Clinical 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 improvement in visual acuity is 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 the general population. Some individuals with LHON, usually women, may also develop a multiple sclerosis-like illness.
Diagnosis/testing: The diagnosis of LHON is established in a proband with bilateral, painless, subacute visual failure that develops during young adult life and/or by the identification of one of three common mtDNA pathogenic variants (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4, or m.14484T>C in MT-ND6) on molecular genetic testing.
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 a mtDNA LHON-causing pathogenic variant; referral to cardiology can be considered and treatment for symptomatic individuals is the same as that in the general population. A multidisciplinary approach for those affected individuals with extraocular neurologic features (ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders) should be considered to minimize the functional consequences of these complications.
Prevention of primary manifestations: Treatment for raised intraocular pressure in individuals who have a LHON-causing pathogenic variant.
Agents/circumstances to avoid: Individuals harboring a mtDNA LHON-causing pathogenic variant should be strongly advised to moderate their alcohol intake and not to smoke. Avoiding exposure to other putative environmental triggers for visual loss, in particular industrial toxins and drugs with mitochondrial-toxic effects, also seems reasonable.
Genetic counseling: Leber hereditary optic neuropathy is caused by pathogenic variants in mtDNA and transmitted by mitochondrial (maternal) inheritance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary mtDNA LHON-causing pathogenic variants. The mother of a proband usually has the mtDNA pathogenic variant 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 pathogenic variant cannot transmit the variant to any of his offspring. A female (affected or unaffected) with a primary LHON-causing mtDNA pathogenic variant transmits the variant to all of her offspring. Prenatal diagnosis for mitochondrial pathogenic variants is possible if the variant 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 pathogenic variant does not predict the occurrence of disease, age of onset, severity, or rate of disease progression.
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