Hereditary optic neuropathies result from genetic defects that cause vision loss and occasionally cardiac or neurologic abnormalities. There is no effective treatment.
Hereditary optic neuropathies include dominant optic atrophy and Leber hereditary optic neuropathy, which are both mitochondrial cytopathies (1). These disorders typically manifest in childhood or adolescence with bilateral, symmetric central vision loss. Optic nerve damage is usually permanent and in some cases progressive. By the time optic atrophy is detected, substantial optic nerve injury has already occurred.
Dominant optic atrophy
Dominant optic atrophy is inherited in an autosomal dominant fashion. It is believed to be the most common of the hereditary optic neuropathies, with prevalence in the range of 1:10,000 to 1:50,000 (2). It is thought to be optic abiotrophy, premature degeneration of the optic nerve leading to progressive vision loss. Onset is often in the first decade of life, but it can be first detected later in life.
Leber hereditary optic neuropathy
Leber hereditary optic neuropathy involves a mitochondrial DNA abnormality that affects cellular respiration. Although mitochondrial DNA throughout the body is affected, vision loss is the primary manifestation. Most cases occur in males (3). The disease is inherited with a maternal inheritance pattern, meaning that all offspring of a woman with the abnormality inherit the abnormality, but only females can pass on the abnormality because the zygote receives mitochondria only from the mother.
General references
1. Kisilevsky E, Freund P, Margolin E: Mitochondrial disorders and the eye. Surv Ophthalmol 65(3):294-311, 2020. doi: 10.1016/j.survophthal.2019.11.001
2. Yu-Wai-Man P, Chinnery PF: Dominant optic atrophy: Novel OPA1 mutations and revised prevalence estimates. Ophthalmology 20(8):1712-1712.e1, 2013. doi: 10.1016/j.ophtha.2013.04.022. Erratum in: Ophthalmology 120(12):2448, 2013.
3. Yu-Wai-Man P, Griffiths PG, Brown DT, et al: The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72(2):333-339, 2003. doi: 10.1086/346066
Symptoms and Signs of Hereditary Optic Neuropathies
Dominant optic atrophy
Most patients with dominant optic atrophy have no associated neurologic abnormalities, although nystagmus and hearing loss have been reported. The only symptom is slowly progressive bilateral vision loss, usually mild until late in life. The entire optic disk or, at times, only the temporal portion is pale without visible vessels. A blue-yellow color vision deficit is characteristic.
Leber hereditary optic neuropathy
Some patients with Leber hereditary optic neuropathy have cardiac conduction defects. Other patients have minor neurologic abnormalities, such as a postural tremor, loss of ankle reflexes, dystonia, spasticity, or a multiple sclerosis–like illness.
Diagnosis of Hereditary Optic Neuropathies
Clinical evaluation
Molecular genetic testing
If the diagnosis of dominant optic atrophy or Leber hereditary optic atrophy is suspected clinically, molecular genetic testing is appropriate to confirm many mutations responsible for both disorders. However, results can be falsely negative because mutations may exist for which molecular testing does not yet detect.
If Leber hereditary optic neuropathy is suspected, electrocardiography (ECG) should be done to diagnose occult cardiac conduction defects.
Treatment of Hereditary Optic Neuropathies
Symptomatic treatment
There is no proven treatment for the hereditary optic neuropathies. Low-vision aids (eg, magnifiers, large-print devices, talking watches) may be helpful. Genetic counseling is suggested.
In patients with Leber hereditary optic neuropathy, corticosteroids, vitamin supplements, and antioxidants have been tried without success. A small study found benefits from quinone analogs (ubiquinone and idebenone) during the early phase (1, 2). Genetic trials for the 11778 mutation are ongoing and have shown a possible mild increase in recovery of vision in both eyes even after a unilateral intravitreal injection (3). Suggestions to avoid agents that might stress mitochondrial energy production (eg, tobacco, alcohol, particularly if excessive) have no proven benefit but are reasonable. Patients with cardiac and neurologic abnormalities should be referred to a specialist.
Treatment references
1. Peragallo JH, Newman NJ: Is there treatment for Leber hereditary optic neuropathy? Curr Opin Ophthalmol 26(6):450-457, 2015. doi: 10.1097/ICU.0000000000000212
2. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al: A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain 134(Pt 9):2677-2686, 2011. doi: 10.1093/brain/awr170
3. Newman NJ, Yu-Wai-Man P, Carelli V, et al: Intravitreal gene therapy vs. natural history in patients with Leber hereditary optic neuropathy carrying the m.11778G>A ND4 mutation: Systematic review and indirect comparison. Front Neurol 12:662838, 2021. doi: 10.3389/fneur.2021.662838
