Leber's hereditary optic neuropathy
|Leber's hereditary optic neuropathy|
|Classification and external resources|
Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. LHON is only transmitted through the mother, as it is primarily due to mutations in the mitochondrial (not nuclear) genome, and only the egg contributes mitochondria to the embryo. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria. Men cannot pass on the disease to their offspring.
This disease was first described by the German ophthalmologist Theodor Leber (1840–1917) in 1871. In this paper Leber described four families in which a number of young men suffered abrupt loss of vision in both eyes either simultaneously or sequentially. This disease was initially thought to be X linked but was subsequently shown to be mitochondrial. The nature of the causative mutation was first identified in 1988 by Wallace et al. who discovered the guanine (G) to adenosine (A) mutation at nucleotide position 11778 in nine families. This mutation converts a highly conserved arginine to histidine at codon 340 in the NADH dehydrogenase subunit 4 of complex I of the mitochondrial respiratory chain. The other two mutations known to cause this condition were identified in 1991 (G to A point mutation at nucleotide position 3460) and 1992 (thymidine (T) to cytosine (C) mutation at nucleotide 14484). These three mutations account for over 95% of cases: the 11778 mutation accounts for 50-70% of cases, the 14484 mutation for 10-15% and the 3460 mutation for 8-25%.
Signs & Symptoms
Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-75 is reported. The age of onset is slightly higher in females (range 19–55 years: mean 31.3 years) than males (range 15–53 years: mean 24.3). The male to female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C.
This typically evolves to very severe optic atrophy and permanent decrease of visual acuity. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely only one eye may be affected. In the acute stage, lasting a few weeks, the affected eye demonstrates an edematous appearance of the nerve fiber layer especially in the arcuate bundles and enlarged or telangectatic and tortuous peripapillary vessels (microangiopathy). The main features are seen on fundus examination, just before or subsequent to the onset of visual loss. A pupillary defect may be visible in the acute stage as well. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination.
"LHON Plus" is a name given to rare strains of the disorder with eye disease together with other conditions. The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia. Many cases of LHON plus have been comparable to multiple sclerosis because of the lack of muscular control.
Leber hereditary optic neuropathy is a condition related to changes in mitochondrial DNA. Although most DNA is packaged in chromosomes within the nucleus, mitochondria have a distinct mitochondrial genome composed of mtDNA.
Mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes cause Leber hereditary optic neuropathy. These genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. Oxidative phosphorylation uses a series of four large multienzyme complexes, which are all embedded in the inner mitochondrial membrane to convert oxygen and simple sugars to energy. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy.
The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world with 70% of Northern European cases and 90% of Asian cases. Due to a Founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.
More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict likelihood of penetrance, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.
Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,  contribute to the development of signs and symptoms. The degree of heteroplasmy, the percentage of mitochondria which have mutant alleles, may play a role. Patterns of mitochondrial alleles called haplogroup may also affect expression of mutations.
The eye pathology is limited to the retinal ganglion cell layer especially the maculopapillary bundle. Degeneration is evident from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nucleii. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells. Also, experiments suggest that normal non LHON affected retinal ganglion cells produce less of the potent superoxide radical than other normal central nervous system neurons. Viral vector experiments which augment superoxide dismutase 2 in LHON cybrids or LHON animal models or use of exogenous glutathione in LHON cybrids have been shown to rescue LHON affected retinal ganglion cells from apoptotic death. These experiments may in part explain the death of LHON affected retinal ganglion cells in preference to other central nervous system neurons which also carry LHON affected mitochondria.
Diagnosis and management
Without a known family history of LHON the diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mitochondrial DNA assessment. It is important to exclude other possible causes of vision loss and important associated syndromes such as heart electrical conduction system abnormalities. The prognosis for those affected left untreated is almost always that of continued significant visual loss in both eyes. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is beneficial treatment available for some cases of this disease especially for early onset disease. Also, experimental treatment protocols are in progress. Genetic counselling should be offered. Health and lifestyle choices should be reassessed particularly in light of toxic and nutritional theories of gene expression. Vision aides assistance and work rehabilitation should be used to assist in maintaining employment.
For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress. For example, fundus photography can monitor nerve fiber layer swelling. Optical coherence tomography can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament blood markers may predict conversion to affected status.
Cyanocobalamin (a form of B12) should be avoided as it may lead to blindness in Leber's disease patients.
Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk. Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. In fact, toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management. Of note, when a patient carrying or suffering from LHON or toxic/nutritional optic neuropathy suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia in response to this anti-hypertensive in particular.
