Leber Hereditary Optic Neuropathy (LHON)

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial genetic disorder that causes rapid, severe, and often permanent vision loss in young adults. It predominantly affects males and is one of the most common inherited optic neuropathies, with an estimated prevalence of 1 in 30,000 to 50,000 people.

Understanding the Disease

Pathophysiology

LHON results from mutations in mitochondrial DNA (mtDNA) that encode subunits of Complex I of the electron transport chain. This impairs cellular energy production (ATP synthesis) specifically in retinal ganglion cells, which have high energy demands. The optic nerve, composed of retinal ganglion cell axons, is particularly vulnerable to this energy failure.

The selective vulnerability of certain cells despite a systemic genetic defect remains an area of active research. Current theories suggest that retinal ganglion cells are especially susceptible due to:

• High metabolic demands from continuous neural signaling
• Long unmyelinated axon segments within the retina
• Unique structural features requiring robust energy supply

Genetics

LHON follows mitochondrial inheritance:

• Mitochondria (and their DNA) come only from the mother
• All children of an affected/carrier mother inherit the mutation
• Fathers cannot pass the mutation to their children
• Having the mutation doesn't guarantee developing symptoms (incomplete penetrance)

Three primary mutations cause approximately 90% of LHON cases:

• m.11778G>A (ND4 gene)—most common, ~70% of cases, worst prognosis
• m.3460G>A (ND1 gene)—~15% of cases
• m.14484T>C (ND6 gene)—~15% of cases, best prognosis for spontaneous recovery

Penetrance

Not everyone with the mutation develops vision loss:

• ~50% of males with the mutation develop LHON
• ~15% of females with the mutation develop LHON
• Reasons for incomplete penetrance not fully understood
• Environmental and other genetic factors likely play a role

Epidemiology

• Prevalence: 1 in 30,000 to 50,000 in most populations
• Higher in certain regions: More common in Northern Europe
• Age of onset: Peak 15-35 years (range: childhood to 60+)
• Male predominance: Male-to-female ratio approximately 4:1

Symptoms

Initial Presentation

• Sudden, painless central vision loss in one eye
• Often noticed upon waking or when covering the other eye
• No eye pain or discomfort (unlike optic neuritis)
• Vision may seem "foggy" or "washed out"

Progression

• Second eye involvement typically within 2-3 months (range: days to years)
• Bilateral simultaneous onset occurs in ~25% of cases
• Vision usually declines to 20/200 or worse (legal blindness)
• Central scotoma (blind spot) develops in each eye
• Color vision severely affected—dyschromatopsia, especially red-green

What's Preserved

• Peripheral vision typically remains intact
• Pupils remain reactive (though may show RAPD)
• No double vision or other neurological symptoms

Risk Factors and Triggers

Several factors may trigger vision loss in genetically susceptible individuals:

Strongly Associated

• Tobacco smoking—significantly increases risk
• Heavy alcohol use—especially in combination with smoking
• Male sex—higher penetrance in males

Potentially Associated

• Certain medications (ethambutol, linezolid, erythromycin)
• Nutritional deficiencies (B vitamins, folate)
• Environmental toxins
• Psychological stress
• Head trauma

Diagnosis

Clinical Features

• Young adult (typically male) with acute/subacute painless vision loss
• Characteristic fundus appearance early: circumpapillary telangiectasia, pseudoedema of the disc
• Later: optic disc pallor (atrophy)
• Central scotoma on visual field testing
• RAPD when asymmetric

Genetic Testing

• Confirmatory: Blood test for mtDNA mutations
• Tests for the three common mutations and can include full mtDNA sequencing
• Turnaround time typically 2-4 weeks
• Should be offered to family members

Imaging and Other Tests

• OCT: Shows characteristic retinal nerve fiber layer (RNFL) changes—initial swelling followed by progressive thinning
• MRI brain and orbits: Usually normal; rules out other causes of optic neuropathy
• Visual field testing: Central or cecocentral scotomas
• Color vision testing: Marked dyschromatopsia

Differential Diagnosis

Other conditions to consider:

• Optic neuritis—typically painful, MS-associated
• Ischemic optic neuropathy—usually older patients, sudden onset
• Compressive optic neuropathy—from tumors or other masses
• Toxic/nutritional optic neuropathy—medication or deficiency history
• Autosomal dominant optic atrophy (Kjer disease)—different inheritance pattern

Treatment

Idebenone (Raxone)

Currently the only approved treatment in many countries:

• Synthetic analogue of coenzyme Q10
• Bypasses defective Complex I in electron transport chain
• Most effective when started early in disease course (within first year)
• Dose: 900 mg/day (300 mg three times daily)
• Best evidence in patients with discordant visual acuity between eyes
• May prevent or reduce second eye involvement if started after first eye affected

Supportive Care

• Low vision rehabilitation—essential for adapting to vision loss
• Occupational therapy—for daily living skills
• Assistive devices—magnifiers, screen readers, audio descriptions
• Counseling and support groups—emotional adjustment

Investigational Therapies

• Gene therapy—clinical trials ongoing with promising early results
• Intravitreal injection of viral vector carrying normal gene
• Stem cell therapy—in early research stages
• EPI-743—antioxidant under investigation

What to Avoid

• Tobacco (essential to stop completely)
• Excessive alcohol
• Medications that may worsen: ethambutol, linezolid, certain antibiotics (discuss all medications with your doctor)

Prognosis

Visual Outcomes

• Final visual acuity typically 20/200 or worse in most patients
• Central scotoma usually permanent
• Spontaneous recovery occurs in some patients:
  • ~4% with m.11778G>A mutation
  • ~15-25% with m.3460G>A mutation
  • ~37-65% with m.14484T>C mutation (best prognosis)
• Recovery, if it occurs, typically begins 1-2 years after onset
• Younger age at onset associated with better recovery rates

With Treatment

• Idebenone may improve outcomes in some patients
• Best results when started early and in patients with recent vision loss
• May prevent or reduce severity in second eye

Living with LHON

Adapting to Vision Loss

• Central vision loss with preserved peripheral vision creates unique challenges
• Face recognition, reading, and driving are most affected
• Many people adapt well and maintain independence with proper support

Practical Strategies

• Use high-contrast materials and good lighting
• Magnification devices for reading
• Audiobooks and text-to-speech technology
• Eccentric viewing training
• Mobility training if needed

Emotional Support

• Sudden severe vision loss is emotionally challenging
• Grief and adjustment are normal processes
• Support groups for LHON patients and families exist
• Mental health support may be helpful

Genetic Implications for Family

• All maternal relatives should be informed of their risk
• Genetic testing available for family members
• Carrier status doesn't predict if/when symptoms will develop
• Female carriers have lower but real risk of vision loss
• Genetic counseling recommended for family planning

Frequently Asked Questions

Can LHON affect both eyes at the same time?

Yes, in about 25% of cases, both eyes are affected simultaneously. More commonly, one eye is affected first, followed by the second eye weeks to months later.

Is there any way to prevent vision loss if I carry the mutation?

Complete prevention isn't guaranteed, but avoiding smoking, limiting alcohol, and possibly taking idebenone may reduce your risk or the severity of vision loss. Not everyone with the mutation develops symptoms.

Will I go completely blind?

No. LHON affects central vision, but peripheral vision is typically preserved. This means you can usually navigate and see objects around you, but fine detail and reading become very difficult.

Can my children develop LHON?

If you are female with the mutation, all your children will inherit it (but may not develop symptoms). If you are male, you cannot pass the mutation to your children since mitochondria come from the mother.

Should my family members get tested?

Yes, genetic counseling and testing should be offered to maternal relatives. This allows for appropriate lifestyle modifications and monitoring.

Are there clinical trials I can participate in?

Yes, several clinical trials are ongoing, particularly for gene therapy. Your neuro-ophthalmologist can provide information about current trials. ClinicalTrials.gov lists ongoing studies.

Is LHON the same as Leber congenital amaurosis?

No. Despite similar names, these are different conditions. Leber congenital amaurosis (LCA) causes blindness from birth or early infancy and involves different genes.

References