Hereditary optic neuropathies include and dominant optic neuropathy. Both diseases are caused by mitochondrial DNA abnormalities. Progressive vision loss is the main symptom, and some diseases include cardiac or neurologic abnormalities.
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 but differ in rate of progression with dominant optic atrophy causing slowly progressive bilateral vision loss over years to decades (2) and Leber hereditary optic neuropathy causing bilateral vision loss over approximately 6 to 8 months (3). Optic nerve damage is usually permanent. 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 caused by premature degeneration of the optic nerve (optic abiotrophy) leading to progressive vision loss. Onset is often in the first decade of life, but can also 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 (4). 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. 2020;65(3):294-311. 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. 2013;20(8):1712-1712.e1. doi: 10.1016/j.ophtha.2013.04.022. Erratum in: Ophthalmology. 120(12):2448, 2013.
3. Hwang TJ, Karanjia R, Moraes-Filho MN, et al. Natural History of Conversion of Leber's Hereditary Optic Neuropathy: A Prospective Case Series. Ophthalmology. 2017;124(6):843-850. doi:10.1016/j.ophtha.2017.01.002
4. 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. 2003;72(2):333-339. 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 beyond vision loss, although nystagmus and hearing loss have been reported (1). The only symptom is slowly progressive bilateral central vision loss, with variable age of onset and severity. The entire optic disc or, at times, only the temporal portion is pale without visible vessels. Visual fields will typically show bilateral central scotomas. A blue-yellow color vision deficit is characteristic.
Leber hereditary optic neuropathy
Vision loss in patients with Leber hereditary optic neuropathy typically begins between 15 and 35 years (2). Painless central vision loss in one eye is usually followed weeks to months later by loss in the other eye. Simultaneous vision loss has been reported. Most patients quickly lose vision and develop worse than 20/200 acuity. Ophthalmoscopic examination may show telangiectatic microangiopathy, swelling of the nerve fiber layer around the optic disc, and an absence of leakage on fluorescein angiography. Eventually, optic atrophy supervenes. Visual fields will typically show bilateral central scotomas.). Painless central vision loss in one eye is usually followed weeks to months later by loss in the other eye. Simultaneous vision loss has been reported. Most patients quickly lose vision and develop worse than 20/200 acuity. Ophthalmoscopic examination may show telangiectatic microangiopathy, swelling of the nerve fiber layer around the optic disc, and an absence of leakage on fluorescein angiography. Eventually, optic atrophy supervenes. Visual fields will typically show bilateral central scotomas.
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.
Symptoms and signs references
1. Lenaers G, Hamel C, Delettre C, et al. Dominant optic atrophy. Orphanet J Rare Dis. 2012;7:46. Published 2012 Jul 9. doi:10.1186/1750-1172-7-46
2. Biousse V, Newman NJ. Diagnosis and clinical features of common optic neuropathies. Lancet Neurol. 2016;15(13):1355-1367. doi: 10.1016/S1474-4422(16)30237-X
Diagnosis of Hereditary Optic Neuropathies
Funduscopy
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 performed to diagnose occult cardiac conduction defects.
Treatment of Hereditary Optic Neuropathies
Symptomatic treatment
Limited availability of gene therapy for Leber hereditary optic neuropathy variant (m.11778G)
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, glucocorticoids, 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, 4). Agents that might stress mitochondrial energy production (eg, tobacco, alcohol, particularly if excessive) should be avoided. 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. 2015;26(6):450-457. 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. 2011;134(Pt 9):2677-2686. doi: 10.1093/brain/awr170
3. Newman NJ, Biousse V, Yu-Wai-Man P, et al. Meta-analysis of treatment outcomes for patients with m.11778G>A MT-ND4 Leber hereditary optic neuropathy. Surv Ophthalmol. 2025;70(2):283-295. doi:10.1016/j.survophthal.2024.10.002
4. Yu-Wai-Man P, Newman NJ, Biousse V, et al. Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy. JAMA Ophthalmol. 2025;143(2):99-108. doi:10.1001/jamaophthalmol.2024.5375
