|Year : 2017 | Volume
| Issue : 11 | Page : 1087-1092
Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy
Agaath Hedina Manickam1, Minu Jenifer Michael1, Sivasamy Ramasamy2
1 Molecular Genetics and Cancer Biology Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tami Nadu, India
2 Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tami Nadu, India
|Date of Submission||19-May-2017|
|Date of Acceptance||09-Sep-2017|
|Date of Web Publication||13-Nov-2017|
Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore - 641 046, Tami Nadu
Source of Support: None, Conflict of Interest: None
Leber's hereditary optic neuropathy (LHON) is a common inherited mitochondrial disorder that is characterized by the degeneration of the optic nerves, leading to vision loss. The major mutations in the mitochondrial genes ND1, ND4, and ND6 of LHON subjects are found to increase the oxidative stress experienced by the optic nerve cell, thereby leading to nerve cell damage. Accurate treatments are not available and drugs that are commercially available like Idebenone, EPI-743, and Bendavia with their antioxidant role help in reducing the oxidative stress experienced by the cell thereby preventing the progression of the disease. Genetic counseling plays an effective role in making the family members aware of the inheritance pattern of the disease. Gene therapy is an alternative for curing the disease but is still under study. This review focuses on the role of mitochondrial genes in causing LHON and therapeutics available for treating the disease. A systematic search has been adopted in various databases using the keywords “LHON,” “mitochondria,” “ND1,” “ND4,” “ND6,” and “therapy” and the following review on mitochondrial genetics and therapeutics of LHON has been developed with obtained articles from 1988 to 2017.
Keywords: Leber's hereditary optic neuropathy, mitochondria, ND1, ND4, ND6
|How to cite this article:|
Manickam AH, Michael MJ, Ramasamy S. Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy. Indian J Ophthalmol 2017;65:1087-92
|How to cite this URL:|
Manickam AH, Michael MJ, Ramasamy S. Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy. Indian J Ophthalmol [serial online] 2017 [cited 2019 Jul 23];65:1087-92. Available from: http://www.ijo.in/text.asp?2017/65/11/1087/218044
The blinding disease with maternal mode of inheritance is Leber's hereditary optic neuropathy (LHON). This condition was first reported in 1871 by Theodore Leber, an ophthalmologist from Germany, who described this as a distinctive clinical unit. Mutations in the genes of mitochondria induce apoptosis of retinal ganglion cells (RGCs) by decreasing the production of adenosine triphosphates (ATPs) and elevating oxidative stress. The dead RGCs are then unable to send vision signals to the brain thereby the output is improperly processed causing blindness and extreme visual damage. Usually, this vision loss progresses from a few days to weeks and is painless, but in rare cases cause discomfort due to inflammation of the optic nerves. Loss of RGC happens in around 50% male and about 10%–15% female patients. Recovering the lost vision is possible depending on the mutation present. LHON is not age dependent as it affects people in all age groups, but men around the age of 20 and 30 are reported to be the most affected. At first, one eye is found to be affected but after a gap of a few months to years, the second eye also develops the symptom.
The mutation in the mitochondrial genome (mtDNA) takes place in the subunit which encodes for the complex-I (CI) of the electron transport chain which is NADH:ubiquinone oxidoreductase and the mutation usually involve a single amino acid exchange. This in turn leads to depletion of energy in the neuron cells that cause death of the neurons. Apart from the CI dysfunction, the impairment of glutamate transport system and increased levels of oxidative stress also lead to dysfunction and death of RGC. Although mtDNA mutation is the major cause of LHON, the environmental factors tend to worsen the symptoms.
There is no proper treatment to completely eradicate LHON, but medicines are available to promote ATP synthesis and to decrease oxidative stress. A permanent cure must be found to protect the mutations happening in the mtDNA which is tough as we are not sure about the mutagens that cause these mutations. Various studies are now under process for validating the use of gene therapy for treating LHON. Till date, promising results are obtained which showed improvement in vision of patients suffering from LHON. In this review, the mitochondrial genetics of LHON and treatments available are discussed.
| Methods|| |
Articles for writing this review were collected using various search engines such as PubMed, Google Scholar, Science Direct, and Elsevier, Boolean search strategy has been followed using the keywords such as “LHON,” “mitochondria,” “ND1,” “ND4,” “ND6,” and “therapy.” Out of all the articles obtained, 62 articles from 1988 to 2017, that exactly match this study, have been chosen and the references mentioned were cross-checked for perfection.
