View source for Leber's hereditary optic neuropathy

{{short description|Mitochondrially inherited degeneration of retinal nerve cells}}
{{Infobox medical condition (new)
| name            = Leber's hereditary optic neuropathy
| synonyms        = '''Leber hereditary optic atrophy'''
| image           = Mitochondrial inheritance.svg
| caption         = Leber's hereditary optic neuropathy has a [[Human mitochondrial genetics|mitochondrial inheritance]] pattern.
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| frequency       = 1:30,000 to 1:50,000
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'''Leber's hereditary optic neuropathy''' ('''LHON''') is a [[Human mitochondrial genetics|mitochondrially inherited]] (transmitted from mother to offspring) degeneration of [[retinal ganglion cell]]s (RGCs) and their [[axon]]s that leads to an acute or subacute loss of central vision; it predominantly affects young adult males. LHON is  transmitted only through the mother, as it is primarily due to [[mutation]]s in the mitochondrial (not nuclear) [[genome]], and only the [[ovum|egg]] contributes [[mitochondria]] to the [[embryo]]. Men cannot pass on the disease to their offspring.<ref>{{cite journal |vauthors=Bandelt HJ, Kong QP, Parson W, Salas A |title=More evidence for non-maternal inheritance of mitochondrial DNA? |journal=J. Med. Genet. |volume=42 |issue=12 |pages=957–60 |date=December 2005 |pmid=15923271 |doi=10.1136/jmg.2005.033589 |pmc=1735965}}</ref> LHON is usually due to one of three pathogenic mitochondrial [[DNA]] (mtDNA) [[point mutation]]s. These mutations are at [[nucleotide]] positions 11778 [[guanine|G]] to [[adenine|A]], 3460 [[guanine|G]] to [[adenine|A]] and 14484 [[thymine|T]] to [[cytosine|C]], respectively in the ND4, ND1 and ND6 subunit [[gene]]s of [[electron transfer chain|complex I]] of the [[oxidative phosphorylation]] chain in mitochondria.
==Signs and symptoms==
Clinically, there is an acute onset of visual loss, first in one [[human eye|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.{{citation needed|date=September 2021}}
This typically evolves to very severe [[optic atrophy]] and a 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 is affected. In the acute stage, lasting a few weeks, the affected eye demonstrates an oedematous appearance of the nerve fiber layer, especially in the arcuate bundles and enlarged or telangiectatic and tortuous peripapillary vessels (microangiopathy). The main features are seen on [[Fundus (eye)|fundus]] [[Fundoscopy|examination]], just before or after the onset of visual loss. A [[Marcus Gunn pupil|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 [[perimetry|visual field examination]].{{citation needed|date=September 2021}}
===LHON with demyelinating lesions or LHON Plus===
LHON Plus is a rare variant of the disorder with eye disease together with other conditions.<ref name="Nikoskelainen1995">{{cite journal  |vauthors=Nikoskelainen EK, Marttila RJ, Huoponen K, etal |title=Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy |journal=J. Neurol. Neurosurg. Psychiatry |volume=59 |issue=2 |pages=160–4 |date=August 1995 |pmid=7629530 |pmc=485991 |doi= 10.1136/jnnp.59.2.160}}</ref> Its symptoms include loss of the brain's ability to control the movement of muscles, tremors, and [[cardiac arrhythmia]].<ref>[http://heart-disease.health-cares.net/cardiac-arrhythmia.php cardiac arrythmia]{{dead link|date=October 2024}}</ref> Many cases of LHON plus have been compared to [[multiple sclerosis]] because of the lack of muscular control<ref>[http://www.mayoclinic.com/health/multiple-sclerosis/DS00188 Mayo Clinic: Multiple Sclerosis]</ref> and the presence of demyelinating lesions in the CNS. It is therefore a subtype of MS, according to McDonald's definition.<ref>David Bargiela, Patrick F Chinnery, Mitochondria in neuroinflammation – Multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS, https://doi.org/10.1016/j.neulet.2017.06.051</ref>
==Genetics==
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.<ref name="titleOMIM - LEBER OPTIC ATROPHY">{{OMIM|535000|LEBER OPTIC ATROPHY}}</ref> 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, 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.{{citation needed|date=September 2021}}
== Pathophysiology ==
