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The prevalence of the disease is estimated at 1/27,000 - 1/54,000 in Europe. Lower prevalence is reported in Australia (1 in 113,300) and in Serbia (1/526,000). The disease predominantly affects males, who are 4-5 times more likely to be affected and to lose vision.

Whilst carriers may remain asymptomatic, there may be recognizable changes on ophthalmological examination. Clinical onset of Leber hereditary optic neuropathy (LHON) is typically in young adulthood (age 18-30) and is divided into subacute (< 6 months from onset) and dynamic (6-12 months) stages. Typically, onset is with sudden, painless central vision loss that can occur in both eyes simultaneously or sequentially with vision loss in the second eye occurring weeks to months after the first eye. Visual loss generally stabilizes within 4 to 6 months. However, many patients will continue to show expansion of their central scotoma, producing a more profound level of blindness over a period of years (chronic stage). Extraocular symptoms (motor disorders, dystonia, postural tremor and cerebellar ataxia) are uncommon, but when present are known as Leber plus disease.

LHON is caused by mutations in the mitochondrial DNA (mtDNA). Over 90% have been identified to occur at nucleotide positions 3460, 11778 or 14484, respectively corresponding to the mtDNA respiratory chain complex I subunit genes MT-ND1, MT-ND4, and MT-ND6. Other genetic or epigenetic factors may have an effect on the development of this disease; in addition, the gene NDUFS2 (1q23.3) may be associated with a LHON-like phenotype.

The diagnosis is based on patient and family history, in addition to an ophthalmologic examination and genetic testing for mtDNA. Baseline examination should include visual acuity, color vision, fundus examination, visual fields, and optical coherence tomography (OCT) imaging. Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON. OCT confirms the swelling of the retinal nerve fiber layer. Red-green dyschromatopsia during color vision testing, and pseudopapilledema during fluorescein angiography are also observed. Snellen vision acuities of 20/200 or worse are typical.

Differential diagnosis includes optic neuritis, autosomal dominant optic atrophy (DOA), Wolfram syndrome, metabolic optic neuropathies (toxic, nutritional, and combinations), chiasmal tumors, and anterior ischemic optic neuropathy.

The prenatal presence of mtDNA pathogenic variant for LHON does not predict occurrence of disease, age of onset, or vision loss.

LHON is a maternally-inherited disease. Female carriers will pass the mutation to all their children, while male carriers will not pass the mutation to any children. Genetic counseling is recommended for affected families, though it is complicated by incomplete penetrance of pathogenic variants. Although, extremely rare, inheritance is autosomal recessive for NDUFS2.

Low-vision aids are the primary supportive care offered to patients. It is important that patients avoid toxic exposures such as alcohol, smoke (tobacco and environmental) and certain antibiotics that interfere with mitochondrial oxidative phosphorylation. Several compounds have shown positive results in moderating the visual loss. Idebenone (approved in the USA and Europe), shows a modest visual improvement after one year, and should be started as soon as possible in patients presenting within subacute and dynamic stages of disease (< 12 months). There is insufficient evidence at this time for treatment in chronic stage patients. Multiple clinical trials for other compounds and gene therapies are ongoing; notably EPI-743 has demonstrated efficacy in a small open label study for LHON.

The age of symptom onset and the causative mutation are factors that determine the disease outcome. Younger patients have a more favorable prognosis. Some patients, especially with the 14484 mutation, show spontaneous partial recovery 1-2 years after onset; whilst visual field improvement is usually incomplete, the recovery in visual acuity can be dramatic. In 30 to 50 % of male carriers and 80 to 90 % of female carriers, blindness will not ensue. Complete blindness is rare.