Leber's hereditary optic neuropathy: Difference between revisions

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'''Leber’s hereditary optic neuropathy (LHON)''' or '''Leber optic atrophy''' is a [[Human mitochondrial genetics|mitochondrially inherited]] (mother to all offspring) degeneration of [[retina]]l [[ganglion cell]]s (RGCs) and their [[axon]]s that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted 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]]. 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. Men cannot pass on the disease to their offspring.<ref>Bandelt HJ, Kong QP, Parson W, Salas A.Bandelt HJ, Kong QP, Parson W, Salas A. More evidence for non-maternal inheritance of mitochondrial DNA? J Med Genet. 2005 Dec;42(12):957-60. [http://www.ncbi.nlm.nih.gov/pubmed/15923271 PMID 15923271]</ref>
'''Leber’s hereditary optic neuropathy (LHON)''' or '''Leber optic atrophy''' is a [[Human mitochondrial genetics|mitochondrially inherited]] (mother to all offspring) degeneration of [[retina]]l [[ganglion cell]]s (RGCs) and their [[axon]]s that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted 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]]. 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. Men cannot pass on the disease to their offspring.<ref>{{cite journal |author=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 |year=2005 |month=Dec |pmid=15923271 |doi=10.1136/jmg.2005.033589 |url=}}</ref>


==Signs & symptoms==
==Signs & symptoms==
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===LHON Plus===
===LHON Plus===
"LHON Plus" is a name given to rare strains of the disorder with eye disease together with other conditions. <ref name="Nikoskelainen1995">Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamminen T, Sonninen P, Savontaus ML. Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry. 1995 Aug;59(2):160-4. [http://www.ncbi.nlm.nih.gov/pubmed/7629530 PMID 7629530]</ref> 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 arrythmia]].<ref>(http://heart-disease.health-cares.net/cardiac-arrhythmia.php)</ref> Many cases of LHON plus have been comparable to [[Multiple Sclerosis]] because of the lack of muscular control.<ref>(http://www.mayoclinic.com/health/multiple-sclerosis/DS00188)</ref>
"LHON Plus" is a name given to rare strains of the disorder with eye disease together with other conditions. <ref name="Nikoskelainen1995">{{cite journal |author=Nikoskelainen EK, Marttila RJ, Huoponen K, ''et al'' |title=Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy |journal=J. Neurol. Neurosurg. Psychiatr. |volume=59 |issue=2 |pages=160–4 |year=1995 |month=Aug |pmid=7629530 |pmc=485991 |doi= |url=}}</ref> 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 arrythmia]].<ref>[http://heart-disease.health-cares.net/cardiac-arrhythmia.php cardiac arrythmia]</ref> Many cases of LHON plus have been comparable to [[Multiple Sclerosis]] because of the lack of muscular control.<ref>[http://www.mayoclinic.com/health/multiple-sclerosis/DS00188 Mayo Clinic: Multiple Sclerosis]</ref>


==Genetics==
==Genetics==
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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.
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 {{Gene|MT-ND1}}, {{Gene|MT-ND4}}, {{Gene|MT-ND4L}}, and {{Gene|MT-ND6}} genes cause Leber hereditary optic neuropathy.<ref name="titleOMIM - LEBER OPTIC ATROPHY">{{cite web |url=http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=535000 |title=OMIM - LEBER OPTIC ATROPHY |accessdate=2007-11-23 |format= |work=}}</ref> These genes code for the [[NADH dehydrogenase]] protein involved in the normal mitochondrial function of [[oxidative phosphorylation]]. Oxidative phosphorylation uses a large multienzyme complex 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.
Mutations in the {{Gene|MT-ND1}}, {{Gene|MT-ND4}}, {{Gene|MT-ND4L}}, and {{Gene|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 large multienzyme complex 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.




