Leber Hereditary Optic Neuropathy (LHON)
Leber Hereditary Optic Neuropathy (LHON): Overview, Symptoms, and Management
Leber Hereditary Optic Neuropathy (LHON) is a rare mitochondrial disorder characterized by sudden, painless vision loss due to degeneration of retinal ganglion cells and the optic nerve. It is the most common inherited mitochondrial disease, affecting approximately 1 in 30,000 to 1 in 50,000 individuals globally6. LHON primarily affects young males, with symptoms typically emerging between ages 15 and 35, though onset can occur from childhood to late adulthood16.
Symptoms
- Vision loss: Central vision deteriorates first, often beginning unilaterally before affecting the second eye within weeks to months16. Visual acuity drops sharply, and color perception is impaired.
- Ocular findings: In the acute phase, fundus examination reveals hyperemic optic discs, telangiectatic vessels, and retinal nerve fiber layer swelling68.
- LHON Plus: A rare variant (5–15% of cases) includes neurological symptoms such as tremors, cardiac conduction defects, or multiple sclerosis-like features16.
Genetic Causes
LHON is caused by mutations in mitochondrial DNA (mtDNA), inherited exclusively from the mother26. Over 90% of cases involve three primary mutations:
- m.11778G>A (MT-ND4 gene, 60–90% of cases)26.
- m.3460G>A (MT-ND1 gene)26.
- m.14484T>C (MT-ND6 gene)26.
These mutations disrupt complex I of the mitochondrial electron transport chain, impairing ATP production and increasing oxidative stress in metabolically active optic nerve cells56.
Epidemiology and Inheritance
- Gender disparity: Males are 3–8 times more likely to develop symptoms than females, though carriers of all genders can transmit the mutation67.
- Penetrance: Only 40–60% of males and 10–15% of females with mutations develop vision loss, suggesting environmental or nuclear genetic modifiers68.
Diagnosis
- Clinical evaluation: Sudden bilateral vision loss with characteristic fundus findings8.
- Genetic testing: Confirms mtDNA mutations via blood or saliva samples36.
- Differential diagnosis: Excludes optic neuritis, toxic/nutritional optic neuropathies, and dominant optic atrophy4.
Treatment and Prognosis
- Idebenone: A synthetic quinone antioxidant may slow progression if initiated early, though evidence of long-term efficacy is limited56.
- Supportive care: Low-vision aids, genetic counseling, and avoidance of triggers (e.g., smoking, alcohol)36.
- Experimental therapies: Gene therapy (e.g., allotopic expression of ND4) and stem cell approaches are under investigation6.
- Prognosis: Vision loss is permanent in most cases, but 4–20% of patients (particularly those with m.14484T>C) experience partial spontaneous recovery68.
Key Summary
| Feature | Details | Sources |
|---|---|---|
| Inheritance | Maternal mitochondrial DNA transmission | 26 |
| Primary Mutations | m.11778G>A, m.3460G>A, m.14484T>C (90% of cases) | 26 |
| Onset | Teens to 30s; rare in childhood or late adulthood | 16 |
| Vision Loss | Acute/subacute, central, bilateral (sequential or simultaneous) | 16 |
| Management | Idebenone, avoidance of toxins, low-vision support | 56 |
| LHON Plus | Neurological symptoms (tremors, cardiac defects, MS-like features) | 16 |
LHON exemplifies the intersection of mitochondrial genetics and neurodegenerative disease, emphasizing the need for early diagnosis and multidisciplinary care. While current treatments are limited, ongoing research into mitochondrial therapeutics offers hope for future interventions36.
Reference:
Carelli V, La Morgia C, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA. Leber Hereditary Optic Neuropathy: Mitochondrial Mutations and More. Biochim Biophys Acta. 2017 Jul;1863(6):1132-1141.
DOI: 10.1016/j.bbabio.2016.11.013
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