| Mitochondrial Genetics of Leber's Hereditary Optic Neuropathy|| |
Present almost in all eukaryotic cells that aid in cellular respiration by a process called oxidative phosphorylation (OXPHOS) is the mitochondria. Being a specialized organelle, the mitochondrion is involved in the regulation of cellular metabolism, synthesis of steroids, and haem, signaling of calcium and apoptosis. Usually, the term “gene” reminds us of nuclear DNA. However, recent research is mainly focused on the genes present in the mitochondria because many hereditary diseases are found to have mutation in the mtDNA which are passed down through maternal inheritance. Mutations in the mitochondria can cause two types of reaction; it can either alter the biosynthesis of mitochondrial proteins, or it can disrupt the OXPHOS by amino acid substitutions.
mtDNA of humans has a special property of replicating ceaselessly in cells without undergoing cell cycle resulting in thousands of identical mtDNA copies, thereby indicating the homoplasmic condition of the cell and heteroplasmic condition results due to mutation in any of the existing mtDNA, resulting in the presence of both mutated and normal mtDNA in a cell. The proportion of normal and mutant mtDNA in the daughter cell varies depending on the process of replicative segregation and in cells, only a definite amount of normal mtDNA can neutralize the effect of mutant mtDNA. When the amount of mutant mtDNA exceeds the normal mtDNA diseases associated with the type of mutation involved prevails in the subject. This property of homoplasmy and heteroplasmy plays a major role in the severity of LHON. The discussed genes have both homoplasmic and heteroplasmic factors that determine the penetrance of the disease that is discussed in the corresponding gene section.
LHON is one of the diseases that have a maternal mode of inheritance. Douglas C. Wallace and colleagues were the first to discover the mtDNA mutations in LHON, which was in the ND4 gene. Three major genes in mitochondria when mutated and found to cause 90%–95% cases of LHON are MT-ND1, MT-ND4, and MT-ND6.,, Mutations such as 3460A, 11778A and 14484C of ND1, ND4, and ND6, respectively, are most common among the LHON subjects, as it is found in 90% of cases.,, Apart from these genes, various others are also involved but these three have the major prevalence, and the mutation usually involves the exchange of a single amino acid in the CI of mitochondria which is NADH: ubiquinone oxidoreductase.
MT-ND1, also known as mitochondrial encoded NADH ubiquinone oxidoreductase core subunit 1 plays a major role in creating NADH dehydrogenase 1, a protein of CI. This gene has 956 bases and the location of the gene starts from 3307 bp from pter and ends at 4262 bp from pter in the mitochondrial genome. Its protein product has 318 amino acids with molecular weight of 35661 Da. Mutation in this gene causes dysfunction of CI, thereby causing LHON.
About 60%–80% of CI activity is reduced due to mutations in 3460 position of ND1 gene which without affecting the activity of proximal NADH dehydrogenase of CI, reduces the sensitivity of rotenone and ubiquinone dependent electron transfer activity., Thus, there is an abundant amount of roteonone which in turn affects the CI activity since rotenone is a potent inhibitor of the CI of mitochondria. Because of this property, rotenone has been used in model studies involving rats to stimulate LHON symptoms by injecting rotenone which causes ganglion cell layers and nerve fiber thinning, loss of RGCs, and thinning of inner plexiform layer, thereby mimicking the human LHON condition. Mutation in the G3640A leads to substitution of the alanine amino acid by threonine in ND1 gene. and LHON due to this mutation shows gradual visual improvement. However, the homoplasmic 3640 mutation of the ND1 in LHON subjects is shown to have resistance to rotenone, resulting in the decreased activity of CI. Another study on the M9a mitochondrial haplogroup shows that the penetrance of LHON is more in Chinese families with ND1 T3394C mutation when present along with G11778A of ND4.
