Clinical Pearls & Morning Reports

Published July 10, 2019


Is there an effective medical therapy for Leber’s hereditary optic neuropathy?

Leber’s hereditary optic neuropathy was the first human disease linked to a mutation in mitochondrial DNA; it is more common in men than in women and typically occurs between 15 and 35 years of age. Read the latest Case Records of the Massachusetts General Hospital here.

Clinical Pearls

Q: What is Leber’s hereditary optic neuropathy (LHON)?

A: LHON is a maternally inherited mitochondrial disorder that is caused primarily by mutations in mitochondrial genes encoding the NADH dehydrogenase subunits and that causes decreased activity of complex 1 of the mitochondrial electron transport chain. Three mutations account for more than 95% of cases of LHON: m.11778G→A (the most common), m.3460G→A, and m.14484T→C. These mutations all ultimately lead to decreased ATP production.

Q: What are some of the features of LHON?

A: LHON causes painless, subacute, severe vision loss in one eye, followed by vision loss in the contralateral eye within several weeks or months. Up to 50% of affected patients do not have a family history of vision loss. Since inflammation is not driving the process, the administration of glucocorticoids does not lead to improvement. MRI typically shows only hyperintensity in the posterior portion of the optic nerve, but enhancement of the optic nerve has been reported during the acute phase. Spontaneous vision recovery can occur in some cases and is most often associated with the m.14484T→C point mutation.

Morning Report Questions

Q: Is LHON caused by the presence of a relevant mitochondrial mutation alone?

A: LHON-related mutations are more likely to occur in males than in females, at ratios of 2.1:1.0 to 7.7:1.0. However, the mutations alone are not sufficient to cause the disease, and other genetic modifiers (mitochondrial DNA copy number, haplotype, and nuclear modifiers), environmental factors (tobacco, alcohol, and toxin exposure), and sex hormone levels play a role in the pathophysiology. In patients with LHON, a combination of these factors is thought to cause an increase in free radicals, a decrease in ATP production, and a disruption in the oxidation–reduction (redox) balance, ultimately leading to retinal ganglion-cell apoptosis and optic-nerve degeneration. 

Q: Is there an effective medical therapy for LHON?

A: Unfortunately, there is no Food and Drug Administration–approved therapy for LHON. Multiple supplements and medications have been proposed as potential treatments. These agents use various mechanisms to boost mitochondrial mass and number, circumvent dysfunction in the respiratory chain complex, or prevent oxidative damage to retinal ganglion cells. One promising medication is idebenone. This short-chain coenzyme Q analogue acts as an electron carrier to directly deliver electrons to complex 3 of the respiratory chain, bypassing the dysfunctional complex 1 of LHON. Idebenone has been approved by the European Medicines Agency for the treatment of LHON. Gene therapy is a potential future treatment. In clinical trials of intravitreal injection of an adenovirus-associated vector that contains wild-type mitochondrial genes encoding functional NADH subunits, preliminary data suggest the potential for some vision recovery in patients with LHON.

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