==Epidemiology==
==Epidemiology==
In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.<ref>{{cite journal
In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.<ref>Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet. 2003 Feb;72(2):333-9. PMID 12518276</ref><ref name="Puomila2007">Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, Nikoskelainen E. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet. 2007 Oct;15(10):1079-89. PMID 17406640</ref> There is a [[prevalence]] of between 1:30,000 to 1:50,000 in Europe.
|author=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 |year=2003 |month=Feb |pmid=12518276 |pmc=379226 |doi=10.1086/346066 |url=}}</ref>
<ref name="Puomila2007">{{cite journal |author=Puomila A, Hämäläinen P, Kivioja S, ''et al'' |title=Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland |journal=Eur. J. Hum. Genet. |volume=15 |issue=10 |pages=1079–89 |year=2007 |month=Oct |pmid=17406640 |doi=10.1038/sj.ejhg.5201828 |url=}}</ref> There is a [[prevalence]] of between 1:30,000 to 1:50,000 in Europe.


The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world
The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world
with 70% of European cases and 90% of Asian cases. Due to a [[Founder effect|founder effect]], the LHON ND6 T14484C mutation accounts for 86% of LHON cases in [[Quebec]], [[Canada]].<ref name="pmid15954041">{{cite journal |author=Laberge AM, Jomphe M, Houde L, ''et al'' |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}}</ref>
with 70% of European cases and 90% of Asian cases. Due to a [[Founder effect|founder effect]], the LHON ND6 T14484C mutation accounts for 86% of LHON cases in [[Quebec]], [[Canada]].<ref name="pmid15954041">{{cite journal |author=Laberge AM, Jomphe M, Houde L, ''et al'' |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}}</ref>


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. 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,<ref name="Hudson2007a">Gavin Hudson, Valerio Carelli, Rita Horvath, Massimo Zeviani, Hubert J. Smeets, Patrick F. Chinnery. X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy. [http://www.molvis.org/molvis/v13/a265/ Mol Vis. 2007 Dec 21;13:2339-43] [http://www.ncbi.nlm.nih.gov/pubmed/18199976 PMID 18199976]</ref><ref name="Hudson2005">Hudson G, Keers S, Yu Wai Man P, Griffiths P, Huoponen K, Savontaus ML, Nikoskelainen E, Zeviani M, Carrara F, Horvath R, Karcagi V, Spruijt L, de Coo IF, Smeets HJ, Chinnery PF. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16380918 Am J Hum Genet. 2005 Dec;77(6):1086-91. Epub 2005 Oct 11.] [http://www.ncbi.nlm.nih.gov/pubmed/16380918 PMID 16380918]</ref> contribute to the development of signs and symptoms. The degree of [[heteroplasmy]], the percentage of mitochondria which have mutant [[alleles]], may play a role. <ref name="Chinnery2001">Chinnery PF, Andrews RM, Turnbull DM, Howell NN. Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet. 2001 Jan 22;98(3):235-43. [http://www.ncbi.nlm.nih.gov/pubmed/11169561 PMID 11169561]</ref> Patterns of mitochondrial alleles called [[haplogroup]] may also affect expression of mutations. <ref name="Hudson2007b">Hudson G, Carelli V, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. 2007 Aug;81(2):228-33.[http://www.ncbi.nlm.nih.gov/pubmed/17668373 PMID 17668373]</ref>
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. 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,<ref name="Hudson2007a">{{cite journal |author=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 |issue= |pages=2339–43 |year=2007 |pmid=18199976 |doi= |url=http://www.molvis.org/molvis/v13/a265/}}</ref>
<ref name="Hudson2005">{{cite journal |author=Hudson G, Keers S, Yu Wai Man P, ''et al'' |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 |year=2005 |month=Dec |pmid=16380918 |pmc=1285165 |doi=10.1086/498176 |url=}}</ref> contribute to the development of signs and symptoms. The degree of [[heteroplasmy]], the percentage of mitochondria which have mutant [[alleles]], may play a role. <ref name="Chinnery2001">{{cite journal
|author=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 |year=2001 |month=Jan |pmid=11169561 |doi= |url=http://dx.doi.org/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
|author=Hudson G, Carelli V, Spruijt L, ''et al'' |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 |year=2007 |month=Aug |pmid=17668373 |pmc=1950812 |doi=10.1086/519394 |url=}}</ref>