Studies involving the genetic analysis of LHON revealed many point mutations in the ND1 gene which are m. 4171C>A/p.L289M, m.3700G>A/p. A132T, and m.3733G>A-C/p. E143K-Q. Other than causing LHON, a mutation of 3697G>A in the ND1 gene is reported in patient having spastic dystonia along with LHON, and this mutation is also responsible for causing mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). A novel mutation in the ND1 gene of homoplasmic cell is reported as m.3635G>A, p. Ser110Asn which is also associated with LHON by impairing the OXPHOS system. Another mutation in the ND1 gene m.3472T>C was observed in LHON affected patient which changes the amino acid is the position 56, which is phenylalanine to leucine and efforts are taken to determine its role in causing mitochondrial complex dysfunction., m. 4171C>A/p.L289M mutation in ND1 is also found to be associated with MELAS and Leigh syndrome in addition to LHON. Alzheimer's disease and Parkinson disease are due mitochondrial dysfunction associated with NADH dehydrogenase subunits 1, 2, 3, 4, 4L, 5, and 6 as a result of MT-ND1 gene defect. Among all the mutations mentioned for the ND1 gene, most of them play a direct role in impairing the CI function thereby causing LHON.
Apart from the MT-ND1 gene mutations, another most common gene in which most mutations happen that leads to LHON is the mutation in the MT-ND4 gene. This ND4 is known as mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4. This gene produces protein called NADH dehydrogenase 4 which also constitutes the CI of mitochondria. The gene is formed with 1378 bases with its genomic location starting from 10,760 bp from pter and ends at 12,137 bp from pter. The protein product of this gene has molecular weight of 51,581 Da with 459 amino acids. About 70% of LHON patients suffer due to mutation in this gene which impairs the CI of the mitochondria.
About 90% of people affected by LHON in Asian countries like China, Thailand, and Japan have point mutation G11778A in MT-ND4 gene,,, which results in the substitution of arginine by histidine at the 340th position of the amino acid of ND4. In a study conducted among the Chinese cohorts, many other mutations in the ND4 gene like m.11204T>C, m.11430C>G, m.11213T>G, m.11447G>A, and m.10934G>A with the incidence of 0,312%, 0.078%, 0.078%, 0.078%, and 0.078%, respectively, were reported., The 11447G>A mutation is limited to the transmembrane domain whereas 11204T>C, 11430C>G, 11213T>G, and 10934G>A mutations are limited to the intermembrane domain, and all mutations in the ND4 gene is reported to alter the structure of the polypeptide of that gene and thereby altering its function., The penetrance of the LHON is found to be more in case of homoplasmic A4435G mutation in tRNAMet of LHON subjects having homoplasmic ND4 G11778A mutation reported in the D5 Asian haplogroup. However, the presence of homoplasmic G11778A alone in the LHON subjects has least penetrance level in causing vision loss. Another study reported the presence of mutation A15951G in the tRNAThr region has a major role to play in the expressivity and penetrance of LHON when present along with the G11778A mutation.
Other diseases associated with mutation in the ND4 gene are Leigh syndrome, by affecting the CI activity; cardiomyopathy, and MELAS due to mitochondrial dysfunction; sporadic myopathy; Parkinson's disease, has more mutation in the ND4 gene; gastric cancer, has elevated expression of ND4; oral cancer, due to mitochondrial dysfunction by mutation in ND4; in acute myeloid leukemia, where the subjects had either germline or somatic ND4 mutations; in blood and breast cancer, mutation in the protein coding regions of ND4 and other genes have been identified; studies show that women with the G11778A mutation develop symptoms similar to multiple sclerosis which makes us to differentiate the disease that the patient actually has.
MT-ND6, mitochondrial-encoded NADH:ubiquinone oxidoreductase core subunit 6 that codes for protein called NADH dehydrogenase 6 plays a major role in the CI of the mitochondria. The gene has a size of about 525 bases, and its location starts from 14,149 bp from pter and ends at 14,673 bp from pter. Many point mutations in the ND6 gene have been reported and out of those T14484C mutation is found frequently in most LHON patients which results in amino acid substitution from methionine to valine. The 14484 mutation is homoplasmic in most LHON cases and found to have low penetrance level. The 14484T>C mutation is found to be homoplasmic in most cases and is found to have an average LHON penetrance rate of 23.8% in Chinese family, and few other secondary mutations reported in the ND6 are m.3497C>T and m.14502T>C. A study on LHON showed complete penetrance in subjects harboring m.14841A>G of ND6 in association with m.4171C>A of ND1.
