Leber hereditary optic neuropathy

Disease Description (Causes and Symptoms)

• Definition summary: Leber hereditary optic neuropathy (LHON) is a mitochondrial (mtDNA) genetic disorder characterized by painless, acute or subacute central vision loss occurring mainly in young adults. Visual impairment may persist throughout life in most cases.
• Causes and inheritance pattern: It is caused by maternally inherited mitochondrial DNA point mutations. Most patients (approximately 90%) have one of three primary point mutations (G11778A, G3460A, or T14484C), and G11778A has been reported to occur at a high frequency worldwide. Approximately 40% are sporadic (spontaneous) cases with an unclear family history.
• Pathophysiology (briefly): mtDNA mutations impair mitochondrial function in optic nerve axons and retinal ganglion cells, reducing energy (ATP) production and increasing oxidative stress, ultimately causing selective damage to optic nerve cells.
• Main symptoms:
  • Acute or subacute central vision loss in one or both eyes (central scotoma, centrocecal scotoma)
  • Reduced color vision (especially red-green) and color desaturation (weakened color intensity)
  • Central visual field defects on visual field testing
  • In the early stage, subtle vascular changes and swelling around the optic disc may be seen on fundus examination; in the chronic stage, optic disc pallor (atrophy) is observed
• Epidemiologic features: Higher expression rate in males (approximately 70–80% are male); the age at onset is generally 18–30 years (mean 25–35 years), but it can occur at any age.

Treatment Methods and Precautions

• Current standard treatment
  • There is no established cure. Conservative and symptomatic treatment in the acute and subacute stages, as well as drug research aimed at visual recovery, is ongoing.
  • Idebenone: Some studies have reported the possibility of improved vision, and it is approved and used in some countries (clinical evidence varies according to mutation type, time of onset, and other factors); early administration may be recommended in some cases. Determine whether it is appropriate in consultation with the treating physician.
  • Gene therapy: Research (clinical trials) targeting specific genes such as ND4 is underway, but it has not been established as standard treatment.
• Supportive and conservative management
  • In cases of early diagnosis, visual rehabilitation/assistive devices (magnifiers and low-vision aids) and vocational rehabilitation counseling are recommended.
  • Evidence for high-dose vitamin therapy is limited, and reports are conflicting. Some reports indicate that certain supplements may be harmful (for example, there is reported controversy regarding vitamin B12); do not take high-dose supplements on your own and follow the instructions of a specialist.
• Lifestyle management and precautions
  • Smoking cessation and abstinence from alcohol: Smoking and alcohol consumption have been reported as major environmental factors that increase the risk of expression, so they must be strictly avoided.
  • Avoidance of mitochondrial-toxic drugs: When possible, consult a neuro-ophthalmologist before using drugs such as linezolid that may adversely affect mitochondrial function.
  • Risk of complications: Limitations in daily life and psychological and social effects (depression and occupational problems) may occur due to permanent central vision loss.
• Prognostic reference values (reported recovery probabilities; differences by mutation)
  • G11778A: Low rate of spontaneous recovery (approximately 4% according to some reports)
  • G3460A: Approximately 22%
  • T14484C: Approximately 37%
  • (Values vary between studies)

Checklist Before an Outpatient Visit (Including Preparation Items and Example Questions)

• Items to prepare (recommended to bring)
  • A list of all medications currently being taken (including prescription drugs, over-the-counter drugs, and nutritional supplements)
  • Family history information (especially visual impairment or similar symptoms on the maternal side)
  • Notes recording when the symptoms began and how they have progressed (when they started, one or both eyes, sudden or gradual, etc.)
  • Copies of previous ophthalmologic examination results, if available (visual acuity chart, visual field testing, OCT, fundus photographs, MRI, etc.)
  • Lifestyle information (smoking and alcohol consumption, occupational exposures, etc.)
• Examinations to expect during an outpatient visit
  • Visual acuity testing, color vision testing, fundus examination, visual field testing (Goldmann or automated perimetry), and evaluation of the optic nerve layer using optical coherence tomography (OCT)
  • Electrophysiologic testing (such as visual evoked potentials, VEP), if necessary
  • Blood tests (if necessary, to rule out vitamin deficiencies and metabolic abnormalities)
  • Imaging (MRI) to rule out pathological causes (central nervous system lesions)
  • Genetic testing: mtDNA mutation testing (PCR/sequencing)—important for confirmation of the diagnosis
• Points to note before the outpatient visit
  • Prepare examination results and symptom records in as much detail as possible
  • Consult a doctor before stopping any supplements or medications currently being taken

Examples of General Questions to Ask the Doctor

• What causes this disease, and how likely is it to be inherited?
• What prognosis can I expect in my current condition (short-term, medium-term, and long-term)?
• What treatments (medications or clinical trials) do you recommend to preserve or restore vision?
• Could any medications I am taking (or planning to take) affect this disease?
• What activities must I avoid in daily life (smoking, alcohol consumption, specific medications, etc.)?

Examples of Disease-Specific Questions

• Should family members (on the maternal side) undergo genetic testing? Is confirmation of the family history and genetic counseling recommended?
• What are the indications, expected benefits, and side effects of idebenone (or medications/gene therapy proposed through clinical trials)?

(Diagnosis and treatment should be determined based on consultation with the treating physician and individualized testing; this information is for general guidance.)