.. A Guide to the Genetics of ..

                    .. Leber's Hereditary Optic Neuropathy 'LHON' ..

                              .. a Mitochondrial Disorder of the Enzyme 'Complex I' ..

A REVIEW OF SOME SCIENTIFIC PAPERS:

There are many scientific papers that discuss LHON and here are a few summaries from recent papers. - Original work from 1871 "Ueber hereditaere und congenital angelegte sehnervenleiden (1871) Graefes Arch Clin Exp Ophthalmol. 17:249-291" by Theodor Leber is
available as a free download (pp. 249-291) - Frequency of LHON: in Brazil Maciel-Guerra(2010), Sacai(2010) in Canada Laberge(2005) in China Kaewsutthi(2011), Shu(2012) in Denmark Rosenberg(1995) in Europe Mascialino(2012) in Finland Puomila(2007), Korkiamäki(2012) in Holland Howell(2003), Schieving(2008) in India Kumar(2012) in Italy Barboni(2006) in the UK Man(2002), Man(2003) - Rare LHON variants: in China Liang(2009), Zhang(2012), Zhou(2012) in Tibet Ji(2012) in Italy Malfatti(2007), Valentino(2004) in Germany Besch(1999) in Turkey Howell(1998) - Papers that accompany the 107 LHON mtDNA sequences on GenBank: 'DQ341083-DQ341088' Carelli(2006) 'EF060363-EF060364' La Morgia(2008) 'EU545470-EU545472' Wang(2008) 'EU558385' Unpublished 'EU807741-EU807742' Brown(2001) 'EU828637' Starikovskaya(2005) 'FJ015040' Zhang(2008) 'FJ147319' Unpublished 'FJ198214-FJ198228' Ji(2008) 'FJ944094' Yang(2009a) 'FJ969382-FJ969383' Yang(2009b) 'FJ986465' Yang(2009c) 'GQ202273' Zhang(2009) 'GQ999958-GQ999963' Yu(2010) 'GU377081-GU377090' Zou(2010) 'HM460791-HM460797' Yu(2010) 'HQ260970-HQ260973' Yu(2010) 'JF896797-JF896801' Zhang(2011a) 'JN133516-JN133517' Guo(2012) 'JN415470-JN415484' Achilli(2012) 'JN635298-JN635306' Unpublished 'JN645818-JN645821' Zhang(2011b) 'JN866824-JN866825 Zhang(2012) 'JQ408982' Caporali(2012) 'JQ446396-JQ446410 Unpublished 'JX024564-JX024568' Bi(2012) - Causation of LHON Symptoms: in the UK Kirkman(2009) by smoking and alcohol. in China Hayashi(2011 after head injury. in France Macarez(2005) after Lyme disease. in France Boyer(2012) after antipsychotic therapy (Rispiridone). in Italy Rufa(2005), Carelli(2007), Ghelli(2009) by chemicals. in Korea Seo(2010) by anti-tuberculosis drugs. in Holland Pott(2006) by B12 deficiency. in Japan Kobayashi(2007) by hyperthyroidism. - the Cuban Epidemic of Optic Neuropathy: The CNFI Team(1995), Johns(1994), Mills(2011) Sadun(1994a), Sadun(1994b), Sadun(1998), Santiesteban-Freixas(1998) - Some of the older LHON papers Erikson(1972) An early paper describing maternal inheritance. Wallace(1988) The first paper to link LHON to the mtDNA mutation G11778A. Huoponen(1991) The first paper to link LHON to the mtDNA mutation G3460A. Vilkki(1991) Is there an X-chromosome link ? Brown(1992) Is this the first paper to mention Complex I ? Juvonen(1993) The X-chromosome link discounted. Degli Esposti(1994) Plant alkaloids inhibit Complex I. Riordan-Eva(1995) A good review from 1995. Black(1996) LHON and the mtDNA mutation G3460A. Taylor(2002) Leigh's disease caused by T12706C. - Some of the more recent LHON and Complex I research papers: Bourges(2004) Baracca(2005) Brandt(2006), Carroll(2006), Santos(2006) Dunning(2007), Grazina(2007), Petruzzella(2007), Vogel(2007) Dieteren(2008), Momtchilova(2008), Shah(2008), Sugiana(2008) Hudson(2009), Porcelli(2009), Saada(2009), Srivastava(2009) Aleyasin(2010), Bi(2010), Calmettes(2010), Gerards(2010), Hunte(2010), Lam(2010), Marella(2010) Quinzii(2010), Tonska(2010), Tuppen(2010), Zhang(2010), Zhou(2010) Bridges(2011), Clay(2011), Drose(2011), Giordano(2011), Gonzales-Halphen(2011), Gouspillou(2011), Guerriero(2011), Hudson(2011) Klopstock(2011), Koilkonda(2011), McKenzie(2011), Newman(2011), Rocca(2011), Swalwell(2011), Treberg(2011), Tucker(2011) Barboni(2012), Chu(2012), Farhoud(2012, Fassone(2012), Giorgio(2012), Gurkan(2012), Haack(2012) Heitz(2012), Kensche(2012), Kumar(2012), Lin(2012), Liu(2012), Mancuso(2012), Marin(2012), Nouws(2012) Pagniez-Mammeri(2012), Rizzo(2012), Roberts(2012), Saada(2012), Sadun(2012), Sharkawi(2012), Sitarz(2012), Wei(2012) Yu(2012) d'Almeida(2013), Aitullina(2013), Badura-Stronka(2013), Carelli(2013), Giordano(2013), Hsu(2013), Istikharah(2013), Iyer(2013), Khan(2013) Khan(2013a), Logan(2013), Meunier(2013), Nucci (2013), Paquay(2013), Pfeffer(2013), Revzani(2013, Schele(2013), Thouin(2013) Behbehani(2014), Chen(2014), Dimitriadis(2014), Jancic(2014), Ji(2014), Jin(2014), Kodrol(2014), Koilonda(2014), La Morgia(2014) Liang(2014), Martinez-Romero(2014), Meng(2014), Romero(2014), Tun(2014), Xiangjuan(2014), Yum(2014), Zhang(2014) Cwerman-Thibault(2015), Feuer(2015).Jiang(2015), Jiang(2015a), Qiao(2015, Zhang(2015), Zhonghua(2015) Barca(2016), Bi(2016), Catarino(2016), Cruz-Bermudez(2016), Ji(2016), Jiang(2016), Kolarova(2016), Rosenberg(2016), Wan(2016), Xie(2016) Bianco(2017), Hwang(2017), Khan(2017), Li(2017), Majander(2017). Soldath(2017), Ueda(2017), Wallace(2017) - Complex I and the rare tumour - the oncocytoma Simonnet(2003), Gasparre(2008), Klomp(2010) ----------------------------------------------------------------------------------------------------------------------- PAPERS DISCUSSING THE FREQUENCY OF LHON IN DIFFERENT COUNTRIES ============================================================== ----------------------------------------------------------------------------------------------------------------------- Ophthalmic Genet. 2010 Sep;31(3):126-8. Leber's hereditary optic neuropathy: clinical and molecular profile of a Brazilian sample. Maciel-Guerra AT, Zanchetta LM, Amaral Fernandes MS, Andrade PB, do Amor Divino Miranda PM, Sartorato EL. Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, São Paulo, Brasil. PURPOSE: The aim of this study was to describe clinical features and search for primary mitochondrial DNA (mtDNA) mutations in 13 unrelated Brazilian patients with Leber's hereditary optic neuropathy (LHON). METHODS: Analysis of the G11778A, G3460A, and T14484C mutations was done by polymerase chain reaction and restriction fragment length polymorphism, and mutations were confirmed by direct sequencing. Mean age of onset was 24.5 years and all cases were bilateral. RESULTS: Sex ratio (12M:1F) and frequency of simultaneous involvement (9/13) were higher than in other studies. In nine cases there was familial recurrence: 24 male and two female relatives. Ten patients had a mutation: G11778A in six, T14484C in three and one G3460A. The frequency of patients bearing a primary mutation was lower than that described in multicentric studies but similar to that observed among Asians. A higher frequency of the T14484C mutation was detected. CONCLUSIONS: The contribution of Amerindians and Africans to the Brazilian mtDNA pool may account for differences in the type and frequency of primary LHON mutations. COMMENT: A survey of LHON in Brazil. Back ----------------------------------------------------------------------------------------------------------------------- Doc Ophthalmol. 2010 Oct;121(2):147-54. Epub 2010 Jul 31. Visual evoked potentials findings in non-affected subjects from a large Brazilian pedigree of 11778 Leber's hereditary optic neuropathy. Sacai PY, Salomão SR, Carelli V, Pereira JM, Belfort R Jr, Sadun AA, Berezovsky A. Departamento de Oftalmologia, Universidade Federal de São Paulo, UNIFESP, R. Botucatu 822, São Paulo, SP, 04023-062, Brazil. To investigate pattern-reversal visual evoked potentials (PRVEP) in asymptomatic maternally and non-maternally related members from a large Brazilian 11778/ND4 LHON pedigree. Transient PRVEP for check sizes 15' and 60' were recorded from asymptomatic mutation carriers and non-mutant descendants of affected/non-affected males, all with best-corrected visual acuity of 20/20. A control group of spouses (off-pedigree) was also included. Parameters of N75, P100 and N135 latencies (ms) and N75-P100 peak-to-peak amplitude (?V) as well as temporal dispersion (latency of N135-latency of N75) were determined. Longitudinal testing was obtained in a subseries of carriers in three annual consecutive visits. We tested 48 asymptomatic mutation