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 nucleus|lateral geniculate nuclei]]. 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]] [[free radical|radical]] than other normal central nervous system neurons.<ref>{{cite journal|vauthors=Hoegger MJ, Lieven CJ, Levin LA |title=Differential production of superoxide by neuronal mitochondria |journal=BMC Neurosci |volume=9|pages=4 |year=2008 |pmid=18182110 |pmc=2266764 |doi=10.1186/1471-2202-9-4 |doi-access=free }}</ref> Viral vector experiments that augment [[superoxide dismutase]] 2 in LHON [[cytoplasmic hybrid|cybrids]]<ref name="Qi">{{cite journal|vauthors=Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J |title=Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation |journal=Arch. Ophthalmol. |volume=125 |issue=2 |pages=268–72 |date=February 2007 |pmid=17296905 |doi=10.1001/archopht.125.2.268 |doi-access=free }}</ref> or LHON animal models or use of exogenous [[glutathione]] in LHON cybrids<ref name="Ghelli2008">{{cite journal|vauthors=Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M |title=Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids |journal=Invest. Ophthalmol. Vis. Sci. |volume=49 |issue=2 |pages=671–6 |date=February 2008 |pmid=18235013 |doi=10.1167/iovs.07-0880 |doi-access=free }}</ref> 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 that also carry LHON-affected mitochondria.{{citation needed|date=September 2021}}
== Diagnosis ==
Without a known family history of LHON the diagnosis usually requires a [[Neuro-ophthalmologist|neuro-ophthalmological]] evaluation and blood testing for mitochondrial DNA assessment.<ref name="Genereviews2016">{{cite journal |url=https://www.ncbi.nlm.nih.gov/books/NBK1174/ |title = Leber Hereditary Optic Neuropathy|vauthors = Yu-Wai-Man P, Chinnery PF|date=June 23, 2016 |website = NCBI |publisher  =Genereviews | pmid=20301353 |access-date= February 25, 2018}}</ref> It is important to exclude other possible causes of vision loss and associated syndromes such as heart electrical conduction system abnormalities.{{citation needed|date=September 2021}}
==Treatment==
The prognosis for those left untreated is almost always continued significant visual loss in both eyes. Regular corrected [[visual acuity]] and [[perimetry]] checks are advised for affected people. There is beneficial treatment for some cases of LHON, especially for early-onset disease,<ref name="Klopstock2011"/> and experimental treatment protocols are in progress.<ref name="Shrader2011"/> [[Genetic counseling]] should be offered. Health and lifestyle choices should be reassessed, particularly in light of toxic and nutritional theories of gene expression. Vision aids assistance and work rehabilitation should be used to assist in maintaining employment.{{citation needed|date=September 2021}}
For those who carry a LHON mutation, preclinical markers may be used to monitor progress.<ref name="Sadun2006">{{cite journal |vauthors=Sadun AA, Salomao SR, Berezovsky A, etal |journal=Trans Am Ophthalmol Soc |volume=104 |pages=51–61 |year=2006 |pmid=17471325 |pmc=1809912 |title=Subclinical carriers and conversions in Leber hereditary optic neuropathy: A prospective psychophysical study }}</ref> 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.{{citation needed|date=September 2021}}
[[Cyanocobalamin]] (a form of B12) should be avoided as it may lead to blindness in LHON patients.<ref>{{cite journal |title=Oliveira C. Toxic-Metabolic and Hereditary Optic Neuropathies. Continuum (Minneap Minn). 2019 Oct;25(5):1265-1288. |year=2019 |doi=10.1212/CON.0000000000000769 |pmid=31584537|last1=Oliveira |first1=C. |journal=Continuum (Minneapolis, Minn.) |volume=25 |issue=5 |pages=1265–1288 |s2cid=203660987 }}</ref><ref>{{cite book |title=Cyanocobalamin. |author=Vasavada A, Sanghavi D. [Updated 2020 Aug 3]. StatPearls Publishing |year=2021 |publisher=StatPearls |pmid=32310424 |url=https://www.ncbi.nlm.nih.gov/books/NBK555964/}}</ref><ref>{{cite web |author=LHON Canada |title=Things to avoid  |url=https://lhoncanada.ca/things-to-avoid/ |access-date=February 21, 2021}}</ref>
Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are potential risks, 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 Neuropathy|toxic and nutritional optic neuropathies]] may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management.<ref name="Carelli2004">{{cite journal|vauthors=Carelli V, Ross-Cisneros FN, Sadun AA |title=Mitochondrial dysfunction as a cause of optic neuropathies |journal=Prog Retin Eye Res |volume=23 |issue=1 |pages=53–89 |date=January 2004 |pmid=14766317 |doi=10.1016/j.preteyeres.2003.10.003 |s2cid=15862778 }}</ref> And when a patient with LHON or [[Toxic and Nutritional Optic Neuropathy|toxic/nutritional optic neuropathy]] has a [[hypertensive crisis]] as a possible complication of the disease process, [[nitroprusside]] (trade name: [[Nipride]]) should not be used, due to increased risk of [[Ischemic optic neuropathy|optic nerve ischemia]] in response to this [[anti-hypertensive]].<ref name="Parkland">{{cite book|last = Katz | first = Jason|author2=Patel, Chetan | title = Parkland Manual of Inpatient Medicine|url = https://archive.org/details/parklandmanualin00katz |url-access = limited | publisher = FA Davis| year = 2006| location = Dallas, TX| page = [https://archive.org/details/parklandmanualin00katz/page/n929 903]| isbn = 9780803613973}}</ref>
[[Idebenone]]<ref name="Klopstock2011">{{cite journal|last1=Klopstock|first1=T.|last2=Yu-Wai-Man|first2=P.|last3=Dimitriadis|first3=K.|last4=Rouleau|first4=J.|last5=Heck|first5=S.|last6=Bailie|first6=M.|last7=Atawan|first7=A.|last8=Chattopadhyay|first8=S.|last9=Schubert|first9=M.|last10=Garip|first10=A.|last11=Kernt|first11=M.|last12=Petraki|first12=D.|last13=Rummey|first13=C.|last14=Leinonen|first14=M.|last15=Metz|first15=G.|last16=Griffiths|first16=P. G.|last17=Meier|first17=T.|last18=Chinnery|first18=P. F.|title=A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy|journal=Brain|volume=134|issue=9|year=2011|pages=2677–2686|issn=0006-8950|doi=10.1093/brain/awr170|pmid=21788663|pmc=3170530}}</ref><ref name="NewcastleTrial">Clinical Idebenone trial recruiting at Newcastle University UK [http://lhon.ncl.ac.uk/ http://lhon.ncl.ac.uk]</ref><ref name="pmid11001192">{{cite journal |vauthors=Mashima Y, Kigasawa K, Wakakura M, Oguchi Y |title=Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? |journal=J Neuroophthalmol |volume=20 |issue=3 |pages=166–70 |date=September 2000 |pmid=11001192 |doi= 10.1097/00041327-200020030-00006|s2cid=22247204 |doi-access=free }}</ref>  has been shown in a small placebo-controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.
α-[[Tocotrienol]]-quinone, a [[vitamin E]] metabolite, has had some success in small open-label trials in reversing early onset vision loss.<ref name="Shrader2011">{{Cite journal | last1 = Shrader | first1 = W. D. | last2 = Amagata | first2 = A. | last3 = Barnes | first3 = A. | last4 = Enns | first4 = G. M. | last5 = Hinman | first5 = A. | last6 = Jankowski | first6 = O. | last7 = Kheifets | first7 = V. | last8 = Komatsuzaki | first8 = R. | last9 = Lee | first9 = E. | doi = 10.1016/j.bmcl.2011.04.085 | last10 = Mollard | first10 = P. | last11 = Murase | first11 = K. | last12 = Sadun | first12 = A. A. | last13 = Thoolen | first13 = M. | last14 = Wesson | first14 = K. | last15 = Miller | first15 = G. | title = Α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 12 | pages = 3693–3698 | year = 2011 | pmid = 21600768 }}</ref><ref name="Sadun2011">[http://www.aosonline.org/annualmeeting/am_program.pdf Sadun, A et al.  "EPI-743 alters the natural history of progression of Leber hereditary optic neuropathy". AOS meeting. May 2011] {{webarchive|url=https://web.archive.org/web/20110904044315/http://www.aosonline.org/annualmeeting/am_program.pdf |date=2011-09-04 }}</ref>
Various treatment approaches have had early trials or been proposed, but so far none with convincing evidence of usefulness or safety for treatment or prevention, including [[brimonidine]],<ref name="Newman2005">{{cite journal |vauthors=Newman NJ, Biousse V, David R, etal |title=Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite |journal=Am. J. Ophthalmol. |volume=140 |issue=3 |pages=407–15 |date=September 2005 |pmid=16083844 |doi=10.1016/j.ajo.2005.03.058 }}</ref> [[minocycline]],<ref name="pmid17822909">{{cite journal  |vauthors=Haroon MF, Fatima A, Schöler S, etal |title=Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): Studies of cybrid cells bearing 11778 mutation |journal=Neurobiol Dis |volume= 28|issue= 3|pages= 237–50|year=2007 |pmid=17822909 |doi=10.1016/j.nbd.2007.07.021|s2cid=30986663 }}</ref>   [[curcumin]],<ref>Clinical Curcurmin trial recruiting at [http://clinicaltrials.nlm.nih.gov/ct2/show?cond=%22Optic+Nerve+Diseases%22&rank=10 ClinicalTrials.nlm.nih.gov] {{webarchive|url=https://web.archive.org/web/20090213192951/http://clinicaltrials.nlm.nih.gov/ct2/show?cond=%22Optic+Nerve+Diseases%22&rank=10 |date=2009-02-13 }}</ref> [[glutathione]],<ref name="Ghelli2008" /> [[Infrared#Photobiomodulation|near infrared]] [[Light therapy|light treatment]],<ref name="WisconsinTrial">[http://www.mcw.edu/neurology/research/LHON.htm Wisconsin near infrared trial] {{webarchive|url=https://web.archive.org/web/20080515222915/http://www.mcw.edu/neurology/research/LHON.htm |date=2008-05-15 }}</ref> and [[viral vector]] techniques.<ref name="Qi"/>
