Clinical characteristics: Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON is in the second and third decades of life, with 90% of those who lose their vision doing so before age 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life. Males are four to five times more likely to be affected than females, but neither sex nor mutational status significantly influences the timing and severity of the initial visual loss. 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 a consistent clinical history and/or one of three common mitochondrial DNA (mtDNA) pathogenic variants identified on molecular genetic testing.
Management: Treatment of manifestations: Management of affected individuals remains mostly supportive, and includes provision of visual aids, occupational rehabilitation, and registration with the relevant social services. Idebenone (Raxone®) has been approved for the treatment of LHON by the European Medicines Agency under exceptional circumstances. The current body of evidence indicates some visual benefit in a subgroup of affected individuals treated with idebenone, particularly those treated within the first year of onset of visual loss.
Referral to a cardiologist for individuals with pre-excitation syndrome on EKG is recommended; treatment for symptomatic individuals is per standard practice.
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.
Agents/circumstances to avoid: Individuals in whom a LHON-causing mtDNA variant has been identified should be strongly advised not to smoke and to moderate alcohol intake, avoiding binge-drinking episodes. It would be reasonable to avoid exposure to other putative environmental triggers for visual loss, such as head trauma, industrial toxins, and drugs with mitochondrial toxic effects.
Genetic counseling: LHON is caused by pathogenic variants in mtDNA and is transmitted strictly by maternal inheritance. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have developed visual loss. 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 variant transmits the variant to all of her offspring. In approximately 60% of families, a history of visual loss affecting maternal relatives is present. Genetic counseling for LHON is complicated by the sex- and age-dependent penetrance of the primary mtDNA LHON-causing pathogenic variants and penetrance can vary markedly in different branches of the same family and between families harboring the same LHON-causing mtDNA pathogenic variant. Once a mtDNA LHON-causing variant in the mother has been identified, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible; 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 LHON-causing variant does not predict the occurrence, age of onset, severity, or rate of progression of visual loss.
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