Leber Hereditary Optic Neuropathy (LHON) is an acute or subacute optic neuropathy caused by point mutations in mitochondrial DNA (mtDNA) and inherited maternally. It predominantly affects young males, causing severe bilateral vision loss and central scotoma. The visual prognosis is poor, and it was designated as an intractable disease in 2015.
Three major mutations (mt3460, mt11778, mt14484) account for approximately 95% of all cases. mt11778 (MT-ND4 gene) is the most common, accounting for about 90% of cases in Asia 1). The prevalence is 1/31,000 to 1/68,000, and the carrier frequency is up to 1/1,000 2). Penetrance is low at 2.5–17.5%, so most carriers do not develop the disease 2).
It is a rare disease with a prevalence of 1/31,000 to 1/68,000, and the total number of patients in Japan is estimated to be about 4,000 to 5,000. A 2014 domestic epidemiological survey reported 117 new cases per year. It is designated as an intractable disease and is eligible for the medical expense subsidy system for intractable diseases.
| Mutation Site | Gene | Complex | Domestic Frequency | Spontaneous Recovery Rate | Severity |
|---|---|---|---|---|---|
| m.11778G>A | MT-ND4 | Complex I | Most common | A few percent (about 11% in those aged 15 and over)3) | Severe |
| m.14484T>C | MT-ND6 | Complex I | 2nd | Highest (37-71%) | Relatively mild |
| m.3460G>A | MT-ND1 | Complex I | 3rd | Intermediate | Severe |
The three major mutations account for approximately 95% of domestic cases. mt11778 is the most common worldwide (about 70% in Europe, about 90% in Asia)1). In cases with onset at age 12 or younger, the rate of spontaneous recovery is high3).
In recent years, LHON due to nuclear gene mutations other than mtDNA mutations has also been reported1).
| Category | Criteria |
|---|---|
| Definite | Meets all of main criteria ①+②, or ①+③ |
| Probable | Meets main criteria ① or ③ + laboratory findings ①+② |
| Possible | Meets main criteria ① or ③ + laboratory findings ②+③ + clear maternal inheritance |
| Carrier | Mutation carrier without visual symptoms among maternal relatives of definite, probable, or possible cases |
There are subtypes with systemic complications such as cardiac conduction abnormalities and multiple sclerosis-like demyelinating lesions. Harding syndrome is a subtype more common in women that combines LHON and multiple sclerosis-like lesions2).
The first nationwide epidemiological survey in Japan was conducted in 2014. The annual number of new cases was estimated at 117 (109 men, 8 women), with 47% occurring by the age of 30. A marked gender difference was observed, with men accounting for 93.1% of cases. The total number of patients in Japan is estimated at approximately 4,000–5,000, with a prevalence similar to or slightly higher than other countries.
The prevalence is 1/31,000 to 1/68,0002), and the carrier frequency is up to 1/1,000. Two peaks of onset are known: young adulthood (10–30s) and middle age2). More than 80% of affected individuals are male4).
mtDNA mutations may exist as a mixture of mutant and normal mtDNA within cells (heteroplasmy). Heteroplasmy is observed in 10–15% of all cases, and if the mutation load is less than 60–75%, the disease may not manifest.
Smoking is an established risk factor for onset, and smoking cessation guidance is important. Heavy alcohol consumption and antituberculosis drugs (e.g., ethambutol) have also been implicated. Haplogroup J (a mtDNA haplogroup) increases penetrance1). Estrogen is thought to have a neuroprotective effect and may contribute to the lower incidence in women2).
Acute Phase Findings
Optic disc hyperemia and swelling: The disc appears uniformly red and swollen.
Peripapillary telangiectasia and tortuosity: May be seen extending to the temporal retina.
Enlargement of the retinal nerve fiber layer: Observed around the optic disc.
Peripapillary hemorrhages: Rarely seen.
Chronic Phase Findings
Optic atrophy: Atrophy predominantly involving the papillomacular bundle.
RNFL thinning: Gradually transitions from the edematous thickening in the acute phase.
Final appearance: Pale optic disc. Atrophy of the papillomacular bundle occurs first, eventually becoming circumferential.
| Stage | Findings |
|---|---|
| Asymptomatic phase (carrier) | OCT shows temporal pRNFL thickening. Fundus may show subtle pseudopapilledema and telangiectasia. |
| Subacute phase (up to 6 months) | Optic disc hyperemia and swelling (pseudopapilledema), peripapillary telangiectasia and tortuosity, no FA leakage, central scotoma. |
| Dynamic phase (6–12 months) | pRNFL edema regression, persistent worsening of visual acuity and visual field. |
| Chronic phase (12 months and beyond) | Established optic atrophy (optic disc pallor), pRNFL thinning, fixed visual acuity loss and central visual field defect. |
Major Item 1) Main Signs
Major Item 2) Laboratory Findings
| Disease | Key differentiating features |
|---|---|
| Optic neuritis | Clearly positive RAPD, pain on eye movement, MRI shows optic nerve enhancement, FAG shows fluorescein leakage |
| Toxic optic neuropathy | History of taking ethambutol etc., symmetric bilateral, possible improvement after drug discontinuation |
| Autosomal dominant optic atrophy (ADOA) | Onset in school age, autosomal dominant inheritance (OPA1 mutation), slow progression, mild vision loss |
| Compressive optic neuropathy | MRI/CT shows space-occupying lesion, often unilateral |
| Nutritional optic neuropathy | Vitamin B12/folate deficiency, poor general nutritional status |
LHON is differentiated from optic neuritis by: ① painless (no pain on eye movement), ② no fluorescein leakage from the optic disc on fluorescein angiography, ③ no optic nerve enhancement on MRI, ④ inconspicuous RAPD (due to similar impairment in both eyes), and ⑤ possible maternal family history. In particular, “no leakage” on fluorescein angiography is the most important differentiating finding.