carriers, 19 descendants of affected males, 9 descendants of non-affected males and 27 off-pedigrees, all of the latter being non-mutant. All non-mutant male descendants did not differ from off-pedigree controls. Statistically prolonged P100 latencies were found in mutation carriers (P = 0.0143) when compared with off-pedigrees for check sizes 15', as well as significantly larger temporal dispersions for both check size 15' (P = 0.0012) and check size 60' (P = 0.0271). Serial testing in 15 mutation carriers disclosed prolonged P100 latencies and larger temporal dispersion that did not change over time. Subclinical PRVEP abnormalities were detected in this large group of asymptomatic carriers of the 11778/ND4 LHON mutation from the same family, confirming and extending previous psychophysical and structural findings of a selective involvement of the parvocellular pathway. PRVEP is a useful test to characterize and monitor visual dysfunction in this devastating disease. COMMENT: LHON in Brazil. Back ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 2005 Aug;77(2):313-7. A "Fille du Roy" introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians. Laberge AM, Jomphe M, Houde L, Vezina H, Tremblay M, Desjardins B, Labuda D, St-Hilaire M, Macmillan C, Shoubridge EA, Brais B. Laboratoire de Neurogénétique, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. The predominance of the T14484C mutation in French Canadians with Leber hereditary optic neuropathy is due to a founder effect. By use of genealogical reconstructions of maternal lineages, a woman married in Quebec City in 1669 is identified as the shared female ancestor for 11 of 13 affected individuals, who were previously not known to be related. These individuals carry identical mitochondrial haplogroups. The current geographic distribution of French Canadian cases overlaps with that of the founder's female descendants in 1800. This is the first example of genealogical reconstruction to identify the introduction of a mitochondrial mutation by a woman in a founder population. Available as a free download COMMENT: 'LHON T14484C' in Canada. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2011 Jul 1;52(7):4742-8. Mitochondrial haplogroup background may influence Southeast Asian G11778A Leber hereditary optic neuropathy. Kaewsutthi S, Phasukkijwatana N, Joyjinda Y, Chuenkongkaew W, Kunhapan B, Tun AW, Suktitipat B, Lertrit P. Department of Biochemistry, Mahidol University, Bangkok, Thailand. PURPOSE: To investigate the role of mitochondrial DNA (mt DNA) background on the expression of Leber hereditary optic neuropathy (LHON) in Southeast Asian carriers of the G11778A mutation. METHODS: Complete mtDNA sequences were analyzed from 53 unrelated Southeast Asian G11778A LHON pedigrees in Thailand and 105 normal Thai controls, and mtDNA haplogroups were determined. Clinical phenotypes were tested for association with mtDNA haplogroup, with adjustment for potential confounders such as sex and age at onset. RESULTS: mtDNA subhaplogroup B was significantly associated with LHON. Follow-up analysis narrowed the association down to subhaplogroup B5a1 (P = 0.008). Survival analyses with Cox's proportional hazards modeling on 469 samples (91 affected and 378 unaffected), adjusted for sex and heteroplasmy, revealed that haplogroup B5a1 tended to increase the risk of visual loss, but the trend was not statistically significant. Conversely, haplogroup F, the second most common haplogroup in the control population, was the least frequent haplogroup in LHON. This negative association was narrowed down to subhaplogroup F1 (P = 0.00043), suggesting that haplogroup F1 confers a protective effect. The distributions of sex, age at onset and heteroplasmy were not significantly different among haplogroups. CONCLUSIONS: The specific mtDNA background B5a1 was significantly associated with Southeast Asian G11778A LHON and appeared to modify the risk of visual loss. Available as a free download COMMENT: An interesting paper about 'LHON G11778A' in Thailand. Back ----------------------------------------------------------------------------------------------------------------------- Int J Ophthalmol. 