"Three person in vitro fertilization" 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.<ref name="Craven2010">{{cite journal|vauthors=Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM |title=Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease |journal=Nature |volume=465 |issue=7294 |pages=82–85 |date=May 2010 |pmid=20393463 |doi=10.1038/nature08958 |pmc=2875160|bibcode=2010Natur.465...82C }}</ref>
===Idebenone===
[[Idebenone]] is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration. When used in people with LHON, it is believed to allow electrons to bypass the dysfunctional complex I.<ref name="pmid21483849">{{cite journal | vauthors = Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, Anklin C, Dallmann R, Gueven N | title = NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels | journal = PLOS ONE | volume = 6 | issue = 3 | pages = e17963 | date = March 2011 | pmid = 21483849 | pmc = 3069029 | doi = 10.1371/journal.pone.0017963 | bibcode = 2011PLoSO...617963H | doi-access = free }}</ref> Successful treatment with idebenone was initially reported in a small number of patients.<ref name="pmid11001192" /><ref>{{Cite journal|last1=Eng|first1=J.G.|last2=Aggarwal|first2=D.|last3=Sadun |first3=A.A.|date=April 2009|title=Idebenone treatment in patients with Leber hereditary optic neuropathy|url=http://iovs.arvojournals.org/article.aspx?articleid=2363866|journal=Invest Ophthalmol Vis Sci|volume=50|issue=13|access-date=March 22, 2016}}</ref>
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.<ref name="Klopstock2011"/><ref name=":0">{{Cite journal|author1=Klopstock T |author2=Metz G |author3=Yu-Wai-Man P |date=2013|title=Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy|pmid=23388409|journal=Brain|doi=10.1093/brain/aws279|display-authors=etal |pmc=3572931 |volume=136 |issue=2 |pages=e230}}</ref> In this study, the group taking idebenone 900&nbsp;mg per day for 24 weeks showed a slight improvement in visual acuity compared to the placebo group, though the difference was not statistically significant. But patients taking idebenone were protected from further vision loss, whereas the placebo group had a steady decline in visual acuity. Further, people taking idebenone demonstrated preservation of color vision and persistence of the effects of idebenone 30 months after discontinuing therapy.<ref name=":0" /><ref>{{Cite journal|last1=Rudolph|first1=G. |last2=Dimitriadis |first2=K. |last3=Büchner |first3=B. |last4=Heck |first4=S. |last5=Al-Tamami |first5=J. |last6=Seidensticker |first6=F. |last7=Rummey |first7=C. |last8=Leinonen |first8=M. |last9=Meier |first9=T. |last10=Klopstock |first10=T.|date=March 2013|title=Effects of idebenone on color vision in patients with Leber hereditary optic neuropathy|pmid=23263355|journal=J Neuroophthalmol|doi=10.1097/WNO.0b013e318272c643|volume=33|issue=1 |pmc=3658961 |pages=30–36}}</ref> A retrospective analysis of 103 LHON patients by Carelli et al. builds upon these results.<ref>{{Cite journal|author1=Carelli V |author2=La Morgia C |author3=Valentino ML |date=September 2011|volume=134|issue=Part 9|title=Idebenone treatment in Leber's hereditary optic neuropathy|pmid=21810891|journal=Brain|doi=10.1093/brain/awr180|display-authors=etal |pages=e188|doi-access=free}}</ref> This study highlighted that 44 subjects who were treated with idebenone within one year of onset of vision loss had better outcomes, and that these improvements persisted for years.{{citation needed|date=September 2021}}
Idebenone, combined with avoidance of smoke and limitation of alcohol intake, is the preferred treatment protocol for people with LHON.<ref name="Karanjia R 1446">{{Cite journal|last2=Sadun|first2=A.A.|date=2015|title=Advances in therapeutic strategies for Leber's hereditary optic neuropathy|journal= Expert Opinion on Orphan Drugs|volume=3|issue=12|pages=1439–1446|doi=10.1517/21678707.2015.1098531|last1=Karanjia|first1=R.|s2cid=74119548}}<!--|access-date=March 22, 2016--></ref> Idebenone doses are prescribed to be taken spaced out throughout the day, rather than all at once. For example, to achieve a dose of 900&nbsp;mg per day, patients take 300&nbsp;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&nbsp;mg daily to keep idebenone in its reduced form,<ref name="Karanjia R 1446"/> as it is most active in this state.<ref>{{Cite journal|last1=Mordente|first1=A.|last2=Martorana|first2=G.E. |last3=Minotti|first3=G|last4=Giardina|first4=B|date=January 1998|volume=11|issue=1|pages=54–63|title=Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone)|journal=Chem Res Toxicol|doi=10.1021/tx970136j|pmid=9477226}}</ref>