== Pathophysiology ==
== 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 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]] [[free radical|radical]] than other normal central nervous system neurons. <ref>Hoegger MJ, Lieven CJ, Levin LA. Differential production of superoxide by neuronal mitochondria. BMC Neurosci. 2008 Jan 8;9:4. PMID 18182110</ref> Viral vector experiments which augment [[superoxide dismutase]] 2 in LHON [[cytoplasmic hybrid|cybrids]] <ref name="Qi">Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J. Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation. Arch Ophthalmol. 2007 Feb;125(2):268-72. PMID 17296905</ref> or LHON animal models or use of exogenous [[glutathione]] in LHON cybrids<ref name="Ghelli2008">Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M. Protection against oxidant-induced apoptosis by exogenous [[glutathione]] in Leber hereditary optic neuropathy cybrids. Invest Ophthalmol Vis Sci. 2008 Feb;49(2):671-6. PMID 18235013</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 which also carry LHON affected mitochondria.
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 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]] [[free radical|radical]] than other normal central nervous system neurons. <ref>{{cite journal
|author=Hoegger MJ, Lieven CJ, Levin LA |title=Differential production of superoxide by neuronal mitochondria |journal=BMC Neurosci |volume=9 |issue= |pages=4 |year=2008 |pmid=18182110 |pmc=2266764 |doi=10.1186/1471-2202-9-4 |url=}}</ref> Viral vector experiments which augment [[superoxide dismutase]] 2 in LHON [[cytoplasmic hybrid|cybrids]] <ref name="Qi">{{cite journal
|author=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 |year=2007 |month=Feb |pmid=17296905 |doi=10.1001/archopht.125.2.268 |url=}}</ref> or LHON animal models or use of exogenous [[glutathione]] in LHON cybrids<ref name="Ghelli2008">{{cite journal
|author=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 |year=2008 |month=Feb |pmid=18235013 |doi=10.1167/iovs.07-0880 |url=}}</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 which also carry LHON affected mitochondria.


== Diagnosis & management ==
== Diagnosis & management ==
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Without a known family history of LHON the diagnosis is difficult and usually requires a [[Neuro-ophthalmologist|neuro-ophthalmological]] evaluation and/or blood testing for DNA assessment that is available only in a few laboratories<ref>[http://www.genetests.org/servlet/access?prg=j&db=genetests&site=gt&id=8888890&fcn=c&qry=2450&res=nous&res=nointl&key=8BaWvqtcN8XtG&show_flag=c GeneTests LHON search]</ref>. Hence the incidence is probably greater than appreciated. The prognosis for those affected is almost always that of continued very severe visual loss. Regular corrected [[visual acuity]] and [[perimetry]] checks are advised for follow up of affected individuals. There is no accepted treatment for this disease. [[Genetic counselling]] should be offered.
Without a known family history of LHON the diagnosis is difficult and usually requires a [[Neuro-ophthalmologist|neuro-ophthalmological]] evaluation and/or blood testing for DNA assessment that is available only in a few laboratories<ref>[http://www.genetests.org/servlet/access?prg=j&db=genetests&site=gt&id=8888890&fcn=c&qry=2450&res=nous&res=nointl&key=8BaWvqtcN8XtG&show_flag=c GeneTests LHON search]</ref>. Hence the incidence is probably greater than appreciated. The prognosis for those affected is almost always that of continued very severe visual loss. Regular corrected [[visual acuity]] and [[perimetry]] checks are advised for follow up of affected individuals. There is no accepted treatment for this disease. [[Genetic counselling]] should be offered.