Out of the previously discussed mutations of T14484C, G3460A, and G11778A, the T14484C mutation show high-visual recovery and also have numerous epigenetic elements other than the genetic one in causing LHON. Another mutation at the nucleotide pair 14459 in the ND6 gene leads to the transition of base G to A, thereby replacing alanine by valine at the 72nd residue of the ND6 which is proved to be the reason behind LHON. This mutation in the ND6 makes the CI more sensitive to ubiquinone and gets inhibited by it, and its analogs and thereby the neuronal activity gets hindered and cause LHON. Other point mutations in the ND6 that cause LHON are m.14495A>G, m.14568C>T, m.14482C>G/A.
Mutation in the ND6 not only causes LHON but other diseases also. Mutation G14569A in ND6 is found to be the cause for autism subjects. T14487C mutation in the ND6 gene has been discovered in patient with Leigh syndrome that affects the stability and assembly of CI. 13885insC and G13997A are two mutations in the ND6 gene which results in high metastasis behavior of the cells resulting in tumor growth by overproduction of reactive oxygen species (ROS) leading to cancer. In colorectal adenocarcinoma and in villous adenomas, the levels of expression of the ND6 is much higher proving its relatedness with cancer.
| Therapeutics of Leber's Hereditary Optic Neuropathy|| |
Therapeutics for any diseases usually involves the use of drugs to reduce the symptoms experienced by the patient. Although LHON is proved to be an untreatable disease with limited rate of success, the drugs that are used for clinical trials which show a potent recovery in patients with LHON, they are now researched further to determine their role in curing the disease. Being an inherited disease, LHON can be prevented from being inherited through genetic counseling to the couples who have a family history of LHON. Gene therapy is also another approach which helps in eliminating the disease-causing gene and replacing with the normal gene thereby preventing the disease.
Drugs for treating Leber's hereditary optic neuropathy
With the trade name Raxone®, Idebenone is a short-chain benzoquinone, which is used to treat visual impairment associated with LHON with its antioxidant nature and ability to carry the mitochondrial electrons to complex III of mitochondria directly thereby promoting the ATP production which in turn activates the ganglion cells of retina leading to vision recovery. Visual recovery was reported in patients in a study with early and prolonged treatment of Idebenone in patients with acute LHON and it was best suggested that treatment with Idebenone should commence in early stages of LHON when there is still some RGC are active to get best vision recovery.,,
EPI-743 is a drug designed to treat mitochondrial diseases that are caused due to defects in respiratory chain by targeting the minimum production of glutathione. In LHON, EPI-743 is used to treat vision loss due to oxidative stress. Use of the EPI-743 drug has proved to improve the vision in 70% patients with LHON without developing any adverse effects on the patients, proving its safe nature. When compared with idebenone, thein vitro activity of EPI-743 has proved to be 1000 times more which makes the irreversible vision loss a reversible one.
The ROS created by the altered proteins in LHON patient damages the mitochondria which are blocked by a drug called Bendavia also known as MTP-131. Being a tetrapeptide, this Bendavia is found to restrict the generation of ROS, ATP synthesis, and also prevents the mitochondrial chain from uncoupling which in a study has been reported that the injury due to oxygen-glucose deprivation can be treated by using Bendavia.
Genetic counseling for preventing Leber's hereditary optic neuropathy
After determining the exact mutation responsible for the LHON in affected subjects, the other members in the family can be checked for the presence of mutation. Since the mutation responsible for LHON resides in the mitochondrial genome, the maternal inheritance pattern can be traced among the affected family members. They are given counseling regarding the inheritance of the mutated gene and are made aware about the problems that their future generation might face when they do not avoid the inheritance of the mutated gene.
Although genetic counseling helps in avoiding the inheritance of the mutated gene, there are two major limitations that are to be overcome to make this genetic counseling a successful one. The primary task is that it is not an easy job to determine a person having the mutated gene to develop the risk of optic atropy, and in secondary, not all the mutated genes in a heteroplasmic female is transferred to the next generation. Also verifying the location of the mutation like homoplasmic or heteroplasmic is important in case of genetic counseling.