There is no established standard treatment. Smoking cessation guidance is most important, and avoidance of heavy drinking is also recommended.
Idebenone is a synthetic derivative of coenzyme Q10, which easily passes through the inner mitochondrial membrane and also crosses the blood-brain barrier. It promotes electron transfer from complex I to complex III of the electron transport chain and has an action that assists ATP production 1).
| Treatment group | Eye-level CRR | Number of patients |
|---|---|---|
| Natural course (no treatment) | 17% (95% CI 7–30%) | 316 eyes |
| Idebenone | 31% (95% CI 24–40%) | 313 eyes |
| Lenadogene nolparvovec (gene therapy) | 59% (95% CI 54–64%) | 348 eyes |
A gradient of treatment effect was observed: gene therapy > idebenone > natural course.
Idebenone is not approved in Japan. In Europe (Raxone®), it is approved for LHON patients from adolescence onward, and some patients obtain it through personal importation. Currently, coenzyme Q10 and vitamins B and C supplements are used at the discretion of individual institutions in Japan. It is advisable to consult a specialist regarding future approval trends in Japan.
mtDNA point mutations cause dysfunction of subunits (ND1/ND4/ND6) of complex I of the electron transport chain. Unused electrons generate reactive oxygen species (ROS), inducing apoptosis of retinal ganglion cells (RGCs). The dual impairment of reduced ATP synthesis and increased ROS production is central to the pathogenesis1).
Most carriers do not develop the disease (penetrance 2.5–17.5%)2). Since onset does not occur until a certain age, environmental factors (smoking, alcohol, drugs) are suspected. Nuclear gene modifiers (PRICKLE3, YARS2, DNAJC30) may contribute to penetrance and sex differences1).
mtDNA mutations are maternally inherited with no sex difference, but about 80% of affected individuals are male. It is suggested that PRICKLE3 gene mutations on the X chromosome affect ATP synthase (complex V) function, and the opposite X chromosome in females may compensate1).
Small-diameter axons of the papillomacular bundle are most vulnerable. This is because the unmyelinated portion near the optic disc is long and has high energy demand. Optic atrophy begins in the papillomacular bundle and eventually becomes circumferential.
In most cases, decreased visual acuity and central visual field defects persist. Final best-corrected visual acuity is often around 0.01. Rarely, some cases improve to a corrected visual acuity of 1.0 even after optic atrophy. The rate of visual function improvement varies depending on the genetic mutation type.
| Mutation | Spontaneous recovery rate | Prognosis |
|---|---|---|
| mt11778 | A few % to 14–20% (approximately 11% in those aged 15 years or older)3) | Worst |
| mt14484 | Highest (37–71%) | Relatively good |
| mt3460 | Intermediate | Severe type |
In the LEROS trial, the treatment effect persisted for up to 24 months, with continued improvement7). In the Welsh cohort, a significant difference was observed at 24 months: CRR 71% vs. 24% in the natural history group (p<0.001)2). The peak of visual improvement occurs around 27 months, after which it tends to be maintained or slightly decline2).
This is a formulation that carries the wild-type MT-ND4 gene in an AAV2 vector, with an added mitochondrial targeting signal sequence3). It uses allotopic expression to introduce the ND4 gene into retinal ganglion cells via intravitreal injection.
Research is underway aiming to restore RGC degeneration through miRNA transfer via bone marrow-derived MSC exosomes. Mitochondrial function recovery by iPSC-MSC transplantation and intercellular transfer of healthy mitochondria via tunneling nanotubes (TNTs) are also being investigated. All of these are at the preclinical stage for clinical application to LHON.
arLHON due to DNAJC30 mutations is characterized by younger age of onset and higher rate of visual recovery. DNAJC30 is a chaperone protein for complex I repair and is attracting attention as a specific therapeutic target. Since its clinical picture overlaps with typical LHON, active genetic panel testing is recommended in young-onset cases. Nuclear gene LHON due to MCAT mutations has also been reported8).
OCT changes (RNFL thickening) before vision loss in carriers have been suggested as potential predictors of onset5), and verification of the efficacy of preventive interventions (e.g., early idebenone administration) remains a future challenge.
In children, LHON may be misdiagnosed as amblyopia. If amblyopia treatment is ineffective, genetic testing with LHON in mind is recommended9).