For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress.<ref name="Sadun2006">Sadun AA, Salomao SR, Berezovsky A, Sadun F, Denegri AM, Quiros PA, Chicani F, Ventura D, Barboni P, Sherman J, Sutter E, Belfort R Jr, Carelli V. Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc. 2006;104:51-61. PMID 17471325</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.
For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress.<ref name="Sadun2006">{{cite journal
|author=Sadun AA, Salomao SR, Berezovsky A, ''et al'' |title=Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study |journal=Trans Am Ophthalmol Soc |volume=104 |issue= |pages=51–61 |year=2006 |pmid=17471325 |pmc=1809912 |doi= |url=}}</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.
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. 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">Carelli V, Ross-Cisneros F, Sadun A: "Mitochondrial dysfunction as a cause of optic neuropathies." ''Prog Retinal & Eye Research''. 23:53-89, 2004. [http://www.ncbi.nlm.nih.gov/pubmed/14766317 PMID 14766317]</ref> Of note, when a patient carrying or suffering from LHON or [[Toxic and Nutritional Optic Neuropathy|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 [[Ischemic optic neuropathy|optic nerve ischemia]] in response to this [[anti-hypertensive]] in particular. <ref name="Parkland">{{cite book|last = Katz | first = Jason| authorlink = | coauthors = Patel, Chetan| title = Parkland Manual of Inpatient Medicine| publisher = FA Davis| date = 2006| location = Dallas, TX| pages = 903|}}</ref>
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. 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
|author=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 |year=2004 |month=Jan |pmid=14766317 |doi=10.1016/j.preteyeres.2003.10.003 |url=}}</ref> Of note, when a patient carrying or suffering from LHON or [[Toxic and Nutritional Optic Neuropathy|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 [[Ischemic optic neuropathy|optic nerve ischemia]] in response to this [[anti-hypertensive]] in particular. <ref name="Parkland">{{cite book|last = Katz | first = Jason| authorlink = | coauthors = Patel, Chetan| title = Parkland Manual of Inpatient Medicine| publisher = FA Davis| date = 2006| location = Dallas, TX| pages = 903|}}</ref>


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:
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]]; <ref name="Newman2005">{{cite journal
[[Brimonidine]]; <ref name="Newman2005">Newman NJ, Biousse V, David R, Bhatti MT, Hamilton SR, Farris BK, Lesser RL, Newman SA, Turbin RE, Chen K, Keaney RP. Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol. 2005 Sep;140(3):407-15.[http://www.ncbi.nlm.nih.gov/pubmed/16083844 PMID 16083844]</ref> [[Minocycline]]; <ref name="pmid17822909">{{cite journal |author=Haroon MF, Fatima A, Schöler S, ''et al'' |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= |pages= 237|year=2007 |pmid=17822909 |doi=10.1016/j.nbd.2007.07.021}}</ref> [[Idebenone]]; <ref name="NewcastleTrial">Clinical Idebenone trial recruiting at Newcastle University UK [http://lhon.ncl.ac.uk/ http://lhon.ncl.ac.uk]</ref> <ref>Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000 Sep;20(3):166-70. [http://www.ncbi.nlm.nih.gov/pubmed/11001192 PMID 11001192]</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]</ref>
|author=Newman NJ, Biousse V, David R, ''et al'' |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 |year=2005 |month=Sep |pmid=16083844 |doi=10.1016/j.ajo.2005.03.058 |url=}}</ref> [[Minocycline]]; <ref name="pmid17822909">{{cite journal |author=Haroon MF, Fatima A, Schöler S, ''et al'' |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= |pages= 237|year=2007 |pmid=17822909 |doi=10.1016/j.nbd.2007.07.021}}</ref> [[Idebenone]]; <ref name="NewcastleTrial">Clinical Idebenone trial recruiting at Newcastle University UK [http://lhon.ncl.ac.uk/ http://lhon.ncl.ac.uk]</ref> <ref>{{cite journal |author=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 |year=2000 |month=Sep |pmid=11001192 |doi= |url=}}</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]</ref>
[[glutathione]]<ref name="Ghelli2008"> </ref>; [[Infrared#Photobiomodulation|Near infrared]] [[Light therapy|light treatment]]; <ref name=WisconsinTrial">[http://www.mcw.edu/neurology/research/LHON.htm Wisconsin near infrared trial]</ref> and [[Viral_vector|Viral vector]] techniques. <ref name="Qi">Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J. Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation. Arch Ophthalmol. 2007 Feb;125(2):268-72. [http://www.ncbi.nlm.nih.gov/pubmed/17296905 PMID 17296905]</ref>
[[glutathione]]<ref name="Ghelli2008"> </ref>; [[Infrared#Photobiomodulation|Near infrared]] [[Light therapy|light treatment]]; <ref name=WisconsinTrial">[http://www.mcw.edu/neurology/research/LHON.htm Wisconsin near infrared trial]</ref> and [[Viral_vector|Viral vector]] techniques. <ref name="Qi">{{cite journal |author=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 |year=2007 |month=Feb |pmid=17296905 |doi=10.1001/archopht.125.2.268 |url=}}</ref>


