What is Leber’s Hereditary Optic Neuropathy?
Leber’s hereditary optic neuropathy (LHON) is a rare, maternally inherited optic neuropathy caused by mitochondrial DNA point mutations and may lead to blindness. LHON typically affects male, young adults, but can occur in women, and at any age. The age of onset is typically between 10-30 years, though onset in the seventh or eighth decade has been reported.
The lifetime risk of vision loss is about 50% for a male LHON carrier compared with 10% for a female LHON carrier. The prevalence of LHON is estimated to be about 1 in 30,000.
- LHON is a rare, mitochondrial DNA disorder.
- Visual prognosis depends on the patient’s point mutation.
- Gene therapy, neuroprotection or stem cell-based treatments are in trials.
Understanding Leber’s Hereditary Optic Neuropathy
Patients with Leber hereditary optic neuropathy (LHON) have severe central vision loss, poor visual prognosis, and legal blindness. The disease begins unilaterally; however, the other eye typically develops similar symptoms within 3 – 6 months of disease onset. In 25% of cases, the disease begins bilaterally with vision worse than 20/200.
LHON is the most common primary mitochondrial DNA (mtDNA) disorder. Most patients have one of three mtDNA point mutations, m.3460G>A, m.11778G>A, and m.14484T>C, with the m.11778G>A mutation being the most common cause of LHON worldwide and accounting for 70-90% of all cases. Those with m.14484T>C may have a higher chance of spontaneous visual recovery.
LHON is caused by point mutations in the mtDNA, which leads to a defect in complex I of the mitochondrial respiratory chain causing dysfunction and degeneration of retinal ganglion cells, followed by optic atrophy.
The loss of retinal ganglion cells in LHON is thought to arise from a combination of impaired mitochondrial oxidative phosphorylation resulting in decreased adenosine triphosphate (ATP) production and increased levels of reactive oxygen species.
Individuals with LHON may have other coexisting diseases including cardiac conduction abnormalities, dystonia, and multiple sclerosis-like illness called “LHON Plus” disease.
Risk Factors for Leber’s Hereditary Optic Neuropathy
Individuals may report a history of progressive vision loss in maternal family members. Males are affected in 80% of cases. Neither age nor lifestyle choices have been shown to increase disease incidence.
Late-onset-LHON patients have higher cumulative tobacco and alcohol consumption when compared with unaffected carriers, suggesting these factors may worsen the severity in an individual with the disease.
Leber’s Hereditary Optic Neuropathy Symptoms
- Unilateral loss of visual acuity in the second through the fourth decade
- Color or light desaturation
- Central or centrocecal scotoma
- If a patient has LHON plus disease, then other symptoms include dystonia, tremor, neuropathy, weakness, myopathy, arrhythmias
Diagnosing Leber’s Hereditary Optic Neuropathy
LHON must be distinguished from other causes of optic neuropathy. A dilated comprehensive eye exam may show normal or pseudo-edematous optic nerves, with optic nerve pallor and atrophy appearing after. Tortuosity of the retinal arteries may also be present.
Visual field testing shows a worsening central or centrocecal scotoma. Color vision testing can demonstrate decreased red-green discrimination. Fluorescein angiography may be performed to rule out true nerve edema; no dye will leak from the border of the swollen nerve. Optical coherence tomography (OCT) of the nerve may show an elevation in the initial phases or atrophy in the later disease stages.
MRI imaging may be ordered to rule out other demyelinating diseases or compressive lesions. Some reports indicate that patients with LHON may show increased T2 signals in the optic nerves, chiasm, and optic tracts.
Gene testing is performed via targeted mutation analysis. Identification of the mutation may be helpful in predicting disease prognosis.
Leber’s Hereditary Optic Neuropathy Treatment
There are limited treatment options for LHON. Until recently, disease management was limited to visual rehabilitation, genetic counseling, and the avoidance of environmental triggers. Patients are cautioned to avoid neurotoxins such as tobacco and alcohol, as these may increase oxidative stress.
There is no established medical treatment for LHON, though there may be a theoretical benefit from using antioxidants to help reduce the neurotoxic stress due to reactive oxygen species. Multiple supplements such as vitamins B12 and C, Coenzyme-Q10, brimonidine, and lutein have shown minimal benefit but may be recommended.
Currently, gene therapy, neuroprotection, and stem cell-based treatments are in clinical trials for treating LHON. Idebenone, a short-chain synthetic benzoquinone, has undergone testing as an agent in the treatment of several neurologic diseases. A trial of idebenone in the treatment of LHON showed promising but limited results.