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Condition report · Ophthalmological

Hereditary Optic Neuropathy (LHON)

Whole genome sequencing reads the complete mitochondrial genome, identifying the three primary LHON variants (m.11778G>A, m.3460G>A, m.14484T>C) that account for 95% of LHON cases and determine visual prognosis. It also reads the nuclear genes behind dominant optic atrophy, led by OPA1, which causes the most common inherited optic neuropathy, along with rarer causes such as OPA3 and WFS1.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A group of inherited disorders characterized by the degeneration of the optic nerve, leading to progressive vision loss.

Hereditary optic neuropathies are inherited conditions that damage the optic nerve. The two main forms are Leber hereditary optic neuropathy (LHON), caused by mitochondrial DNA variants, and autosomal dominant optic atrophy, most often caused by OPA1 variants and the most common inherited optic neuropathy overall. Dominant optic atrophy usually causes gradual, bilateral vision loss beginning in childhood, in contrast to the sudden onset of LHON in young adults.

LHON is a maternally inherited mitochondrial optic neuropathy caused by pathogenic variants in the mitochondrial genome (mtDNA). Three primary variants account for approximately 95% of all LHON cases: m.11778G>A (MT-ND4, ~70% of cases), m.3460G>A (MT-ND1, ~13%), and m.14484T>C (MT-ND6, ~14%). These variants impair mitochondrial complex I function, causing selective degeneration of retinal ganglion cells, the neurons whose axons form the optic nerve. LHON affects approximately 1 in 25,000-50,000 and shows marked male predominance (~5:1 male-to-female ratio), suggesting modifying nuclear or hormonal factors.

LHON typically presents in young adults (median onset age 20-30 years) with acute or subacute painless central vision loss, initially unilateral then rapidly progressing to bilateral involvement within weeks to months. Vision deteriorates to legal blindness (visual acuity typically 20/200 to counting fingers) with dense central scotoma. The acute phase shows optic disc pseudoedema and peripapillary telangiectatic microangiopathy on fundoscopy. Spontaneous partial visual recovery occurs in approximately 20-25% of patients with m.11778G>A and up to 50-65% of patients with m.14484T>C, making genotype the strongest predictor of visual prognosis.

Idebenone (Raxone/Catena), a synthetic analog of coenzyme Q10, was approved by the EMA in 2015 for treatment of LHON. Idebenone bypasses the complex I defect, shuttling electrons directly to complex III. Clinical trials demonstrated that idebenone preserves or improves visual acuity when initiated early after symptom onset, before retinal ganglion cell loss becomes irreversible. The treatment window is narrow: benefit is greatest when idebenone is started within the first year of vision loss, particularly in the first affected eye (before the second eye becomes involved). Gene therapy (lenadogene nolparvovec, intravitreal AAV delivery of MT-ND4) is approved in several countries for m.11778G>A LHON.

The m.14484T>C variant has the best spontaneous recovery rate (~50-65%) while m.11778G>A has the worst (~20-25%). Genotype is the strongest predictor of visual prognosis, directly affecting treatment urgency and counseling.

The condition we analyse

Hereditary Optic Atrophy

Inherited loss of optic nerve fibres, most often autosomal dominant optic atrophy caused by changes in OPA1, and including rarer types caused by OPA3, DNM1L, SSBP1 and other genes.

Genes analysed

Also known as

hereditary optic Atrophies

Includes 26 related subtypes ↓
  • ACO2-related optic atrophy with or without extraocular features
  • Al Gazali Khidr Prem Chandran syndrome
  • autosomal dominant optic atrophy and peripheral neuropathy
  • autosomal dominant optic atrophy plus syndrome
  • autosomal dominant optic atrophy, classic form
  • autosomal recessive optic atrophy, OPA7 type
  • cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
  • Leber hereditary optic neuropathy
  • Leber optic atrophy and dystonia
  • optic atrophy 10 with or without ataxia, intellectual disability, and seizures
  • optic atrophy 11
  • optic atrophy 12
  • optic atrophy 13 with retinal and foveal abnormalities
  • optic atrophy 14
  • optic atrophy 15
  • optic atrophy 16
  • optic atrophy 2
  • optic atrophy 3
  • optic atrophy 4
  • optic atrophy 5
  • optic atrophy 6
  • optic atrophy 8
  • optic atrophy 9
  • optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy
  • optic atrophy, hearing loss, and peripheral neuropathy, autosomal dominant
  • osteogenesis imperfecta-retinopathy-seizures-intellectual disability syndrome
MONDO:0043878MedGen 45207

Why whole genome sequencing

LHON is mitochondrial, maternally inherited, and variably penetrant. Whole genome sequencing reads both nuclear and mitochondrial genomes, identifying the LHON variant and assessing heteroplasmy levels that influence penetrance.

Idebenone and gene therapy require rapid molecular diagnosis: the treatment window closes as retinal ganglion cells die

Idebenone produces the best visual outcomes when started within months of symptom onset, before retinal ganglion cell degeneration becomes irreversible. Gene therapy (lenadogene nolparvovec) is specifically approved for m.11778G>A LHON and requires molecular confirmation for prescribing. Any young adult presenting with acute painless bilateral sequential vision loss should have immediate mtDNA evaluation for LHON. Delays in molecular diagnosis directly translate to treatment delays that reduce the chance of visual recovery.

Maternal family members carry the same mtDNA variant: presymptomatic identification enables lifestyle modification and early treatment readiness

All maternal relatives of a confirmed LHON patient carry the same mtDNA variant, though penetrance varies widely (approximately 50% of males and 15% of females become symptomatic). Presymptomatic carriers benefit from lifestyle counseling: tobacco smoking and heavy alcohol use are established triggers for LHON conversion. Additionally, presymptomatic carriers can be educated about early symptoms, enabling immediate idebenone initiation at the first sign of vision change rather than after delayed clinical evaluation.

Other ophthalmological conditions

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