=== Estrogen replacement therapy ===
[[Estrogen]]s have been shown to have a protective role in the pathogenesis of LHON. Experiments using LHON cybrids have demonstrated that the estrogen receptor localizes to the mitochondria where it directly mediates mitochondrial biogenesis. Estrogens upregulate the antioxidant enzyme [[Superoxide dismutase|superoxide dismutase 2]] and mitochondrial DNA synthesis. These experiments helped to explain the mechanism behind the lower penetrance of disease among female carriers.<ref name="Giordano, C 353">{{Cite journal|last2=Iommarini|first2=L|last3=Giordano|first3=L|last4=Maresca|first4=A|last5=Pisano|first5=A|last6=Valentino|first6=M L|last7=Caporali|first7=L|last8=Liguori|first8=R|last9=Deceglie|first9=S|last10=Roberti|first10=M|last11=Fanelli|first11=F|last12=Fracasso|first12=F|last13=Ross-Cisneros|first13=F N|last14=D'Adamo|first14=P|last15=Hudson|first15=G|last16=Pyle|first16=A|last17=Yu-Wai-Man|first17=P|last18=Chinnery|first18=P F|last19=Zeviani|first19=M|last20=Salomao|first20=S R|last21=Berezovsky|first21=A|last22=Belfort Jr|first22=R|last23=Ventura|first23=D F|last24=Moraes|first24=M|last25=Filho|first25=M.M.|last26=Barboni|first26=P|last27=Sadun|first27=F|last28=De Negri|first28=A|last29=Sadun|first29=A.A.|last30=Tancredi|first30=A|last31=Mancini|first31=M|last32=d'Amati|first32=G|last33=Polosa|first33=P L|last34=Cantatore|first34=P|last35=Carelli|first35=V|date=2013|title= Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy |journal=Brain|volume=137|issue=Pt 2|pages=335–353|doi=10.1093/brain/awt343|pmid=24369379|pmc=3914475|last1=Giordano|first1=C.}}<!--|access-date=September 22, 2019--></ref><ref name="Giordano, C 234">{{Cite journal|last2=Montopoli|first2=M|last3=Perli|first3=E|last4=Orlandi|first4=M|last5=Fantin|first5=M|last6=Ross-Cisneros|first6=F.N. L|last7=Caparrotta|first7=L|last8=Martinuzzi|first8=A|last9=Ragazzi|first9=E|last10=Ghelli|first10=A|last11=Sadun|first11=A.A.|last12=d'Amati|first12=G|last13=Carelli|first13=V|date=2011|title= Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy|journal=Brain|volume=134|issue=Pt 1|pages=220–234|doi=10.1093/brain/awq276|pmid=20943885|pmc=3025718|last1=Giordano|first1=C.}}<!--|access-date=September 22, 2019--></ref><ref name="Pisano, A.">{{Cite journal|last2=Preziuso|first2=C|last3=Iommarini|first3=L|last4=Perli|first4=E|last5=Grazioli|first5=P|last6=Campese|first6=A.F.|last7=Maresca|first7=A|last8=Montopoli|first8=M|last9=Masuelli|first9=L|last10=Sadun|first10=A.A.|last11=d'Amati|first11=G|last12=Carelli|first12=V|last13=Ghelli|first13=A.M.|last14=Giordano|first14=C|date=2015|title=Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy|journal=Human Molecular Genetics|volume=24|issue=24|pages=6921–6931|doi=10.1093/hmg/ddv396|pmid=26410888|last1=Pisano|first1=A.|doi-access=free}}<!--|access-date=September 22, 2019--></ref> While additional factors have been theorized, the protective role of estrogens appears to be a significant contributor.{{citation needed|date=September 2021}}
In addition to the experimental evidence, clinical data also points towards the protective role of estrogens. Penetrance among female carriers is substantially lower (between 3 and 8 to 1 male to female ratios depending on the mutation) while average age at onset is significantly higher. Multiple case series of various LHON pedigrees have described female carriers converting after menopause or cessation of hormone replacement therapies.<ref name="Fantini, M">{{Cite journal|last2=Asanad|first2=S|last3=Karanjia|first3=R|last4=Sadun|first4=A.A.|date=2019|title= Hormone replacement therapy in Leber's hereditary optic neuropathy: Accelerated visual recovery in vivo|journal=Journal of Current Ophthalmology|volume=31|pages=102–105|doi=10.1016/j.joco.2018.10.003|pmid=30899856|last1=Fantini|first1=M.|issue=1|doi-access=free|pmc=6407313}}<!--|access-date=September 22, 2019--></ref><ref name="Hwang, T.J.">{{Cite journal|last2=Karanjia|first2=R|last3=Moraes-Filho|first3=M.N.