Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON), also known as Leber optic atrophy, is a maternally inherited mitochondrial disorder that primarily affects the optic nerves, leading to rapid and severe loss of central vision. The disease is caused by point mutations in mitochondrial DNA (mtDNA) that impair complex I of the mitochondrial respiratory chain. The three most common pathogenic variants account for approximately 90% of cases: m.11778G>A (in MT-ND4), m.3460G>A (in MT-ND1), and m.14484T>C (in MT-ND6). LHON predominantly affects young adult males, with a male-to-female ratio of approximately 4-5:1, though the reasons for this sex bias remain incompletely understood. The hallmark presentation is painless, acute or subacute loss of central vision, typically beginning in one eye and affecting the second eye within weeks to months (sequential bilateral involvement). Patients experience blurred vision, loss of color perception (dyschromatopsia), and a central or cecocentral scotoma (blind spot). In the acute phase, the optic disc may appear hyperemic with peripapillary telangiectatic microangiopathy and swelling of the retinal nerve fiber layer, though the disc can also appear normal. Over time, optic atrophy develops. While LHON primarily affects the visual system, some patients may develop additional neurological features such as tremor, peripheral neuropathy, or dystonia, sometimes referred to as "LHON plus" syndromes. Cardiac conduction abnormalities, including pre-excitation syndromes, have also been reported in some families. The treatment landscape for LHON has evolved significantly. Idebenone (a synthetic analogue of coenzyme Q10) has been approved in Europe for the treatment of LHON and may improve visual outcomes, particularly when initiated early in the disease course. Gene therapy using intravitreal injection of an adeno-associated viral vector carrying the wild-type ND4 gene (lenadogene nolparvovec) has been approved in some jurisdictions for patients with the m.11778G>A mutation. Spontaneous partial visual recovery can occur, most commonly in patients carrying the m.14484T>C mutation. Patients are advised to avoid tobacco smoking and excessive alcohol consumption, as these environmental factors may trigger or worsen visual loss. Genetic counseling is important, as all children of an affected mother will inherit the mitochondrial mutation, though incomplete penetrance means not all carriers will develop symptoms.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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