==Eponym==
==Eponym==
Leber’s hereditary optic neuropathy is sometimes confused with [[Leber's congenital amaurosis]], which is a different disease also first described by [[Theodore Leber]] in the 19th century.<ref>{{WhoNamedIt|doctor|1158}}</ref><ref name="Leber1869">T. Leber. Über Retinitis pigmentosa und angeborene Amaurose. Albrecht von Graefes. Archiv für Ophthalmologie, Berlin, 1869, 15, 3: 1-25.</ref>
Leber’s hereditary optic neuropathy is sometimes confused with [[Leber's congenital amaurosis]], which is a different disease also first described by [[Theodore Leber]] in the 19th century.<ref>{{WhoNamedIt|doctor|1158}}</ref><ref name="Leber1869">{{cite journal |author=Leber T |title=Über Retinitis pigmentosa und angeborene Amaurose Albrecht von Graefes |journal=Archiv für Ophthalmologie |volume=15 |issue=3 |pages=1–25 |year=1869}}</ref>




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* {{NLM|leberhereditaryopticneuropathy}}
* {{NLM|leberhereditaryopticneuropathy}}
* Yu-Wai-Man P, Chinnery P (2008) Leber Hereditary Optic Neuropathy. [http://www.genetests.org/query?dz=lhon GeneReviews]
* Yu-Wai-Man P, Chinnery P (2008) Leber Hereditary Optic Neuropathy. [http://www.genetests.org/query?dz=lhon GeneReviews]
* John B. Kerrison and Nancy J. Newman (1997) Clinical Spectrum of Leber's Optic Neuropathy. Clinical Neuroscience. Volume 4, Number 5, pages 295-301. [http://ifond.org/kerrison.php3 IFOND reprints]
*{{cite journal |author=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 |doi= |url=http://ifond.org/kerrison.php3 |format=IFOND reprints}}
* Carelli V, Ross-Cisneros F, Sadun A: "Mitochondrial dysfunction as a cause of optic neuropathies." ''Prog Retinal & Eye Research''. 23:53-89, 2004. PMID 14766317
*{{cite journal |author=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 |year=2004 |month=Jan |pmid=14766317 |doi=10.1016/j.preteyeres.2003.10.003 |url=}}


{{Eye pathology}}
{{Eye pathology}}

Revision as of 08:39, 30 August 2008

Leber's hereditary optic neuropathy
SpecialtyOphthalmology Edit this on Wikidata

Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (mother to all 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. However, 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.[1]

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 8-60 is reported. This typically evolves to very severe optic atrophy and permanent decrease of visual acuity. 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). These main features are seen on fundus examination, just before or subsequent to the onset of visual loss. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination.

LHON Plus

"LHON Plus" is a name given to rare strains of the disorder with eye disease together with other conditions. [2] 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 arrythmia.[3] Many cases of LHON plus have been comparable to Multiple Sclerosis because of the lack of muscular control.[4]

Genetics

Leber’s hereditary optic neuropathy has a mitochondrial inheritance pattern.