2012;5(1):28-31. Complete mitochondrial DNA sequence analysis in two southern Chinese pedigrees with Leber hereditary optic neuropathy revealed secondary mutations along with the primary mutation. Shu L, Zhang YM, Huang XX, Chen CY, Zhang XN. Hangzhou Red Cross Hospital, Hangzhou 310003, Zhejiang Province, China. AIM: To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS: Two unrelated southern Chinese families with LHON and 10 matched healthy controls were recruited, and their entire mitochondrial DNA (mtDNA) was amplified and sequenced with the universal M13 primer. Then DNA sequence analysis and variation identification were perfomed by DNAssist and Chromas 2 software and compared with authoritative databases such as Mitomap. RESULTS: Mutational analysis of mtDNA in these two Chinese pedigrees revealed one common LHON-associated mutation, G11778A (Arg?His), in the MT-ND4 gene. In addition, there were two secondary mutations in Pedigree 1: C3497T (Ala?Val), and C3571T (Leu?Phe) in the MT-ND1 gene, which have not been reported; and two secondary mutations occurred in Pedigree 2: A10398G (Thr?Ala) in the MT-ND3 gene, and T14502C (Ile?Val) in the MT-ND6 gene. Three polymorphisms, A73G, G94A and A263G in the mtDNA control region, were also found. CONCLUSION: Our study confirmed that the known MT-ND4*G11778A mutation is the most significant cause of LHON. The C3497T and C3571T mutations in Pedigree 1 were also both at hot-spots of MT-ND1; they may affect the respiratory chain in coordination with the primary mutation G11778A. In Pedigree 2, the two secondary mutations A10398G of MT-ND3 and T14502C of MT-ND6 may influence mitochondrial respiratory complex I, leading to the mitochondrial respiratory chain dysfunction which results in optic atrophy together with G11778A. Therefore, not only the common primary LHON mutation is responsible for the visual atrophy, but other secondary mtDNA mutations should also be considered when giving genetic counseling. Available as a free download COMMENT: A good discussion of 'LHON G11778A' disease in China. Back ----------------------------------------------------------------------------------------------------------------------- Ugeskr Laeger. 1995 May 8;157(19):2707-11. Hereditary optic nerve atrophy. A clinical-genealogical status over Danish families with Leber disease. Rosenberg T, Kann E, Nørby S. Statens Ojenklinik, Hellerup. An update on Leber's hereditary optic neuropathy (LHON) in Denmark disclosed 32 families with at least one live affected member, or recent disease onset (Table 1). Mitochondrial DNA analysis in the 30 families available for blood sampling identified the pathogenic mutation in all of them: ND4/11778 (26 families), ND1/3460 (three families), and ND6/14484 (one family). A previous distinct male dominance (sex ratio 4.6:1 in 157 ND4-patients with onset before 1968) seems to level (sex ratio 2.6:1 in 69 ND4-patients with onset in 1968 or later). Among possible explanations, we discuss improved diagnostic abilities and possible changes in women's alcohol consumption and smoking habits. COMMENT: LHON in Denmark. Back ----------------------------------------------------------------------------------------------------------------------- Eur J Ophthalmol. 2012 May-Jun;22(3):461-5. Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe. Mascialino B, Leinonen M, Meier T. Stockholm University, Stockholm, Sweden. PURPOSE: A meta-analysis was conducted to estimate the prevalence of patients with molecularly confirmed Leber hereditary optic neuropathy (LHON) carrying any of the 3 primary mtDNA mutations (m.11778G>A, m.14484T>C, m.3460G>A) which cause this inherited form of blindness. METHODS: A literature search was conducted to identify primary reports with LHON prevalence data reported for Europe. The overall prevalence of LHON with molecularly confirmed diagnosis was evaluated by weighting