There are various treatment approaches which have had early trials or are proposed, none yet with convincing evidence of usefulness or safety for treatment or prevention including brimonidine, minocycline, curcumin, glutathione, near infrared light treatment, and viral vector techniques.
"Three person in vitro fertilisation" is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.
Idebenone is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration. When used in individuals with LHON, it is believed to allow electrons to bypass the dysfunctional complex I. Successful treatment using idebenone was initially reported in a small number of patients.
Two large-scale studies have demonstrated the benefits of idebenone. The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) evaluated the effects of idebenone in 85 patients with LHON who had lost vision within the prior five years. In this study, the group taking idebenone 900 mg per day for 24 weeks showed a slight improvement in visual acuity compared to the placebo group, though this difference was not statistically significant. Importantly, however, patients taking idebenone were protected from further vision loss, whereas the placebo group had a steady decline in visual acuity. Further, individuals taking idebenone demonstrated preservation of color vision and persistence of the effects of idebenone 30 months after discontinuing therapy. A retrospective analysis of 103 LHON patients by Carelli et al. builds upon these results. This study highlighted that 44 subjects who were treated with idebenone within one year of onset of vision loss had better outcomes, and, further, that these improvements with idebenone persisted for years.
Idebenone, combined with avoidance of smoke and limitation of alcohol intake, is the preferred standard treatment protocol for patients affected by LHON. Idebenone doses are prescribed to be taken spaced out throughout the day, rather than all at one time. For example, to achieve a dose of 900 mg per day, patients take 300 mg three times daily with meals. Idebenone is fat soluble, and may be taken with a moderate amount of dietary fat in each meal to promote absorption. It is recommended that patients on idebenone also take vitamin C 500 mg daily to keep idebenone in its reduced form, as it is most active in this state.
Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in LHON. In these trials, participants affected by LHON with the G11778A mutation will have a virus expressing the functional version of ND4 – the gene mutated in this variant of LHON – injected into one eye. A sham injection will be administered to the other eye for comparison. It is hypothesized that introduction of the viral vector may be able to rescue the function of the mutant gene. Preliminary results have demonstrated tolerability of the injections in a small number of subjects.
Stealth BioTherapeutics is presently investigating the potential use of bendavia (MTP-131), a mitochondrial protective agent, as a therapy for LHON. Bendavia helps stabilize cardiolipin  – an important component of mitochondrial inner membranes – and has been shown to reduce damaging reactive oxygen species in animal models. Clinical trials in LHON patients are planned for the future.
- Dominant optic atrophy
- Ischemic optic neuropathy
- List of eye diseases and disorders
- Optic atrophy
- Toxic and Nutritional Optic Neuropathy
- Bandelt HJ, Kong QP, Parson W, Salas A (December 2005). "More evidence for non-maternal inheritance of mitochondrial DNA?". J. Med. Genet. 42 (12): 957–60. doi:10.1136/jmg.2005.033589. PMC 1735965. PMID 15923271.
- Leber T. Ueber hereditaere und congenital angelegte sehnervenleiden (1871) Graefes Arch Clin Exp Ophthalmol. 17:249–291
- Erickson RP (1972). "Leber's optic atrophy, a possible example of maternal inheritance". Am J Hum Genet 24 (3): 348–349.
- Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK (1988). "Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy". Science 242 (4884): 1427–1430. doi:10.1126/science.3201231. PMID 3201231.
- Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML (1991). "A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy". Am J Hum Genet 48 (6): 1147–1153.
- Johns DR, Neufeld MJ, Park RD (1992). "An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy". Biochem Biophys Res Commun 187 (3): 1551–1557. doi:10.1016/0006-291x(92)90479-5.
- Nikoskelainen EK, Marttila RJ, Huoponen K, et al. (August 1995). "Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy". J. Neurol. Neurosurg. Psychiatr. 59 (2): 160–4. doi:10.1136/jnnp.59.2.160. PMC 485991. PMID 7629530.
- cardiac arrythmia
- Mayo Clinic: Multiple Sclerosis
- Online 'Mendelian Inheritance in Man' (OMIM) LEBER OPTIC ATROPHY -535000
- Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (February 2003). "The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England". Am. J. Hum. Genet. 72 (2): 333–9. doi:10.1086/346066. PMC 379226. PMID 12518276.
- Puomila A, Hämäläinen P, Kivioja S, et al. (October 2007). "Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland". Eur. J. Hum. Genet. 15 (10): 1079–89. doi:10.1038/sj.ejhg.5201828. PMID 17406640.
- Laberge AM, Jomphe M, Houde L, et al. (2005). "A "Fille du Roy" Introduced the T14484C Leber Hereditary Optic Neuropathy Mutation in French Canadians". Am. J. Hum. Genet. 77 (2): 313–7. doi:10.1086/432491. PMC 1224533. PMID 15954041.
