Leber's hereditary optic neuropathy

A mitochondrially inherited degeneration of retinal cells in human

Leber's hereditary optic neuropathy
Synonyms	Leber hereditary optic atrophy
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Field	Ophthalmology, Neurology, Genetics
Symptoms	Sudden vision loss, optic atrophy, color vision impairment, ceco-central scotoma, pupillary defect
Complications	Permanent vision loss, cardiac arrhythmia, neuropathy, multiple sclerosis-like symptoms (LHON Plus)
Onset	Typically 15–35 years (range 7–75 years)
Duration	Progressive and permanent
Types	Classical LHON, LHON Plus (with neurological features)
Causes	Mitochondrial DNA mutations in MT-ND1, MT-ND4, MT-ND4L, MT-ND6 genes
Risks	Male sex, smoking, alcohol, certain medications, environmental factors
Diagnosis	Genetic testing, fundus photography, optical coherence tomography, visual field test, electroretinogram, MRI
Differential diagnosis	Optic neuritis, ischemic optic neuropathy, dominant optic atrophy, toxic optic neuropathy
Prevention	Avoiding smoking, alcohol, and mitochondrial-toxic drugs
Treatment	Idebenone, estrogen replacement therapy (in women), antioxidant therapies, experimental gene therapy
Medication	Idebenone, vitamin B2, antioxidants
Prognosis	Variable; some spontaneous recovery, but most cases lead to permanent vision impairment
Frequency	1:30,000 to 1:50,000 (Europe); more common in certain populations
Deaths	Rare, but associated neurological complications may be life-threatening

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited condition characterized by the degeneration of retinal ganglion cells (RGCs) and their associated axons. This degeneration leads to a rapid and often irreversible loss of central vision, predominantly affecting young adult males. The disorder is inherited exclusively through the maternal lineage, as the mitochondrial DNA (mtDNA) is transmitted only through the egg, ensuring that males cannot pass it on to their offspring.

The primary cause of LHON is specific mutations in mitochondrial genes that disrupt the function of oxidative phosphorylation within the electron transport chain. The three most common point mutations occur at nucleotide positions 11778 in the MT-ND4 gene, 3460 in the MT-ND1 gene, and 14484 in the MT-ND6 gene. These mutations affect complex I of the mitochondrial respiratory chain, leading to increased reactive oxygen species production and subsequent cell death of optic nerve fibers.

Signs and Symptoms

The initial symptoms of LHON typically involve painless, subacute visual loss, which usually begins in one eye and progresses to involve the second eye within weeks or months. The onset age ranges from 7 to 75 years, though it is most common in young adulthood. Onset is slightly later in females than in males.

Key clinical features include:

• Sudden central vision loss leading to severe visual impairment.
• Optic atrophy, visible as pallor of the optic disc upon fundoscopy.
• Cecocentral scotoma, an area of visual field loss affecting the center of vision.
• Loss of color vision, specifically in the red-green spectrum.
• Afferent pupillary defect, indicating asymmetric optic nerve dysfunction.

The progression of LHON usually stabilizes within six months to a year, but in most cases, visual acuity remains significantly impaired.

LHON Plus

A more severe variant known as LHON Plus is associated with additional neurological symptoms, including:

• Dystonia, an involuntary muscle contraction leading to repetitive movements.
• Multiple sclerosis-like features, including demyelination and ataxia.
• Cardiac arrhythmia, which can lead to complications such as heart block.

This form of LHON suggests that mitochondrial dysfunction extends beyond the optic nerve, affecting other parts of the central nervous system.

Genetics

LHON is caused by mutations in mitochondrial genes involved in the NADH dehydrogenase complex:

• MT-ND1 (3460G>A mutation)
• MT-ND4 (11778G>A mutation, the most common)
• MT-ND6 (14484T>C mutation, associated with better visual recovery)

Because these genes are located in the mitochondrial genome, LHON follows maternal inheritance, meaning all affected individuals inherit the mutation from their mother.

Factors influencing disease expression include:

• Heteroplasmy – The proportion of mutated mtDNA within a cell influences disease severity.
• Mitochondrial haplogroups – Some genetic backgrounds are more susceptible to disease onset.
• Environmental triggers – Tobacco, alcohol, and certain medications (e.g., ethambutol) may increase the likelihood of symptom manifestation.

Pathophysiology

The retinal ganglion cells are particularly susceptible to mitochondrial dysfunction due to their high energy demands. Key pathological mechanisms include:

• Increased oxidative stress due to mitochondrial dysfunction.
• Disruption of ATP production, leading to impaired neuronal signaling.
• Excitotoxicity, where excessive glutamate accumulation damages neurons.
• Selective vulnerability of the maculopapillary bundle, leading to loss of central vision while peripheral vision remains intact.

Diagnosis

LHON is diagnosed based on:

• Clinical findings – Sudden, painless central vision loss in young individuals.
• Fundoscopic examination – Shows optic disc edema followed by optic atrophy.
• Molecular genetic testing – Confirms the presence of MT-ND mutations.
• Optical coherence tomography (OCT) – Assesses retinal nerve fiber layer thinning.
• Visual evoked potentials (VEP) – Measures optic nerve function.

Treatment

There is no universally effective cure for LHON, but several therapeutic approaches have been explored:

• Idebenone – A synthetic analog of Coenzyme Q10, which may improve mitochondrial function and reduce oxidative damage.
• Gene therapy – Experimental techniques using viral vectors to deliver functional copies of the ND4 gene are under investigation.
• Mitochondrial-targeted antioxidants – Compounds such as EPI-743 and MTP-131 (elamipretide) aim to stabilize mitochondrial membranes.
• Hormone replacement therapy (HRT) – Estrogens may offer neuroprotection by reducing oxidative stress, particularly in female carriers.

Supportive Care:

• Low-vision aids – To help individuals adapt to visual impairment.
• Avoidance of environmental triggers – Smoking, alcohol, and certain medications should be avoided.
• Regular monitoring – Follow-up with an ophthalmologist and neurologist is recommended.

Epidemiology

The prevalence of LHON is approximately 1 in 30,000 to 1 in 50,000 individuals. The condition is most common in Northern European and Asian populations, with the 11778 mutation being predominant.

Men are significantly more affected than women, with a male-to-female ratio of 4:1 to 8:1, depending on the mutation type. However, many individuals carrying the mutation remain asymptomatic, suggesting that additional genetic and environmental factors influence disease expression.

History

LHON was first described by Theodor Leber in 1871, who observed maternal inheritance patterns of vision loss among young men. It was initially thought to be an X-linked disorder, but later studies confirmed its mitochondrial inheritance.

In 1988, the first mitochondrial DNA mutation (11778G>A) associated with LHON was identified, paving the way for genetic diagnosis and research into mitochondrial diseases.

Research and Future Directions

Several experimental approaches are under investigation for treating LHON:

• Gene therapy – The use of AAV (adeno-associated virus) vectors to deliver functional ND4 genes into the retina.
• Stem cell therapy – Exploring the potential of neural progenitor cells to regenerate damaged optic nerve fibers.
• Mitochondrial transplantation – Transferring healthy mitochondria into affected optic nerve cells.
• Three-parent IVF – A technique to prevent LHON transmission by using donor mitochondria in fertilized embryos.

See Also

• Optic atrophy
• Dominant optic atrophy
• Ischemic optic neuropathy
• Multiple sclerosis
• Toxic and Nutritional Optic Neuropathy
• Gene therapy

External Links

• NCBI Genetic Testing Registry
• Online Mendelian Inheritance in Man (OMIM) – LHON

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