Gene therapy for treating Leber's hereditary optic neuropathy
Other than the use of drugs to suppress the progression of the LHON in the affected subjects, an alternative way of treating the disease has been used, which is gene therapy, where the defective gene is replaced with the normal wildtype gene so that the normal gene product is expressed. The limitations of this technique lie in the fact that the introduced normal gene must be successfully integrated into the mitochondrial genome of the affected subject, and no technique is available presently to successfully integrate the normal gene into the mitochondrial genome.
Gene therapy for LHON is still under clinical trials and one such trial (Phase I) involving adeno-associated virus as a vector of different doses showed slight improvement in the visual loss of LHON subjects with G11778A mutation of ND4, where no other major adverse events were observed but minor discomforts such as a sore throat, subconjunctival hemorrhage, keratitis due to exposure, and intraocular pressure were observed along with the presence of developed antibodies against the adeno-associated virus vector. When these minor discomforts experienced by the subjects can be reduced, gene therapy would eliminate LHON completely. Another clinical trial for gene therapy in targeting the ND4 LHON mutations in the retina of mouse and nonhuman primate models reveal that powerful and longer expression interval nature of adeno-associated viral vectors with added advantage of safety over other viral vectors.
Allotropic expression is an advanced method used to overcome the difficulty faced with gene therapy. In allotropic expression, the nuclear version of the mitochondrial gene is constructed, and the proteins are synthesized cytoplasmically by targeting the sequence in the reading frame, and the mutation in the ND4 has been corrected using this technique which is reported to improve the survival rate. In a study of human therapy for LHON, the mRNAs of ND1 and ND4 are localized on the membrane of mitochondria. The same method can be used for other genes, thereby the LHON subjects affected with different mutations can be treated effectively.
| Conclusion|| |
The vision loss in LHON is mainly due to the oxidative stress experienced by the optic nerves by the impaired OXPHOS of the mitochondria due to mutations in the genes ND1, ND4, and ND6. The exact pathway in which the oxidative stress cause vision loss is still a debate. The treatments currently available reduce the stress in the optic nerves to some extent and do not completely eradicate the condition. Gene therapy is the major key to completely eradicate LHON. However, gene therapy is yet to be standardized as many limitations are present that prevent the technique from completely curing the disease. At present, many works are being done to improve the gene therapy, and in the future, the LHON will be completely cured without any complications, and other kinds of specified-targeted treatments will be available in curing any mitochondrial gene-related diseases.
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Conflicts of interest
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| References|| |
Abu-Amero KK, Bosley TM. Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest Ophthalmol Vis Sci 2006;47:4211-20.
Sadun AA, La Morgia C, Carelli V. Leber's hereditary optic neuropathy. Curr Treat Options Neurol 2011;13:109-17.
Levin LA. Mechanisms of retinal ganglion specific-cell death in leber hereditary optic neuropathy. Trans Am Ophthalmol Soc 2007;105:379-91.
Vergani L, Martinuzzi A, Carelli V, Cortelli P, Montagna P, Schievano G, et al.
MtDNA mutations associated with Leber's hereditary optic neuropathy: Studies on cytoplasmic hybrid (cybrid) cells. Biochem Biophys Res Commun 1995;210:880-8.
Kirches E. LHON: Mitochondrial mutations and more. Curr Genomics 2011;12:44-54.
Zhuo Y, Luo H, Zhang K. Leber hereditary optic neuropathy and oxidative stress. Proc Natl Acad Sci U S A 2012;109:19882-3.
van der Giezen M, Tovar J. Degenerate mitochondria. EMBO Rep 2005;6:525-30.
Ravn K, Wibrand F, Hansen FJ, Horn N, Rosenberg T, Schwartz M, et al.
An mtDNA mutation, 14453Grg T, SchwarNADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Eur J Hum Genet 2001;9:805-9.
Zeviani M, Di Donato S. Mitochondrial disorders. Brain 2004;127:2153-72.
Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: Current perspectives. Clin Ophthalmol 2015;9:1165-76.
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al.
Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988;242:1427-30.
Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 1991;48:1147-53.
Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associated with leber hereditary optic neuropathy. Biochem Biophys Res Commun 1992;187:1551-7.
Brown MD, Starikovskaya E, Derbeneva O, Hosseini S, Allen JC, Mikhailovskaya IE, et al.
The role of mtDNA background in disease expression: A new primary LHON mutation associated with Western Eurasian haplogroup J. Hum Genet 2002;110:130-8.
