About LHON
What is LHON?
Leber hereditary optic neuropathy (LHON) is an inherited form of mitochondrial disease resulting in rapid central vision loss.1,2
- LHON was the first human condition linked to a point mutation in the mitochondrial DNA (mtDNA). These mutations affect subunit genes of Complex I.3
- LHON presents with subacute, simultaneous or sequential, bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells (RGCs) and their axons.2 These cells are particularly vulnerable to mitochondrial dysfunction leading to optic nerve atrophy and loss of central vision.2
- Most patients with LHON end up legally blind.1
Eliane, Living with LHON
LHON is a mitochondrial disorder that results from point mutations in the mtDNA that encode components of respiratory Complex I (see figure below). Approximately 90% of the LHON cases come from three primary mtDNA mutations (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, and m.14484T>C in MT-ND6) that are maternally inherited.2,4
Although an mtDNA pathogenic mutation is an important factor, other mitochondrial, nuclear genetic, and environmental factors are also known to trigger LHON.5Membrane complexes in the mitochondrial respiratory chains4
ADP, adenosine diphosphate; ATP, adenosine triphosphate; CyC, cytochrome C; LHON, Leber hereditary optic neuropathy; NAD+/NADH, nicotinamide adenine dinucleotide; UC, uncoupling protein.
LHON affects predominantly men in their 20s or 30s and is most commonly seen in teenage boys and young men, which account for 80% of new cases.1,6
However, it can occur in individuals of all ages, including children and the elderly.1 Unlike men, women have no peak onset age.7 Men are three times more likely to be affected than women, but neither gender nor mutational status significantly influences the timing and severity of the initial visual loss.7 Recent evidence also suggests a protective role of estrogen and could explain LHON vision loss in menopausal women, given the declining levels of estrogen.8Who is at risk
.png)
Eliane (in green), Living with LHON
Genetic confirmation of an LHON mutation means everyone on the maternal bloodline is at risk9
.png)
PAOLA AND GIANFRANCO, Living with LHON
LHON affects both men and women7
.png)
SEBASTIAN, Living with LHON
LHON is most frequently diagnosed in men in their teens or early 20s1,6
What LHON eyesight looks like
People with LHON experience sudden, painless visual loss either in both eyes simultaneously (one in four cases) or sequentially with the second eye showing symptoms within 8 weeks (three in four cases).5 The most characteristic feature of LHON is an enlarging central or centrocecal scotoma.5 As the field defect increases in size and density, visual acuity deteriorates to the level of counting fingers or worse.5
Sebastian, Living with LHON
Optic disc images of 17-year-old boy with LHON from presymptomatic to chronic stage10
A
B
A
6 weeks before onset of visual loss: initial papillomacular bundle defect in the inferotemporal sector associated with diffuse hyperemia of the disc (*)10
B
4 weeks before onset: progression of the papillomacular bundle defect(**)10
C
D
C
9 months after onset: optic atrophy with complete loss of papillomacular bundle10
D
17 months after onset: complete and severe optic atrophy10
Signs and symptoms
Patients are usually entirely asymptomatic until they develop painless visual blurring affecting the central visual field in one eye (acute phase).11 Similar symptoms appear in the other eye within weeks or months, with at least 97% of affected individuals having bilateral involvement within one year.4 Unilateral LHON is very rare.5
Bilateral, painless subacute visual failure that develops during young adult life11
- Disease progression is rapid in the acute phase, with visual acuity being diminished to ≤2/20 within 5 to 6 weeks of the onset of symptoms5
- Visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma11
No periocular pain, no pain at eye mobilization4
Disc hyperemia, edema of the peripapillary retinal nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity11
- ~20% of affected individuals show no fundal abnormalities in the acute stage
Optic disc atrophy11
Green-red dyschromatopsia11,12
Optic nerve dysfunction and absence of other retinal disease alterations on electrophysiologic studies9
Pupillary reflexes are preserved in the early phase (6–12 months) and patients usually report no pain on eye movement4
Potential risk factorsand triggers
A number of environmental factors are also known to trigger LHON in unaffected carriers. Advise patients about avoiding potentially preventable lifestyle risk factors for vision loss.12
Risk factors:
Smoke in general (not just tobacco smoking)
Heavy alcohol consumption
Cyanide-containing products
Exposure to environmental factors, like pesticides and methanol, especially during the acute phase of visual loss
Further triggers of LHON may include:
Medications with mitochondrial toxicity, including antibiotics such as ethambutol, chloramphenicol, linezolid, aminoglycosides, and antiretroviral drugs (for HIV)12
References
- Theodorou-Kanakari A, et al. Adv Ther. 2018;35(10):1510-1518.
- Kirches E. Curr Genomics. 2011;12(1):44-54.
- Carelli V, et al. Hum Mol Genet. 2017;26(R2):R139-R150.
- Carelli V, et al. European Ophthalmic Review. 2019;13(Suppl 2).
- Karaarslan C. Adv Ther. 2019;36(12):3299-3307.
- Stenton SL, et al. J Clin Invest. 2021;131(6):e138267.
- Poincenot L, et al. Ophthalmology. 2020;127(5):679-688.
- Asanad S, et al. J Curr Ophthalmol. 2019;31(3):251-253.
- Fraser JA, et al. Surv Ophthalmol. 2010;55(4):299-334.
- Atlas of Leber’s Hereditary Optic Neuropathy, 2018, MEDonline, ISBN: 978-90-828166-0-0
- Yu-Wai-Man P, et al. Leber Hereditary Optic Neuropathy. 2000. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Updated March 2021.
- Sadun A, et al. Curr Treat Options Neurol. 2011;13(1):109-117.