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Leber hereditary optic neuropathy
Leber's hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease affecting the optic nerve and often characterized by sudden vision loss in young adult carriers.
Prevalence of the disease is not well known but is estimated at 1/15,000 - 1/50,000 people worldwide.
Sudden, painless, acute or subacute central vision loss is often noted between the ages of 18 to 30. It affects both eyes simultaneously or sequentially with vision loss in the second eye occurring weeks to months after the first. Visual loss generally occurs subacutely (over a period of several weeks) and then stabilizes. However, many patients will continue to expand the size of their central scotoma which, over a period of years, produces a more profound level of blindness. Other neurological symptoms can also be present. These abnormalities are known as Leber ``plus'' (see this term), and include motor disorders, dystonia, postural tremor and cerebellar ataxia.
LHON is caused by mutations in the mitochondrial DNA (mtDNA). Over 90% have been identified to occur at nucleotide positions 11778, 3460 or 14484. All produce defects in the mtDNA respiratory chain complex I subunit genes MT-ND1, MT-ND4 and MT-ND6. Since LHON is seen more frequently in males and not all individuals with these mtDNA mutations develop LHON (incomplete penetrance), other genetic or epigenetic factors may have an effect on the development of this disease.
Diagnosis is based on an ophthalmoscopic examination. Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON. An optical coherence tomography (OCT) scan confirms swelling of the retinal nerve fiber layer. Red-green dyschromatopsia during color vision testing and pseudopapilledema during fluorescein angiography are also observed. Snellen vision acuities of 20/200 or worse are typical. Optic neuritis, a common sign of multiple sclerosis (MS; see this term) is one of the first diseases to eliminate. Other genetic optic neuropathies such as Wolfram syndrome, and classic type autosomal dominant optic atrophy (see these terms) should also be excluded. Since LHON is a maternally-inherited disease, female carriers will pass the mutation to all their children but father carriers will not. The presence of a mutation can be found by genetic testing but does not imply that the disease will manifest itself.
Management and treatment
As of yet there is no cure for LHON. Low-vision aids are the primary supportive care offered to patients. Several compounds have shown positive results in recovering vision. Idebenone (granted an orphan drug designation for this disease in 2007), a synthetic analogue of coenzyme Q10, has resulted in visual improvement after one year. Third generation quinones are now being tested as well. It is important that patients refrain from alcohol, tobacco and certain antibiotics that also interfere with mitochondrial oxidative phosphorylation.
The age of symptom onset (younger patients having a more favorable prognosis) and the causative mutation (patients with MT-ND6 mutations showing highest recovery rates) are factors that determine the disease outcome. Some patients, especially with the 14484 mutation, show spontaneous partial recovery 1-2 years after onset. In 30 to 50 % of male carriers and 80 to 90 % of women carriers, blindness will not ensue. Complete blindness (no light perception) is rare. While visual field improvement is usually incomplete, the recovery in visual acuity can be dramatic.