Mackey DA, Oostra RJ, Rosenberg T, Nikoskelainen E, Bronte-Stewart J, Poulton J, et al.
Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 1996;59:481-5.
La Morgia C, Carbonelli M, Barboni P, Sadun AA, Carelli V. Medical management of hereditary optic neuropathies. Front Neurol 2014;5:141.
Baracca A, Solaini G, Sgarbi G, Lenaz G, Baruzzi A, Schapira AH, et al.
Severe impairment of complex I-driven adenosine triphosphate synthesis in Leber hereditary optic neuropathy cybrids. Arch Neurol 2005;62:730-6.
Majander A, Huoponen K, Savontaus ML, Nikoskelainen E, Wikström M. Electron transfer properties of NADH: Ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS Lett 1991;292:289-92.
Singer TP, Ramsay RR. The reaction sites of rotenone and ubiquinone with mitochondrial NADH dehydrogenase. Biochim Biophys Acta 1994;1187:198-202.
Zhang L, Liu L, Philip AL, Martinez JC, Guttierez JC, Marella M, et al.
Long-term evaluation of Leber's hereditary optic neuropathy-like symptoms in rotenone administered rats. Neurosci Lett 2015;585:171-6.
Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, et al.
Leber hereditary optic neuropathy: Identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 1991;49:939-50.
Sharkawi E, Oleszczuk JD, Holder GE, Raina J. Clinical and electrophysiological recovery in leber hereditary optic neuropathy with G3460A mutation. Doc Ophthalmol 2012;125:71-4.
Carelli V, Ghelli A, Ratta M, Bacchilega E, Sangiorgi S, Mancini R, et al.
Leber's hereditary optic neuropathy: Biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Neurology 1997;48:1623-32.
Zhang M, Zhou X, Li C, Zhao F, Zhang J, Yuan M, et al.
Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation. Mol Genet Metab 2010;101:192-9.
Achilli A, Iommarini L, Olivieri A, Pala M, Hooshiar Kashani B, Reynier P, et al.
Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy. PLoS One 2012;7:e42242.
Spruijt L, Smeets HJ, Hendrickx A, Bettink-Remeijer MW, Maat-Kievit A, Schoonderwoerd KC, et al.
AMELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia. Arch Neurol 2007;64:890-3.
Carreño-Gago L, Gamez J, Cámara Y, Alvarez de la Campa E, Aller-Alvarez JS, Moncho D, et al.
Identification and characterization of the novel point mutation m.3634A>G in the mitochondrial MT-ND1 gene associated with LHON syndrome. Biochim Biophys Acta 2017;1863:182-7.
Martínez-Romero Í, Herrero-Martín MD, Llobet L, Emperador S, Martín-Navarro A, Narberhaus B, et al.
New MT-ND1 pathologic mutation for leber hereditary optic neuropathy. Clin Exp Ophthalmol 2014;42:856-64.
Sheremet NL, Nevinitsyna TA, Zhorzholadze NV, Ronzina IA, Itkis YS, Krylova TD, et al.
Previously unclassified mutation of mtDNA m.3472T>C: Evidence of pathogenicity in Leber's hereditary optic neuropathy. Biochemistry (Mosc) 2016;81:748-54.
La Morgia C, Caporali L, Gandini F, Olivieri A, Toni F, Nassetti S, et al.
Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. BMC Neurol 2014;14:116.
Blanch M, Mosquera JL, Ansoleaga B, Ferrer I, Barrachina M. Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in Parkinson disease. Am J Pathol 2016;186:385-97.
Jia X, Li S, Xiao X, Guo X, Zhang Q. Molecular epidemiology of mtDNA mutations in 903 Chinese families suspected with Leber hereditary optic neuropathy. J Hum Genet 2006;51:851-6.
Phasukkijwatana N, Chuenkongkaew WL, Suphavilai R, Suktitipat B, Pingsuthiwong S, Ruangvaravate N, et al.
The unique characteristics of Thai Leber hereditary optic neuropathy: Analysis of 30 G11778A pedigrees. J Hum Genet 2006;51:298-304.
Yen MY, Wang AG, Chang WL, Hsu WM, Liu JH, Wei YH, et al.
Leber's hereditary optic neuropathy – The spectrum of mitochondrial DNA mutations in chinese patients. Jpn J Ophthalmol 2002;46:45-51.
