LHON is caused by pathogenic variants in mitochondrial DNA (mtDNA) genes encoding subunits of Complex I (NADH dehydrogenase). Three common mtDNA variants — located in MT-ND1, MT-ND4, and MT-ND6 — account for approximately 90% of LHON cases. These mitochondrial genes are not captured in standard nuclear gene databases, representing a known data gap rather than an absence of established genetic etiology. The MT-ND4 variant is present in 60 to 70% of affected individuals of northern European descent and approximately 90% of those of Asian descent. The MT-ND6 variant predominates among individuals of French Canadian descent due to a founder effect. Inheritance is strictly maternal: affected males do not transmit the condition to any offspring, while carrier females transmit the variant to all offspring. Penetrance is reduced and variable. The two most important risk factors for developing visual loss are male sex (approximately 50% of male carriers develop blindness versus roughly 10% of female carriers) and age, with the 95th centile for age at onset being approximately 50 years across the three primary variants. Additional genetic and environmental factors interact with the primary mtDNA variant to influence whether visual loss ultimately develops. Heteroplasmy — the presence of a mixture of mutated and wild-type mtDNA — confers lower disease risk.

No published consensus clinical diagnostic criteria exist for LHON. The condition is suspected in individuals presenting with bilateral, painless subacute visual failure in young adulthood, with characteristic ophthalmologic findings: disk hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, increased vascular tortuosity, and optic disc atrophy. Visual field testing demonstrates an enlarging dense central or centrocecal scotoma. Approximately 20% of affected individuals show no fundal abnormalities in the acute stage. Extraocular features, when present, may include postural tremor, peripheral neuropathy, and cardiac arrhythmias. MRI is often normal but may reveal white matter lesions or high signal within the optic nerves. Biochemical studies show respiratory chain defects. Family history consistent with maternal inheritance provides supporting evidence. A diagnosis of LHON is established by molecular genetic testing demonstrating one of the three common mtDNA pathogenic variants. Targeted mtDNA analysis for the three primary variants is the recommended first step; if negative, a mitochondrial disease multigene panel including MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6 may be pursued. Complete mtDNA sequencing is available as a further option.

Management of LHON is largely supportive and includes provision of low-vision aids and occupational rehabilitation. Idebenone (Raxone) has been approved for the treatment of LHON under exceptional circumstances by the European Medicines Agency; available evidence suggests visual benefit in a subgroup of affected individuals, particularly those treated within the first year of disease onset. Three orphan drug designations target the underlying mitochondrial defect: elamipretide, idebenone, and lenadogene nolparvovec (an AAV-based gene therapy). Two additional gene therapy vectors targeting the ND1 and ND4 mitochondrial subunits have also received orphan designation. Individuals found to have pre-excitation syndrome on electrocardiogram may be referred to cardiology for assessment. Neurologic complications, when present, are managed within a multidisciplinary framework. Gene therapy is the most active area of therapeutic development, with multiple pivotal clinical trials ongoing.

Following the nadir of visual loss, some recovery of visual acuity may occur, though recovery is typically incomplete. Recovery rates vary substantially by the underlying mtDNA variant. In individuals with the MT-ND4 variant (the most common), visual recovery occurs in approximately 14% of all ages and 11% of those aged 15 years or older. The MT-ND6 variant is associated with recovery rates of 37 to 64%, while the MT-ND1 variant shows recovery in 15 to 25%, though it is regarded by experts as carrying the worst long-term prognosis. Predictors of better visual recovery include earlier age of onset (12 years or younger), a subacute presentation with slow visual deterioration, and a relatively large optic disc. LHON does not affect life expectancy in the majority of individuals. A small minority develop more severe neurologic complications, including an MS-like illness, which can compound visual impairment.

Gene therapy represents the most advanced area of LHON research. Multiple clinical trials are currently active or recruiting, including a Phase 3 multicenter randomized controlled trial (NCT07406854) evaluating intravitreal AAV2 delivery of the MT-ND4 gene for individuals with the m.11778G>A variant, a Phase 2 recruiting trial (NCT04912843), and a Phase 1 trial (NCT05293626) for the ND4 mutation. Published results from ongoing gene therapy programs have demonstrated significant visual improvement in treated individuals beyond what would be expected from the natural history of LHON. Hormone therapy investigation using estrogens in LHON cybrid cell lines has shown reduced reactive oxygen species levels and increased antioxidant enzyme activity. Metabolomics research (NCT06682819) is examining retinal nerve fiber layer changes. Mitochondrial replacement techniques, including pronuclear transfer and metaphase II spindle transfer, are under development as strategies to prevent maternal transmission of mtDNA pathogenic variants.