|last4=Gale|first4=J|last5=Show Tran|first5=J.|last6=Chu|first6=E.R.|last7=Salomao|first7=S.R.|last8=Berezovsky|first8=A|last9=Belfort Jr.|first9=R|last10=Nunes Moraes|first10=M|last11=Sadun|first11=F|last12=DeNegri|first12=A.M.|last13=La Morgia|first13=C|last14=Barboni|first14=P|last15=Ramos|first15=C.|last16=Chicani|first16=C.F.|last17=Quiros|first17=P.A.|last18=Carelli|first18=V|last19=Sadun|first19=A.A.|date=2017|title=Natural History of Conversion of Leber's Hereditary Optic Neuropathy |journal=Ophthalmology|volume=124|issue=6|pages=843–850|doi=10.1016/j.ophtha.2017.01.002|pmid=28196731|last1=Hwang|first1=T.J.}}<!--|access-date=September 22, 2019--></ref> Together, these form a shifting paradigm towards considering reduced estrogen states, such as menopause, as potential triggers of visual loss similar to smoking or excessive alcohol consumption.
[[Hormone replacement therapy]] (HRT) is emerging as an effective therapeutic target for female mutation carriers. In one recent case study where the affected female converted following cessation of HRT, [[idebenone]], and HRT were given together.<ref name="Fantini, M">{{Cite journal|last2=Asanad|first2=S|last3=Karanjia|first3=R|last4=Sadun|first4=A.A.|date=2019|title= Hormone replacement therapy in Leber's hereditary optic neuropathy: Accelerated visual recovery in vivo|journal=Journal of Current Ophthalmology|volume=31|pages=102–105|doi=10.1016/j.joco.2018.10.003|pmid=30899856|last1=Fantini|first1=M.|issue=1|doi-access=free|pmc=6407313}}<!--|access-date=September 22, 2019--></ref> Visual acuity improved much faster than is typically expected. The patient's vision returned to 20/40 and 20/60 from 20/60 and 20/200 in the right and left eyes respectively after only one month and was back normal by 8 months compared to the months to years timeframe seen in most cases. While the balance between risks and benefits of HRT remains controversial, the decision to start HRT requires an individualized approach based on the patient's context. While not applicable for all post-menopausal women, prophylactic (and therapeutic) HRT should be considered in all female carriers of a known LHON mutation given the substantial risk of vision loss associated with menopause.<ref name="Giordano, C 234">{{Cite journal|last2=Montopoli|first2=M|last3=Perli|first3=E|last4=Orlandi|first4=M|last5=Fantin|first5=M|last6=Ross-Cisneros|first6=F.N. L|last7=Caparrotta|first7=L|last8=Martinuzzi|first8=A|last9=Ragazzi|first9=E|last10=Ghelli|first10=A|last11=Sadun|first11=A.A.|last12=d'Amati|first12=G|last13=Carelli|first13=V|date=2011|title= Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy|journal=Brain|volume=134|issue=Pt 1|pages=220–234|doi=10.1093/brain/awq276|pmid=20943885|pmc=3025718|last1=Giordano|first1=C.}}<!--|access-date=September 22, 2019--></ref><ref name="Hutchinson, C.V.">{{Cite journal|last2=Walker|first2=J.A.|last3=Davidson|first3=C|date=2014|title= Oestrogen, ocular function and low-level vision: a review|journal=Journal of Endocrinology|volume=223|issue=2|pages=R9–R18|doi=10.1530/JOE-14-0349|pmid=25143633|last1=Hutchinson|first1=C.V.|doi-access=free}}<!--|access-date=September 22, 2019--></ref><ref name="Fantini, M">{{Cite journal|last2=Asanad|first2=S|last3=Karanjia|first3=R|last4=Sadun|first4=A.A.|date=2019|title= Hormone replacement therapy in Leber's hereditary optic neuropathy: Accelerated visual recovery in vivo|journal=Journal of Current Ophthalmology|volume=31|pages=102–105|doi=10.1016/j.joco.2018.10.003|pmid=30899856|last1=Fantini|first1=M.|issue=1|doi-access=free|pmc=6407313}}<!--|access-date=September 22, 2019--></ref>
==Epidemiology==
In Northern European populations about one in 9,000 people carries one of the three primary LHON mutations.<ref>{{cite journal|vauthors=Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF |title=The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England |journal=Am. J. Hum. Genet. |volume=72 |issue=2 |pages=333–9 |date=February 2003 |pmid=12518276 |pmc=379226 |doi=10.1086/346066 }}</ref><ref name="Puomila2007">{{cite journal  |vauthors=Puomila A, Hämäläinen P, Kivioja S, etal |title=Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland |journal=Eur. J. Hum. Genet. |volume=15 |issue=10 |pages=1079–89 |date=October 2007 |pmid=17406640 |doi=10.1038/sj.ejhg.5201828 |doi-access=free }}</ref> There is a [[prevalence]] of between 1:30,000 to 1:50,000 in Europe.
