Overview
Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder causing acute or subacute bilateral central vision loss, predominantly in young males. It is caused by point mutations in mitochondrial DNA affecting Complex I of the respiratory chain, leading to retinal ganglion cell degeneration and optic atrophy. The three primary mutations (m.11778G>A, m.3460G>A, m.14484T>C) account for ~95% of cases. Males are affected 4–5x more often than females due to incomplete penetrance modifiers.
Genetics
Mitochondrial inheritance (maternal). Three primary mtDNA mutations account for ~95% of cases. Penetrance is incomplete — only 50% of males and 10% of females with a primary mutation develop vision loss.
| Gene | Locus | Inheritance | Notes |
|---|---|---|---|
| MT-ND4 (m.11778G>A) | mtDNA | Mitochondrial | Most common (70%); worst visual prognosis |
| MT-ND1 (m.3460G>A) | mtDNA | Mitochondrial | ~13% of cases |
| MT-ND6 (m.14484T>C) | mtDNA | Mitochondrial | ~14% of cases; best prognosis for spontaneous recovery |
Clinical Presentation
Acute phase (weeks–months)
- Painless central vision loss in one eye
- Second eye affected within weeks to months
- Central or cecocentral scotoma
Chronic phase
- Bilateral central vision loss (typically 20/200 or worse)
- Optic disc pallor
- Color vision severely affected
Spontaneous recovery (subset)
- Partial recovery possible, especially m.14484T>C
- More likely within first year
- Rare after 1 year
Diagnosis
- Clinical: Acute painless central vision loss in young male with family history
- Fundus: Peripapillary telangiectatic microangiopathy, disc pseudoedema (acute)
- OCT: Retinal nerve fiber layer (RNFL) thickening then thinning
- Visual field: Central or cecocentral scotoma
- Genetic testing: mtDNA sequencing for primary mutations
Current Research & Treatment
Idebenone (Raxone) is approved in Europe for LHON treatment. Gene therapy using AAV delivering a nuclear-encoded ND4 allophane (lenadogene nolparvovec/GenSight) received conditional approval in Europe (2021) for m.11778G>A LHON. Multiple additional gene therapy programs are in clinical trials.
Active Clinical Trials
The following active clinical trials are investigating treatments for Leber Hereditary Optic Neuropathy. Trial status and enrollment may change; always verify directly on ClinicalTrials.gov.