESS) nonparametric local regression model, a progressive and sustained improvement in best-corrected visual acuity from 12 to 51.5 months after the onset of vision loss.

For clinicians

• European Medicines Agency: Summary of opinion: Raxone (idebenone) (PDF, two pages)
• Gene Vision (about rare genetic eye disorders)
• GeneReviews: Leber Hereditary Optic Neuropathy
• LHON Society: Clinical trials in progress
• NHS England: National Genomic Test Directory
• US National Library of Medicine: ClinicalTrials.gov database

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