The LHON ND4 G11778A mutation is 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.<ref name="pmid15954041">{{cite journal  |vauthors=Laberge AM, Jomphe M, Houde L, etal |title=A "Fille du Roy" Introduced the T14484C Leber Hereditary Optic Neuropathy Mutation in French Canadians |journal=Am. J. Hum. Genet. |volume=77 |issue=2 |pages=313–7 |year=2005 |pmid=15954041 |doi=10.1086/432491 |pmc=1224533}}</ref>
More than 50% of males with a mutation and more than 85% of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the 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.{{citation needed|date=September 2021}}
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, though studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,<ref name="Hudson2007a">{{cite journal |vauthors=Hudson G, Carelli V, Horvath R, Zeviani M, Smeets HJ, Chinnery PF |title=X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy |journal=Mol. Vis. |volume=13 |pages=2339–43 |year=2007 |pmid=18199976 |url=http://www.molvis.org/molvis/v13/a265/}}</ref>
<ref name="Hudson2005">{{cite journal  |vauthors=Hudson G, Keers S, Yu Wai Man P, etal |title=Identification of an X-Chromosomal Locus and Haplotype Modulating the Phenotype of a Mitochondrial DNA Disorder |journal=Am. J. Hum. Genet. |volume=77 |issue=6 |pages=1086–91 |date=December 2005 |pmid=16380918 |pmc=1285165 |doi=10.1086/498176 }}</ref> contribute to the development of signs and symptoms. The degree of [[heteroplasmy]], the percentage of mitochondria that have mutant [[alleles]], may play a role.<ref name="Chinnery2001">{{cite journal|vauthors=Chinnery PF, Andrews RM, Turnbull DM, Howell NN |title=Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? |journal=Am. J. Med. Genet. |volume=98 |issue=3 |pages=235–43 |date=January 2001 |pmid=11169561 |doi=10.1002/1096-8628(20010122)98:3<235::AID-AJMG1086>3.0.CO;2-O}}</ref> Patterns of mitochondrial alleles called [[haplogroup]] may also affect expression of mutations.<ref name="Hudson2007b">{{cite journal |vauthors=Hudson G, Carelli V, Spruijt L, etal |title=Clinical Expression of Leber Hereditary Optic Neuropathy Is Affected by the Mitochondrial DNA–Haplogroup Background |journal=Am. J. Hum. Genet. |volume=81 |issue=2 |pages=228–33 |date=August 2007 |pmid=17668373 |pmc=1950812 |doi=10.1086/519394 }}</ref>
==History==
LHON was first described by the German ophthalmologist [[Theodor Leber]] (1840–1917) in 1871.<ref name=Leber1871>Leber T. Ueber hereditaere und congenital angelegte sehnervenleiden (1871) Graefes Arch Clin Exp Ophthalmol. 17:249–291</ref> In a paper, Leber described four families in which a number of young men had 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.<ref name=Erickson1972>{{cite journal | vauthors = Erickson RP | title = Leber's optic atrophy, a possible example of maternal inheritance | journal = American Journal of Human Genetics | volume = 24 | issue = 3 | pages = 348–9 | date = May 1972 | pmid = 5063796 | pmc = 1762279 }}</ref> 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.<ref name=Wallace1988>{{cite journal | vauthors = Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK | title = Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy | journal = Science | volume = 242 | issue = 4884 | pages = 1427–30 | date = December 1988 | pmid = 3201231 | doi = 10.1126/science.3201231| bibcode = 1988Sci...242.1427W }}</ref> This mutation converts a highly conserved [[arginine]] to [[histidine]] at [[codon]] 340 in the [[NADH dehydrogenase]] subunit 4 of [[complex I]] of the [[mitochondria]]l respiratory chain. The other two mutations known to cause this condition were identified in 1991 (G to A point mutation at nucleotide position 3460)<ref name=Huoponen1991>{{cite journal |vauthors=Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML | year = 1991 | title = A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy | journal = Am J Hum Genet | volume = 48 | issue = 6| pages = 1147–1153 | pmid = 1674640 | pmc = 1683111 }}</ref> and 1992 ([[thymidine]] (T) to [[cytosine]] (C) mutation at nucleotide 14484).<ref name=Johns1992>{{cite journal |vauthors=Johns DR, Neufeld MJ, Park RD | year = 1992 | title = An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy | journal = Biochem Biophys Res Commun | volume = 187 | issue = 3| pages = 1551–1557 | doi=10.1016/0006-291x(92)90479-5 | pmid=1417830| doi-access = free }}</ref> 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%.
