Excerpt

DISEASE CHARACTERISTICS:

Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless, subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected. Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye; similar symptoms appear in the other eye an average of two to three months later. In about 25% of cases, visual loss is bilateral at onset. Visual acuity is severely reduced to counting fingers or worse in the majority of cases, and visual field testing shows an enlarging dense central or centrocecal scotoma. After the acute phase, the optic discs become atrophic. Significant improvements in visual acuity are rare and most persons qualify for registration as legally blind (visual acuity ≤20/200). Neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in controls. Some individuals with LHON, usually women, may also develop a multiple sclerosis (MS)-like illness.

DIAGNOSIS/TESTING:

The diagnosis is based on ophthalmologic findings. Testing includes dilated fundus examination to identify characteristic optic disc and vascular changes in the acute phase; kinetic (Goldmann) or static perimetry to delineate the characteristic central or centrocecal scotoma; electrophysiologic studies in selected cases (visual evoked potentials to confirm optic nerve dysfunction and pattern electroretinogram to confirm the absence of retinal disease); and neuroimaging to exclude compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. Approximately 90% of individuals with LHON have one of three point mutations of mitochondrial DNA (mtDNA): m.3460G>A, m.11778G>A, or m.14484T>C. Clinical molecular genetic testing for these mutations is available.

MANAGEMENT:

Treatment of manifestations: Management of affected individuals is largely supportive, with the provision of visual aids, help with occupational rehabilitation, and registration with the relevant social services. ECG may reveal a pre-excitation syndrome in individuals harboring mtDNA LHON-causing mutations, but no further intervention is required in the absence of cardiac symptoms. Agents/circumstances to avoid: Individuals harboring mtDNA LHON-causing mutations should be strongly advised to moderate their alcohol intake and not to smoke. Therapies under investigation: A recent randomized controlled trial suggests that oral administration of idebenone could benefit individuals with LHON who are at an early stage of the disease process and still at high risk for further visual loss.

GENETIC COUNSELING:

Leber hereditary optic neuropathy is caused by mutations in mtDNA and it is transmitted by maternal inheritance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary mtDNA LHON-causing mutations. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. In most cases a history of visual loss affecting maternal relatives at a young age is present, but up to 40% of cases are simplex (i.e., occur in a single individual in a family). A male (affected or unaffected) with a primary LHON-causing mtDNA mutation cannot transmit the mutation to any of his offspring. A female (affected or unaffected) with a primary LHON-causing mtDNA mutation transmits the mutation to all of her offspring. Prenatal diagnosis for mitochondrial mutations is possible if the disease-causing mutation in a family is known; however, accurate interpretation of a positive prenatal test result is difficult because the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues, and the presence of the mtDNA mutation does not predict the occurrence, age of onset, severity, or rate of disease progression. Prenatal testing may be available through laboratories offering custom prenatal testing.

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