- Hudson G, Carelli V, Horvath R, Zeviani M, Smeets HJ, Chinnery PF (2007). "X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy". Mol. Vis. 13: 2339–43. PMID 18199976.
- Hudson G, Keers S, Yu Wai Man P, et al. (December 2005). "Identification of an X-Chromosomal Locus and Haplotype Modulating the Phenotype of a Mitochondrial DNA Disorder". Am. J. Hum. Genet. 77 (6): 1086–91. doi:10.1086/498176. PMC 1285165. PMID 16380918.
- Chinnery PF, Andrews RM, Turnbull DM, Howell NN (January 2001). "Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?". Am. J. Med. Genet. 98 (3): 235–43. doi:10.1002/1096-8628(20010122)98:3<235::AID-AJMG1086>3.0.CO;2-O. PMID 11169561.
- Hudson G, Carelli V, Spruijt L, et al. (August 2007). "Clinical Expression of Leber Hereditary Optic Neuropathy Is Affected by the Mitochondrial DNA–Haplogroup Background". Am. J. Hum. Genet. 81 (2): 228–33. doi:10.1086/519394. PMC 1950812. PMID 17668373.
- Hoegger MJ, Lieven CJ, Levin LA (2008). "Differential production of superoxide by neuronal mitochondria". BMC Neurosci 9: 4. doi:10.1186/1471-2202-9-4. PMC 2266764. PMID 18182110.
- Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J (February 2007). "Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation". Arch. Ophthalmol. 125 (2): 268–72. doi:10.1001/archopht.125.2.268. PMID 17296905.
- Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M (February 2008). "Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids". Invest. Ophthalmol. Vis. Sci. 49 (2): 671–6. doi:10.1167/iovs.07-0880. PMID 18235013.
- GeneTests LHON search
- Klopstock, T.; Yu-Wai-Man, P.; Dimitriadis, K.; Rouleau, J.; Heck, S.; Bailie, M.; Atawan, A.; Chattopadhyay, S.; Schubert, M.; Garip, A.; Kernt, M.; Petraki, D.; Rummey, C.; Leinonen, M.; Metz, G.; Griffiths, P. G.; Meier, T.; Chinnery, P. F. (2011). "A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy". Brain 134 (9): 2677–2686. doi:10.1093/brain/awr170. ISSN 0006-8950.
- Shrader, W. D.; Amagata, A.; Barnes, A.; Enns, G. M.; Hinman, A.; Jankowski, O.; Kheifets, V.; Komatsuzaki, R.; Lee, E.; Mollard, P.; Murase, K.; Sadun, A. A.; Thoolen, M.; Wesson, K.; Miller, G. (2011). "Α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging". Bioorganic & Medicinal Chemistry Letters 21 (12): 3693–3698. doi:10.1016/j.bmcl.2011.04.085. PMID 21600768.
- Sadun AA, Salomao SR, Berezovsky A, et al. (2006). "SUBCLINICAL CARRIERS AND CONVERSIONS IN LEBER HEREDITARY OPTIC NEUROPATHY: A PROSPECTIVE PSYCHOPHYSICAL STUDY". Trans Am Ophthalmol Soc 104: 51–61. PMC 1809912. PMID 17471325.
- Carelli V, Ross-Cisneros FN, Sadun AA (January 2004). "Mitochondrial dysfunction as a cause of optic neuropathies". Prog Retin Eye Res 23 (1): 53–89. doi:10.1016/j.preteyeres.2003.10.003. PMID 14766317.
- Katz, Jason; Patel, Chetan (2006). Parkland Manual of Inpatient Medicine. Dallas, TX: FA Davis. p. 903.
- Clinical Idebenone trial recruiting at Newcastle University UK http://lhon.ncl.ac.uk
- Mashima Y, Kigasawa K, Wakakura M, Oguchi Y (September 2000). "Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?". J Neuroophthalmol 20 (3): 166–70. doi:10.1097/00041327-200020030-00006. PMID 11001192.
- Sadun,A et al. "EPI-743 alters the natural history of progression of Leber hereditary optic neuropathy". AOS meeting. May 2011
- Newman NJ, Biousse V, David R, et al. (September 2005). "Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite". Am. J. Ophthalmol. 140 (3): 407–15. doi:10.1016/j.ajo.2005.03.058. PMID 16083844.
- Haroon MF, Fatima A, Schöler S, et al. (2007). "Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): Studies of cybrid cells bearing 11778 mutation". Neurobiol Dis 28 (3): 237–50. doi:10.1016/j.nbd.2007.07.021. PMID 17822909.