the prevalence estimates of the individual studies by the inverse of their variance. RESULTS: Based on this meta-analysis of 5 European studies providing appropriate information, the estimated prevalence of LHON disease associated with the combined m.11778G>A, m.14484T>C, m.3460G>A mutations was ~1:45,000 (2.23 x 10(-5); 95% confidence interval [CI] 2.01-2.44 x 10(-5)). Patients with LHON carrying either the m.11778G>A or the m.3460G>A mutation have a more severe clinical presentation and a much lower chance of spontaneous recovery from vision loss compared to patients with the m.14484T>C mutation. The estimated prevalence for patients with LHON in Europe carrying either of these severe mutations (m.11778G>A or m.3460G>A) was ~1:65,000 (1.54 x 10(-5); 95% CI 1.33-1.74 x 10(-5)). CONCLUSIONS: Although this meta-analysis summarizes the existing prevalence data for the primary, disease-causing mitochondrial DNA mutations of LHON in Europe, there is still a clear lack of reliable primary epidemiologic data for this devastating ophthalmologic disease. COMMENT: Tries to give occurrence rates in Europe. Back ----------------------------------------------------------------------------------------------------------------------- Eur J Hum Genet. 2007 Oct;15(10):1079-89. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, Nikoskelainen E. Department of Medical Genetics, University of Turku, Turku, Finland. anu.puomila@utu.fi We have performed an entire-population-based survey of the epidemiology and penetrance of Leber hereditary optic neuropathy (LHON) in Finland - a country that is among the best-studied genetic isolates in the world. During our long-term clinical follow-up period since 1970, we have so far identified 36 LHON families in Finland, comprised of almost 1000 family members. Counting the unaffected family members has been possible thanks to accessible genealogical records, and this has improved the accuracy of our penetrance figures by minimizing the sample bias. Our results, although confirming some well-known features of LHON, indicate that the overall penetrance of LHON is lower than previously estimated, and that affected females have a higher incidence of affected offspring compared to the unaffected females. The prevalence of LHON in Finland is 1:50 000, and one in 9000 Finns is a carrier of one of the three LHON primary mutations. Available as a free download COMMENT:LHON in Finland. Back ------------------------------------------------------------------------------------------------------------------------ Acta Ophthalmol. 2012 Sep 12 Prevalence of the primary LHON mutations in Northern Finland associated with bilateral optic atrophy and tobacco-alcohol amblyopia. Korkiamäki P, Kervinen M, Karjalainen K, Majamaa K, Uusimaa J, Remes AM. Department of Ophthalmology, Institute of Clinical Medicine, University of Oulu Leber hereditary optic neuropathy (LHON) is regarded as the most common mitochondrial disease. We have previously reported comprehensive population-based epidemiological data on common mitochondrial DNA (mtDNA) mutations including m.3243A>G, m.8344A>G and large-scale mtDNA deletions in Northern Finland. Our aim was to investigate the prevalence of primary LHON mutations and mutations in the four mtDNA genes considered hot spots for LHON in the same population. Methods:? The study population consisted of 42 adult patients with an aetiologically undefined bilateral optic atrophy. The major LHON mutations m.3460G>A, m.11778G>A and m.14484T>C were analysed by restriction fragment length polymorphism (RFLP), and MTND1, MTND6 and MTATP6 genes were sequenced. MTND5 gene was analysed by conformation-sensitive gel electrophoresis(CSGE). Results:? No major LHON mutations were found in the population of the province of Northern Ostrobothnia giving the prevalence of these mutations 0-1.36:100?000 (95% CI). However, two main mutations were found elsewhere in Northern Finland, homoplasmic m.11778G>A from Kainuu and heteroplasmic m.3460G>A from Central