Leber’s Hereditary Optic Neuropathy (LHON)

Description

Leber’s hereditary optic neuropathy (LHON) is an unusual genetically transmitted disorder, because it is a maternally inherited condition that more commonly affects male progeny. LHON produces rapid and severe visual loss, with a poor prognosis for improvement. Mitochondrial function appears to be compromised in the highly metabolically active optic nerve.

LHON is caused by mutations in mitochondrial DNA, which is maternally inherited. The 3 most common mutations are located at nucleotide positions 11778 (over 50 percent of cases), 3460 and 14484. The penetrance and severity of LHON are highly variable, and may be influenced by the relative proportions of mutated and normal mitochondrial DNA (i.e., ‘heteroplasmy’). Carrier mothers transmit the mutation to all of their sons, of whom at least 50 percent develop LHON. All daughters of carrier mothers are carriers, and approximately 10 percent develop LHON themselves. Males cannot transmit the disease.

Symptoms

The patient experiences painless, rapidly progressive and severe monocular visual loss, often with a central scotoma. It usually begins unilaterally and involves the other eye within days to weeks.

Signs

In the acute stage, there is often mild optic disc swelling and hyperemia; however, the disc may appear normal. Acuity varies from 6/60 to counting fingers, with a centrocaecal visual field defect (i.e., in the field of vision corresponding to the space between the macula and optic disc). After several weeks, the acute changes resolve and the optic disc becomes flat, pale and atrophic. In asymptomatic members of affected families, the presence of dilated peripapillary capillaries may suggest an increased risk of developing LHON.

Prevalence

Rare. Men are affected more often than women (approximately 7 to 1), particularly in the second to third decades of life. Rarely, cases are diagnosed at the extremes of age.

Significance

LHON causes severe, painless loss of vision of rapid onset that fails to improve.

Differential Diagnosis

Optic Neuritis, Papilledema, Anterior Ischemic Optic Neuropathy (Arteritic or Non-Arteritic), Toxic Optic Neuropathy.

Management

Additional investigations

Fluorescein angiography is often useful when the diagnosis is uncertain. Characteristically, the optic nerve head does not stain, and the dilated peripapillary blood vessels do not leak fluorescein.

Genetics

See above for genetic inheritance. Laboratory tests for the mitochondrial DNA mutations associated with LHON are performed on blood and hair specimens. Genetic counseling is offered to patients and their families.

Advice and referral

Unfortunately, no treatment is known to improve the visual prognosis of LHON. Various vitamin and enzyme supplements have been employed to alleviate this proposed metabolic deficiency. To date, however, no treatment has been shown to improve the visual prognosis of LHON in a prospective clinical trial. Avoidance of cigarette smoking and excessive alcohol consumption is advised, with the intention of minimizing mitochondrial metabolic stress. Cardiology consultation is recommended, since patients with LHON have an increased incidence of cardiac abnormalities.

Refractive correction or low vision aids

Most patients are left with acuity of 6/60 or worse. (In general, patients with the 11778 mutation carry the worst prognosis.) Partial restoration of vision rarely occurs later in life. The patient’s remaining vision is optimized with correction of refractive errors, and provision of low vision aids and vocational rehabilitation.