Última actualización:
02/02/2023
Años publicados: 1988, 1989, 1994, 1995, 1997, 2005, 2013, 2016, 2019, 2023
NORD gratefully acknowledges Joseph Kim, NORD Intern from the University of Notre Dame, and Alfredo A. Sadun, MD, PhD, F. Thornton Endowed Chair and Professor of Ophthalmology, Doheny Eye Institute / UCLA, for assistance in the preparation of this report.
Leber hereditary optic neuropathy (LHON) is often characterized by bilateral, painless subacute loss of central vision most commonly during young adult life. In most cases, symptoms begin with one eye first, followed a few weeks later by visual failure in the other eye. Extremely rarely there may be neurologic abnormalities, such as peripheral neuropathy, postural tremor, nonspecific myopathy, and movement disorders. LHON is caused by changes (called variants or mutations) in mitochondrial DNA and it is strictly transmitted by maternal inheritance. The prevalence of LHON in carriers and affected is approximately 1:50,000 people. Many carriers never suffer significant visual loss; males are about four to five times more likely than females to lose vision and be affected. The incidence of visual loss, therefore, is much less and about 1:10 million/year
Individuals with LHON typically display symptoms while young adult. If vision is lost, then it usually occurs before 40 years of age.
The acute phase of LHON is characterized by a loss of central vision, including blurring and reduced perception of color. Individuals usually lose vision in one eye first and then lose vision in the other eye after two to three months. The atrophic phase is characterized by bilateral optic atrophy, resulting in lifelong blindness.
Depending on the mutation and pedigree, most female carriers do not lose vision but up to half of males do.
LHON is caused by genetic mutations in the mitochondrial DNA (mtDNA). Mothers with a LHON gene mutation may not show symptoms, but family history often reveals maternal relatives with visual loss at an early age.
Mutations in mitochondrial DNA can only be inherited maternally because mitochondria derive from ova, not sperm. All of the offspring of a mother with an mtDNA mutation will inherit the gene. A male with a mitochondrial DNA mutation cannot transmit the mutated gene to any of his children.
The three primary mitochondrial DNA LHON-causing mutations are mt.3460G>A, mt.11778G>A, and mt.14484T>C, which account for over 90% of LHON patients. The most common LHON-causing mutation is mt.11778G>A. The greatest penetrance (chance of a carrier to lose vision) is for mt.3460G>A and the least is for mt.14484T>C.
The prevalence of visual loss from LHON is approximately 1:50,000 people. Most carriers never suffer significant visual loss; males are about four to five times more likely than females to lose vision and be affected.
LHON is diagnosed based on ophthalmologic findings, which include specialized visual testing. The testing involves dilated fundus examination to identify characteristic changes in the optic disc and vascular changes during the acute phase, visual fields, electrophysiologic studies and imaging, particularly OCT. Molecular genetic testing for mitochondrial genes associated with LHON can be used to confirm diagnosis. Most affected individuals know if their family members also are affected by LHON.
Treatment
Affected individuals should receive supportive management and treatment through the usage of visual aids, occupational rehabilitation and local social services. Several studies have shown that therapies involving ubiquinone and idebenone may provide possible benefits during both the acute and chronic phases of the disorder. Affected individuals should avoid smoking and excessive alcohol consumption, which generate reactive oxygen species (ROS) producing or amplifying mitochondrial impairments.
Clinical Testing and Work-Up
Consistent monitoring and surveillance of asymptomatic individuals with LHON-causing mutations is not necessary. However, if visual disturbance is experienced, affected individuals should immediately seek medical attention from an ophthalmologist or neuro-ophthalmologist.
Individuals should follow-up frequent to their own circumstances and availability of local healthcare.
Genetic counseling is recommended for patients and their families. The key to understanding is that female carriers always transmit the gene and male carriers never do.
Several other modalities of treatment are being tested in clinical trials. These include gene therapy (for mtDNA 11778) and MTP-131 as eye drops or subcutaneous injection.
Information on current clinical trials is posted on the Internet at https://www.clinicaltrials.gov/. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about Leber hereditary optic neuropathy:
Alfredo A. Sadun, MD, PhD
Flora Thornton Chair, Doheny Eye Institute
Vice-Chair, Ophthalmology, UCLA
800 Fairmont St. suite 215
Pasadena, CA 91105
TEXTBOOKS
Biousse V, Newman NJ. Leber Hereditary Optic Neuropathy. In: The NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott, Williams and Wilkins; 2003:653.
JOURNAL ARTICLES
Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros PA, Sadun F, DeNegri AM, Andrade R, Moraes M, Passos A, Kjaer P, Pereira J, Valentino ML, Schein S, Belfort R. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2003 Aug;136(2):231-8.
Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the northeast of England. Am J Hum Genet. 2003;72:333-9.
Horvath R, Abicht A, Scoubridge EA, et al. Leber’s hereditary optic neuropathy presenting as multiple sclerosis-like disease of the CNS. J Neurol. 2000;247:65-7.
Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, DaCosta J, Harding AE. The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995;118(pt 2):319-37.
Mashima Y, Hilda Y, Oguchi Y. Remission of Leber’s hereditary optic neuropathy with idebenone. Lancet. 1992;340:368-9.
Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242:1427-30.
INTERNET
Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. 2000 Oct 26 [Updated 2021 Mar 11]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1174/ Accessed Nov 22, 2022.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Leber Optic Atrophy. Entry No: 535000. Last Edited:05/03/22. Available at: https://omim.org/entry/535000 Accessed Nov 22, 2022.
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