==Research==
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 [[Allotopic expression|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.<ref>{{Cite journal|first1= J.A.|last1=Sahel|first2=S.|last2=Uretsky|first3=J.P.|last3=Combal|first4=A. |last4=Galy|first5=N.|last5=Thomasson|first6=S.|last6=Fitoussi |first7=M.|last7=Corral-Debrinsky|first8=G.|last8=Honnet|first9= C.|last9=Vignal|date=June 2015|volume=56|issue=7|page=1088|title=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|journal=Invest. Ophthalmol. Vis. Sci.|access-date=March 22, 2016|url=http://iovs.arvojournals.org/article.aspx?articleid=2330770}}</ref>
Stealth BioTherapeutics is investigating the use of elamipretide (MTP-131), a mitochondrial protective agent, as a therapy for LHON. Elamipretide helps stabilize cardiolipin<ref>{{Cite journal|last1=Birk |first1=A.V. |last2=Liu |first2=S. |last3=Soong |first3=Y. |last4=Mills |first4=W. |last5=Singh |first5=P. |last6=Warren |first6=J.D. |last7=Seshan |first7=S.V. |last8=Pardee |first8=J.D. |last9=Szeto |first9=H.H.|date=July 2013|volume=24|issue=8|pages=1250–61|title=The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin|pmid=23813215|journal=J Am Soc Nephrol|doi=10.1681/ASN.2012121216 |pmc=3736700}}</ref><ref>{{Cite journal|first1=D.A. |last1=Thomas |first2=C. |last2=Stauffer |first3=K. |last3=Zhao |first4=H. |last4=Yang |first5=V.K. |last5=Sharma |first6=H.H. |last6=Szeto |first7=M. |last7=Suthanthiran |date=January 2007|volume=18|issue=1|pages=213–222|title=Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function|url=http://jasn.asnjournals.org/content/18/1/213.full|journal=J Am Soc Nephrol|doi=10.1681/asn.2006080825|pmid=17151329|access-date=March 22, 2016|doi-access=free }}</ref>—an important component of mitochondrial inner membranes—and has been shown to reduce damaging reactive oxygen species in animal models.<ref>{{Cite journal|author1=Brown DA |author2=Hale SL |author3=Baines CP |date=January 2014|volume=19|issue=1|pages=121–132|title=Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia|pmid=24288396|journal=J Cardiovasc Pharmacol Ther|doi=10.1177/1074248413508003|display-authors=etal |pmc=4103197}}</ref>
==See also==
* [[Amaurosis]]
* [[Dominant optic atrophy]]
* [[Glaucoma]]
* [[Ischemic optic neuropathy]]
* [[Optic atrophy]]
* [[Toxic and nutritional optic neuropathy]]
==References==
{{Reflist}}
==Further reading==
* {{NLM|leberhereditaryopticneuropathy}}
* {{cite journal |vauthors=Kerrison JB, Newman NJ |title=Clinical spectrum of Leber's hereditary optic neuropathy |journal=Clin. Neurosci. |volume=4 |issue=5 |pages=295–301 |year=1997 |pmid=9292259 |url=http://ifond.org/kerrison.php3 |format=IFOND reprints}}
* {{cite journal |vauthors=Carelli V, Ross-Cisneros FN, Sadun AA |title=Mitochondrial dysfunction as a cause of optic neuropathies |journal=Prog Retin Eye Res |volume=23 |issue=1 |pages=53–89 |date=January 2004 |pmid=14766317 |doi=10.1016/j.preteyeres.2003.10.003 |s2cid=15862778 }}
== External links ==
{{Medical resources
|  DiseasesDB      = 7340
|  ICD10           = {{ICD10|H|47|2|h|46}}
|  ICD9            = {{ICD9|377.16}}
|  ICDO            =
|  OMIM            = 535000
|  MedlinePlus     =
|  eMedicineSubj   =
|  eMedicineTopic  =
|  MeshID          = D029242
}}
* [https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=norrie/ NCBI Genetic Testing Registry]
{{Eye pathology}}
{{Mitochondrial diseases}}
[[Category:Mitochondrial diseases]]
[[Category:Disorders of optic nerve and visual pathways]]
[[Category:Diseases named after discoverers]]