Leber's Hereditary Optic Neuropathy (LHON) is a subacute form of blindness that develops in early adulthood. Found to occur in males at least 4-5 times more commonly, it is painless and bilateral, with an insidious, but progressive course.

Clinical Features

LHON typically begins with blurring of the central visual field, first in one eye. The other eye is not usually affected until two or three months later, though one in four patients may have bilateral blurring from the beginning. Severe visual loss is typical, with a central scotoma or visual field defect, which grows. Eventually the optic disc atrophies.

Other manifestations include postural tremor, symptoms relating to the peripheral nerves, myopathy of nonspecific origin and movement disorders, as well as a demyelination-like illness that may resemble multiple sclerosis.

Inheritance

The disorder is caused by mutations in mtDNA and is therefore due to maternal inheritance. The onset in early adult life means that the affected mother may not be symptomatic at the time of the birth of a child. A suggestive family history (of blindness in young adulthood in maternal relatives) may or may not be present, because in 40% of cases only one person is affected in the family. One explanation is that a male with LHON due to a mitochondrial DNA (mtDNA) mutation will have unaffected children, while in the case of a female with the condition, her offspring will receive the mutation. Prenatal prognostication of the extent, age of onset, or severity of the condition is difficult, because of the disparity between the amount of mtDNA in amniotic or chorionic cells and other adult tissues, and also because no mutation can predict the course of the disease.

Diagnosis and Management

The diagnosis is based on the typical clinical history, with the finding of a central or centrocecal scotoma on visual field examination. Fundoscopy shows (in 80% of cases) a hyperemic optic disc and peripapillary edema, tortuous retinal vessels and telangiectasia of the retina. These are often pre-symptomatic occurrences.

An electroretinogram and visual evoked potential testing shows no evidence of retinal disease, but optic nerve dysfunction. It may be confirmed by molecular genetic testing to detect any of three mtDNA mutations, namely, in MT-ND1, MT-ND4 or MT-ND6. The mutation affects mitochondrial respiration, but in a more subtle way than other related disorders.

Management is supportive, with visual aids in the early stages coupled with rehabilitation to prepare for the eventual loss of vision and helping the affected individual to make use of available social services.

Screening for other related manifestations should be done, including an ECG to detect pre-excitation syndromes, which requires treatment if it becomes symptomatic. Other neurologic features must be looked for and treated appropriately to minimize their functional impact on the daily living of the patient. Raised intraocular pressure is common and must be anticipated and prevented. Alcohol and smoking exposure will worsen and speed up mitochondrial dysfunction and should be avoided, as well as other toxic exposures and drugs that depress mitochondrial function.

New Research

Investigational treatments include:

• Idebenone with vitamin B12 and vitamin C supplementation, which may help with visual recovery especially with significantly different extents of visual loss between the two eyes and ongoing visual loss in the better eye.
• EPI-743 is a vitamin E derivative, which is being studied in LHON for its antioxidant effect.
• Targeted gene therapy is being considered for the m.11778G>A mutation using a viral vector to replace the mutated gene.
• Estrogen therapy may increase the activity of superoxide dismutase, a potent antioxidant enzyme, and reduce levels of reactive oxygen species, facilitating better mitochondrial respiration.
• Mitochondrial replacement during in vitro fertilization may help prevent mtDNA from being transmitted from the mother to the child in known cases at risk.