Ostrobothnia. Furthermore, tobacco-alcohol amblyopia was diagnosed in five patients in the study population and one of them had m.11778G>A. Conclusion: The prevalence of the three major LHON mutations is lower in Northern Finland than elsewhere in Finland or in Western Europe. As LHON and tobacco-alcohol amblyopia have a similar phenotype, we recommend analysing the known LHON-associated mutations before setting tobacco-alcohol amblyopia diagnosis. COMMENT: A small study of LHON in Finland but complete mtDNA sequencing was not used. Back ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 2003 Jun;72(6):1460-9. Epub 2003 May 6. Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Howell N, Oostra RJ, Bolhuis PA, Spruijt L, Clarke LA, Mackey DA, Preston G, Herrnstadt C. MitoKor, San Diego, CA 92121, USA. howelln@mitokor.com The complete mitochondrial DNA (mtDNA) sequences for 63 Dutch pedigrees with Leber hereditary optic neuropathy (LHON) were determined, 56 of which carried one of the classic LHON mutations at nucleotide (nt) 3460, 11778, or 14484. Analysis of these sequences indicated that there were several instances in which the mtDNAs were either identical or related by descent. The most striking example was a haplogroup J mtDNA that carried the 14484 LHON mutation. Four different but related mitochondrial genotypes were identified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus. The control region of the founder sequence for these Dutch pedigrees with LHON matches the control-region sequence that Macmillan and colleagues identified in the founder mtDNA of French Canadian pedigrees with LHON. In addition, we obtained a perfect match between the Dutch 14484 founder sequence and the complete mtDNA sequences of two Canadian pedigrees with LHON. Those results indicate that these Dutch and French Canadian 14484 pedigrees with LHON share a common ancestor, that the single origin of the 14484 mutation in this megalineage occurred before the year 1600, and that there is a 14484/haplogroup J founder effect. We estimate that this lineage--including the 14484 LHON mutation--arose 900-1,800 years ago. Overall, the phylogenetic analyses of these mtDNA sequences conservatively indicate that a LHON mutation has arisen at least 42 times in the Dutch population. Finally, analysis of the mtDNA sequences from those pedigrees that did not carry classic LHON mutations suggested candidate pathogenic mutations at nts 9804, 13051, and 14325. Available as a free download COMMENT: The 'LHON T14484C' mutation was in Holland before Canada. Back ----------------------------------------------------------------------------------------------------------------------- Ned Tijdschr Geneeskd. 2008 Oct 25;152(43):2313-6. Sudden blindness: consider Leber's hereditary optic neuropathy]. Schieving JH, de Vries BB, Hol F, Stroink H. Universitair Medisch Centrum St Radboud, Postbus 9101, 6500 HB Nijmegen. In 3 young male patients, aged 10, 19 and 21 years respectively, sequential, severe, painless bilateral visual loss occurred. Ophthalmological examination revealed no other abnormalities and this delayed the diagnosis Leber's hereditary optic neuropathy (LHON). LHON is a mitochondrial genetic disease characterised by bilateral acute or subacute painless loss of central vision. LHON causes blindness, predominantly in young adult males but less frequently in women and children as well. Occasionally, LHON is associated with other neurological and cardiac changes. The first patient recovered his vision within 2 years, but the other 2 remained blind. All 3 patients had a m.11778G > A mutation in the mitochondrial DNA (mtDNA). Over 95% of LHON cases are primarily the result of one of three mitochondrial DNA point mutations. In addition, analysis of patients grouped according to mtDNA mutation has demonstrated differences in both the clinical features of visual failure and in recurrence risks for relatives that are associated with each of the pathogenic mtDNA mutations. Depending on the type of mutation, recovery of vision occurs in 4-58% of