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.[5] These genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. Oxidative phosphorylation uses a large multienzyme complex 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.


Epidemiology

In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.[6] [7] There is a prevalence of between 1:30,000 to 1:50,000 in Europe.

The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world with 70% of 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.[8]

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. 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,[9] [10] contribute to the development of signs and symptoms. The degree of heteroplasmy, the percentage of mitochondria which have mutant alleles, may play a role. [11] Patterns of mitochondrial alleles called haplogroup may also affect expression of mutations. [12]

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 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. [13] Viral vector experiments which augment superoxide dismutase 2 in LHON cybrids [14] or LHON animal models or use of exogenous glutathione in LHON cybrids[15] 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 & management

Without a known family history of LHON the diagnosis is difficult and usually requires a neuro-ophthalmological evaluation and/or blood testing for DNA assessment that is available only in a few laboratories[16]. Hence the incidence is probably greater than appreciated. The prognosis for those affected is almost always that of continued very severe visual loss. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is no accepted treatment for this disease. Genetic counselling should be offered.

For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress.[17] 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.

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. In fact, toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management. [18] 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. [19]

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; [20] Minocycline; [21] Idebenone; [22] [23]; Curcumin;[24] glutathione[15]; Near infrared light treatment; [25] and Viral vector techniques. [14]

Eponym

Leber’s hereditary optic neuropathy is sometimes confused with Leber's congenital amaurosis, which is a different disease also first described by Theodore Leber in the 19th century.[26][27]



See also

References

  1. ^ Bandelt HJ, Kong QP, Parson W, Salas A (2005). "More evidence for non-maternal inheritance of mitochondrial DNA?". J. Med. Genet. 42 (12): 957–60. doi:10.1136/jmg.2005.033589. PMID 15923271. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Nikoskelainen EK, Marttila RJ, Huoponen K; et al. (1995). "Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy". J. Neurol. Neurosurg. Psychiatr. 59 (2): 160–4. PMC 485991. PMID 7629530. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ cardiac arrythmia
  4. ^ Mayo Clinic: Multiple Sclerosis
  5. ^ Online Mendelian Inheritance in Man (OMIM): LEBER OPTIC ATROPHY - 535000
  6. ^ Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Puomila A, Hämäläinen P, Kivioja S; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ 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. PMID 15954041. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Hudson G, Keers S, Yu Wai Man P; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Chinnery PF, Andrews RM, Turnbull DM, Howell NN (2001). <235::AID-AJMG1086>3.0.CO;2-O "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. PMID 11169561. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Hudson G, Carelli V, Spruijt L; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  14. ^ a b Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "Qi" was defined multiple times with different content (see the help page).
  15. ^ a b Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ GeneTests LHON search
  17. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  18. ^ Carelli V, Ross-Cisneros FN, Sadun AA (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Katz, Jason (2006). Parkland Manual of Inpatient Medicine. Dallas, TX: FA Davis. p. 903. {{cite book}}: Cite has empty unknown parameter: |1= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Newman NJ, Biousse V, David R; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ 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: 237. doi:10.1016/j.nbd.2007.07.021. PMID 17822909. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  22. ^ Clinical Idebenone trial recruiting at Newcastle University UK http://lhon.ncl.ac.uk
  23. ^ Mashima Y, Kigasawa K, Wakakura M, Oguchi Y (2000). "Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?". J Neuroophthalmol. 20 (3): 166–70. PMID 11001192. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Clinical Curcurmin trial recruiting at ClinicalTrials.nlm.nih.gov
  25. ^ Wisconsin near infrared trial
  26. ^ doctor/1158 at Who Named It?
  27. ^ Leber T (1869). "Über Retinitis pigmentosa und angeborene Amaurose Albrecht von Graefes". Archiv für Ophthalmologie. 15 (3): 1–25.


External links

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