Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder characterized by bilateral, progressive, central vision loss secondary to loss of the retinal ganglionic cell layer ^1,2.

Epidemiology

Leber hereditary optic neuropathy classically presents in young, Caucasian, adult men aged 14-26 years, with worldwide prevalence estimated at 1:50,000 ³. Approximately 10% of patients report symptom onset after the age of 50 ⁴.

Clinical presentation

Symptom onset typically involves unilateral blurred vision, with the majority of cases sequentially affecting the contralateral eye at a median delay of eight weeks. Simultaneous vision impairment has also been described in 25% of patients ⁵. One week after symptom onset, the most common visual field defects are central or paracentral scotoma. Six months after onset, diffuse visual field defects are more common ⁶. Fundoscopy may reveal telangiectasias, although negative fundoscopy findings do not exclude Leber hereditary optic neuropathy ⁷.

Additional clinical features may also be present, encompassing what has been described as an 'LHON plus' phenotype ^17-19:

• movement disorders: dystonia, tremor

• peripheral neuropathy

• multiple sclerosis-like illness

• ataxia

• cardiac conduction anomalies and arrhythmias

Pathology

Genetics

Leber hereditary optic neuropathy is caused by mitochondrial DNA (mtDNA) mutation coding for enzyme Complex I, a key component of the electron transport chain ¹⁷. The majority of the cases being homoplasmic (all inherited mtDNA contains the mutation) ¹⁷. Only 10-15% of Leber hereditary optic neuropathy mutations are heteroplasmic ¹⁷. Being due to an mtDNA mutation, this condition is maternally inherited ¹⁷. Up to 60% of patients with Leber hereditary optic neuropathy will endorse a positive maternal history as de novo mutation is rare ¹⁶.

Radiographic Features

MRI

Classically, MRI findings in Leber hereditary optic neuropathy have been described as resembling multiple sclerosis ^8,9. However, other features may be present across the visual system. In one study in patients less than 12 months since symptom onset, bilateral T2 hyperintensity in the posterior optic nerves and optic chiasm with associated T2 white matter lesions not resembling multiple sclerosis ¹⁰. Patients may also present with decreased volume of the optic chiasm, optic tract and primary visual cortex ^11,12. Patients may also have increased volume of the bilateral lateral ventricles, third ventricle, and fourth ventricle ¹².

Treatment and prognosis

Whilst there is no current treatment to improve the visual effects of Leber hereditary optic neuropathy, idebenone, vitamin B2 and vitamin C supplementation has been described to improve visual recovery in one study ¹³. In most patients, visual dysfunction is permanent. Spontaneous recovery may rarely occur in some patients and is associated with mutational status and younger age of symptom onset ¹⁴.

To prevent visual loss, mutation carriers should be counseled on smoking cessation and reduction of alcohol consumption ^15,17.

Differential diagnosis

Leber hereditary optic neuropathy may be diagnosed clinically, however, the differential diagnosis should include other causes of optic neuropathy, such as compressive optic neuropathy, optic neuritis, and toxic optic neuropathy.