Ishikawa S, Ichibe Y, Yokoe J, Wakakura M. Leber's hereditary optic neuropathy among Japanese. Muscle Nerve Suppl 1995;3:S85-9.
Jiang P, Liang M, Zhang J, Gao Y, He Z, Yu H, et al
. Prevalence of mitochondrial ND4 mutations in 1281 Han Chinese subjects with Leber's hereditary optic neuropathy prevalence of ND4 mutations in Chinese subjects with LHON. Invest Ophthalmol Vis Sci 2015;56:4778-88.
Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE, et al.
Bovine complex I is a complex of 45 different subunits. J Biol Chem 2006;281:32724-7.
Scheffler IE. Mitochondrial disease associated with complex I (NADH-coQ oxidoreductase) deficiency. J Inherit Metab Dis 2015;38:405-15.
Qu J, Li R, Zhou X, Tong Y, Lu F, Qian Y, et al.
The novel A4435G mutation in the mitochondrial tRNAMet may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation. Invest Ophthalmol Vis Sci 2006;47:475-83.
Qu J, Zhou X, Zhang J, Zhao F, Sun YH, Tong Y, et al.
Extremely low penetrance of Leber's hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation. Ophthalmology 2009;116:558-64000.
Li R, Qu J, Zhou X, Tong Y, Hu Y, Qian Y, et al.
The mitochondrial tRNA(Thr) A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family. Gene 2006;376:79-86.
Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet 2014;7:221-34.
Hsu YH, Yogasundaram H, Parajuli N, Valtuille L, Sergi C, Oudit GY, et al.
MELAS syndrome and cardiomyopathy: Linking mitochondrial function to heart failure pathogenesis. Heart Fail Rev 2016;21:103-16.
DiMauro S, Tanji K. Sporadic myopathy. Mitochondrial Case Studies: Underlying Mechanisms and Diagnosis. 2015. p. 83.
Rice AC, Bennett JP, Arkun K. Effect of lewy bodies on mitochondrial DNA copy numbers and deletion burden in Parkinson's disease Substantia Nigra neurons. J Alzheimers Dis Parkinsonism 2015;5:2161-460.
Ma JT, Han CB, Zhou Y, Zhao JZ, Jing W, Zou HW, et al
. Altered expression of mitochondrial cytochrome c oxidase I and NADH dehydrogenase 4 transcripts associated with gastric tumorigenesis and tumor dedifferentiation. Mol Med Rep 2012;5:1526-30.
Chattopadhyay E, De Sarkar N, Singh R, Ray A, Roy R, Paul RR, et al.
Genome-wide mitochondrial DNA sequence variations and lower expression of OXPHOS genes predict mitochondrial dysfunction in oral cancer tissue. Tumour Biol 2016;37:11861-71.
Damm F, Bunke T, Thol F, Markus B, Wagner K, Göhring G, et al.
Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia. Leukemia 2012;26:289-95.
Li LH, Kang T, Chen L, Zhang W, Liao Y, Chen J, et al.
Detection of mitochondrial DNA mutations by high-throughput sequencing in the blood of breast cancer patients. Int J Mol Med 2014;33:77-82.
Zhang AM, Jia X, Bi R, Salas A, Li S, Xiao X, et al.
Mitochondrial DNA haplogroup background affects LHON, but not suspected LHON, in Chinese patients. PLoS One 2011;6:e27750.
Howell N, Herrnstadt C, Shults C, Mackey DA. Low penetrance of the 14484 LHON mutation when it arises in a non-haplogroup J mtDNA background. Am J Med Genet A 2003;119A: 147-51.
Zhang J, Zhao F, Fu Q, Liang M, Tong Y, Liu X, et al.
Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T<C (MT-ND6) mutation in Chinese families. Mitochondrion 2013;13:772-81.
Yang J, Zhu Y, Chen L, Zhang H, Tong Y, Huang D, et al.
Novel A14841G mutation is associated with high penetrance of LHON/C4171A family. Biochem Biophys Res Commun 2009;386:693-6.
Yamada K, Mashima Y, Kigasawa K, Miyashita K, Wakakura M, Oguchi Y, et al.
High incidence of visual recovery among four japanese patients with Leber's hereditary optic neuropathy with the 14484 mutation. J Neuroophthalmol 1997;17:103-7.
Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci U S A 1994;91:6206-10.
Jun AS, Trounce IA, Brown MD, Shoffner JM, Wallace DC. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes leber hereditary optic neuropathy and dystonia. Mol Cell Biol 1996;16:771-7.
Houshmand M, Mousavizadeh K, Askari M, Nikpour AR, Mazidi M, Tavafjadid M. Association of mtDNA mutation with autism in Iranian patients. Int J Pediatr 2013;1:39-43.
Ugalde C, Triepels RH, Coenen MJ, van den Heuvel LP, Smeets R, Uusimaa J, et al.
Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene. Ann Neurol 2003;54:665-9.
Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, et al.
ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 2008;320:661-4.
Wallace L, Mehrabi S, Bacanamwo M, Yao X, Aikhionbare FO. Expression of mitochondrial genes MT-ND1, MT-ND6, MT-CYB, MT-COI, MT-ATP6, and 12S/MT-RNR1 in colorectal adenopolyps. Tumour Biol 2016;37:12465-75.
Lyseng-Williamson KA. Idebenone: A Review in Leber's hereditary optic neuropathy. Drugs 2016;76:805-13.
Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, et al.
Idebenone treatment in Leber's hereditary optic neuropathy. Brain 2011;134:e188.
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;20:166-70.
Klopstock T, Metz G, Yu-Wai-Man P, Büchner B, Gallenmüller C, Bailie M, et al.
Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy. Brain 2013;136:e230.
Shrader WD, Amagata A, Barnes A, Enns GM, Hinman A, Jankowski O, et al.
A-tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg Med Chem Lett 2011;21:3693-8.
Enns GM, Kinsman SL, Perlman SL, Spicer KM, Abdenur JE, Cohen BH, et al.
Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab 2012;105:91-102.
Chicani C, Chu E, Ross-Cisneros F, Rockwell S, Murase K, Thoolen M, et al
. Treatment of Leber's Hereditary Optic Neuropathy (LHON): Results using a novel quinone, EPI-743. Invest Ophthalmol Vis Sci 2013;54:4574.
Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, et al.
Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol 2012;69:331-8.
Brown DA, Hale SL, Del Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, et al
. Bendavia, a mitochondria-targeting peptide, reduces reperfusion injury and reactive oxygen species levels through a mechanism independent of direct oxygen radical scavenging: A multicenter study. Circulation 2012;126:A10740-A.
Imai T, Mishiro K, Takagi T, Isono A, Nagasawa H, Tsuruma K, et al.
Protective effect of bendavia (SS-31) against oxygen/glucose-deprivation stress-induced mitochondrial damage in human brain microvascular endothelial cells. Curr Neurovasc Res 2017;14:53-9.
Huoponen K, Puomila A, Savontaus ML, Mustonen E, Kronqvist E, Nikoskelainen E, et al.
Genetic counseling in Leber Hereditary Optic Neuropathy (LHON). Acta Ophthalmol Scand 2002;80:38-43.
Carrasco Salas P, Palma Milla C, López Montiel J, Benito C, Franco Freire S, López Siles J, et al.
Leber hereditary optic neuropathy: Usefulness of next generation sequencing to study mitochondrial mutations on apparent homoplasmy. Med Clin (Barc) 2016;146:163-6.
Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, et al.
Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009;461:367-72.
Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, et al.
Gene therapy for Leber hereditary optic neuropathy: Initial results. Ophthalmology 2016;123:558-70.
Vignal-Clermont C, Corral Debrinski M, Sahel JA. Gene therapy in LHON. Acta Ophthalmol 2015;93.
Lam BL, Feuer WJ, Abukhalil F, Porciatti V, Hauswirth WW, Guy J, et al.
Leber hereditary optic neuropathy gene therapy clinical trial recruitment: Year 1. Arch Ophthalmol 2010;128:1129-35.
Bonnet C, Augustin S, Ellouze S, Bénit P, Bouaita A, Rustin P, et al.
The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochim Biophys Acta 2008;1783:1707-17.
Qu J, Li R, Zhou X, Tong Y, Lu F, Qian Y, et al
. The novel A4435G mutation in the mitochondrial tRNAMet may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation. Investigative ophthalmology & visual science 2006;47:475-83.