- Clinical Curcurmin trial recruiting at ClinicalTrials.nlm.nih.gov
- Wisconsin near infrared trial
- Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM (May 2010). "Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease". Nature 465 (7294): 82–85. doi:10.1038/nature08958. PMC 2875160. PMID 20393463.
- Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, Anklin C et al. (2011). "NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels". PLoS One 6 (3): e17963. doi:10.1371/journal.pone.0017963. PMC 3069029. PMID 21483849.
- Eng, J.G.; Aggarwal, D.; Sadun, A.A. (April 2009). "Idebenone treatment in patients with Leber hereditary optic neuropathy". Invest Ophthalmol Vis Sci 50 (13). Retrieved March 22, 2016.
- Klopstock T; Metz G; Yu-Wai-Man P; et al. (2013). "Klopstock T, Metz G, Yu-Wai-Man P, et al". Brain. doi:10.1093/brain/aws279.
- Rudolph, G.; Dimitriadis, K.; Büchner, B.; Heck, S.; Al-Tamami, J.; Seidensticker, F.; Rummey, C.; Leinonen, M.; Meier, T.; Klopstock, T. (March 2013). "Effects of idebenone on color vision in patients with Leber hereditary optic neuropathy". J Neuroophthalmol 33 (1). doi:10.1097/WNO.0b013e318272c643. Retrieved March 22, 2016.
- Carelli V; La Morgia C; Valentino ML; et al. (September 2011). "Idebenone treatment in Leber’s hereditary optic neuropathy". Brain 134 (Part 9). doi:10.1093/brain/awr180. Retrieved March 22, 2016.
- Karanjia, R.; Sadun, A.A. (2015). "Advances in therapeutic strategies for Leber’s hereditary optic neuropathy". Expert Opinion Orphan Drugs 3 (12). doi:10.1517/21678707.2015.1098531.
- Mordente, A.; Martorana, G.E.; Minotti, G; Giardina, B (January 1998). "Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone)". Chem Res Toxicol. 11 (1): 54–63. PMID 9477226. Retrieved March 22, 2016.
- Sahel, J.A.; Uretsky, S.; Combal, J.P.; Galy, A.; Thomasson, N.; Fitoussi, S.; Corral-Debrinsky, M.; Honnet, G.; Vignal, C. (June 2015). "Preliminary safety and tolerability results of intravitreal administration of GS010, a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing human wildtype mitochondrial NADH dehydrogenase 4 (ND4) gene in patients with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial DNA mutation". Invest. Ophthalmol. Vis. Sci. 56 (7): 1088. Retrieved March 22, 2016.
- Birk, A.V.; Liu, S.; Soong, Y.; Mills, W.; Singh, P.; Warren, J.D.; Seshan, S.V.; Pardee, J.D.; Szeto, H.H. (July 2013). "The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin". J Am Soc Nephrol. 24\issue=8: 1250–61. doi:10.1681/ASN.2012121216. Retrieved March 22, 2016.
- Thomas, D.A.; Stauffer, C.; Zhao, K.; Yang, H.; Sharma, V.K.; Szeto, H.H.; Suthanthiran, M. (January 2007). "Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function". J Am Soc Nephrol. 18 (1): 213–222. Retrieved March 22, 2016.
- Brown DA; Hale SL; Baines CP; et al. (January 2014). "Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia". J Cardiovasc Pharmacol Ther. 19 (1): 121–132. doi:10.1177/1074248413508003. Retrieved March 22, 2016.
- Leber's hereditary optic neuropathy at NLM Genetics Home Reference
- Yu-Wai-Man P, Chinnery P (2011) Leber Hereditary Optic Neuropathy. GeneReviews
- Kerrison JB, Newman NJ (1997). "Clinical spectrum of Leber's hereditary optic neuropathy" (IFOND reprints). Clin. Neurosci. 4 (5): 295–301. PMID 9292259.
- Carelli V, Ross-Cisneros FN, Sadun AA (January 2004). "Mitochondrial dysfunction as a cause of optic neuropathies". Prog Retin Eye Res 23 (1): 53–89. doi:10.1016/j.preteyeres.2003.10.003. PMID 14766317.
- LHONsociety.org a Charity Registered with the Charity Commission for England & Wales number 1157206 - The LHON Society was established by the Trustees to create a home for those in the British Isles affected by and with an interest in, LHON. Our aspiration is that through the LHON Society you have access to:
•Shared experiences of those living with LHON and their families •Sources of practical and emotional support •Up-to-date information on practical innovation and scientific progress into LHON