the patients. Whilst pathogenic mtDNA mutations are required for the development of LHON, other factors must be responsible for the variable penetrance and male predominance. Familiarity with the clinical spectrum of LHON is necessary for early diagnosis. There is no proven treatment. COMMENT: G11778A LHON in Holland. Back ------------------------------------------------------------------------------------------------------------------------ Mol Vis. 2012;18:2687-99. Clinical characterization and mitochondrial DNA sequence variations in Leber hereditary optic neuropathy. Kumar M, Kaur P, Kumar M, Saxena R, Sharma P, Dada R. Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. PURPOSE: Leber hereditary optic neuropathy (LHON), a maternally inherited disorder, results from point mutations in mitochondrial DNA (mtDNA). MtDNA is highly polymorphic in nature with very high mutation rate, 10-17 fold higher as compared to nuclear genome. Identification of new mtDNA sequence variations is necessary to establish a clean link with human disease. Thus this study was aimed to assess or evaluate LHON patients for novel mtDNA sequence variations. MATERIALS AND METHODS: Twenty LHON patients were selected from the neuro-ophthalmology clinic of the All India Institute of Medical Sciences, New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. For structural analysis (molecular modeling and simulation) the MODELER 9.2 program in Discovery Studio (DS 2.0) was used. RESULTS: MtDNA sequencing revealed a total of 47 nucleotide variations in the 20 LHON patients and 29 variations in 20 controls. Of 47 changes in patients 21.2% (10/47) were nonsynonymous and the remaining 78.72% (37/47) were synonymous. Five nonsynonymous changes, including primary LHON mutations (NADH dehydrogenase subunit 1 [ND1]:p.A52T, NADH dehydrogenase subunit 6 [ND6]:p.M64V, adenosine triphosphate [ATP] synthase subunit a (F-ATPase protein 6) [ATPase6]:p.M181T, NADH dehydrogenase subunit 4 [ND4]:p.R340H, and cytochrome B [CYB]:p.F181L), were found to be pathogenic. A greater number of changes were present in complex I (53.19%; 25/47), followed by complex III (19.14%; 9/47), then complex IV (19.14%; 9/47), then complex V (8.5%; 4/47). Nonsynonymous variations may impair respiratory chain and oxidative phosphorylation (OXPHOS) pathways, which results in low ATP production and elevated reactive oxygen species (ROS) levels. Oxidative stress is the underlying etiology in various diseases and also plays a crucial role in LHON. CONCLUSIONS: This study describes the role of mtDNA sequence variations in LHON patients. Primary LHON mutations of mtDNA are main variants leading to LHON, but mutations in other mitochondrial genes may also play an important role in pathogenesis of LHON as indicated in the present study. Certain alleles in certain haplogroups have protective or deleterious roles and hence there is a need to analyze a large number of cases for correlating phenotype and disease severity with mutation and mtDNA haplogroups. COMMENT: LHON in India. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5303-9. Leber's hereditary optic neuropathy with childhood onset. Barboni P, Savini G, Valentino ML, La Morgia C, Bellusci C, De Negri AM, Sadun F, Carta A, Carbonelli M, Sadun AA, Carelli V. Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy. p.barboni@eyeproject.com PURPOSE: To characterize the clinical features of childhood-onset Leber's hereditary optic neuropathy (LHON) as defined by a pathogenic mtDNA mutation and age at onset equal to or less than 10 years of age. METHODS: Fifty-six LHON Italian pedigrees including 180 affected individuals were reviewed, and 14 of 18 patients with childhood LHON were enrolled. LHON was classified as acute bilateral, acute unilateral, slowly progressive, and subclinical, according to disease features. All patients underwent a complete ophthalmic examination and optical coherence tomography (OCT), including retinal nerve fiber layer (RNFL) and optic nerve head analysis (ONH), and were compared with age- and optic disc size-matched control groups. RESULTS: The prevalence of childhood LHON in this case series was 11.5%. Five patients had an acute bilateral course, three an acute unilateral course with subclinical signs in the fellow eye, and six a slowly progressive course. Four of five acute patients with acute bilateral disease experienced visual recovery. Slowly progressive cases presented a better visual acuity and visual field outcome than acute cases. A significant diffuse reduction of RNFL was evident in children with acute LHON compared with the control group, whereas a significant reduction of the temporal quadrant was present in the slowly progressive and subclinical LHON cases. Acute LHON children had a smaller disc area and vertical disc diameter than did the control subjects. CONCLUSIONS: This study systematically characterized for the first time the subgroup of LHON with childhood onset. The peculiar clinical and anatomic features of childhood LHON offer insights for the understanding of LHON's pathophysiology as well as a basis for the differential diagnosis of visual loss in childhood. Available as a free download COMMENT: A detailed paper about Childhood LHON in Italy. Back ----------------------------------------------------------------------------------------------------------------------- J Med Genet. 2002 Mar;39(3):162-9. Leber hereditary optic neuropathy. Man PY, Turnbull DM, Chinnery PF. Department of Neurology, School of Neurosciences and Psychiatry, The Medical School, University of Newcastle Upon Tyne, UK. Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disease that preferentially causes blindness in young adult males, affecting about 1 in 25 000 of the British population. It is characterised by bilateral subacute loss of central vision owing to focal degeneration of the retinal ganglion cell layer and optic nerve. Over 95% of LHON cases are primarily the result of one of three mitochondrial DNA (mtDNA) point mutations, G3460A, G11778A, and T14484C, which all involve genes encoding complex I subunits of the respiratory chain. An intriguing feature of LHON is that only approximately 50% of males and approximately 10% of females who harbour a pathogenic mtDNA mutation actually develop the optic neuropathy. This marked incomplete penetrance and gender bias imply that additional mitochondrial and/or nuclear genetic factors must be modulating the phenotypic expression of LHON. It is also likely that environmental factors contribute to the onset of visual failure. However, these secondary precipitating factors remain poorly defined at present. In this review, we describe the natural history of this optic nerve disorder and highlight issues relating to clinical diagnosis, management, and genetic counselling. We also discuss the findings of recently published studies and the light they shed on the complex aetiology and pathophysiology of LHON. Available as a free download COMMENT: An important review of LHON at the time. Back ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 2003 Feb;72(2):333-9. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. We performed the first population-based clinical and molecular genetic study of Leber hereditary optic neuropathy (LHON) in a population of 2,173,800 individuals in the North East of England. We identified 16 genealogically unrelated families who harbor one of the three primary mitochondrial DNA (mtDNA) mutations that cause LHON. Two of these families were found to be linked genetically to a common maternal founder. A de novo mtDNA mutation (G3460A) was identified in one family. The minimum point prevalence of visual failure due to LHON within this population was 3.22 per 100,000 (95% CI 2.47-3.97 per 100,000), and the minimum point prevalence for mtDNA LHON mutations was 11.82 per 100,000 (95% CI 10.38-13.27 per 100,000). These results indicate that LHON is not rare but has a population prevalence similar to autosomally inherited neurological disorders. The majority of individuals harbored only mutant mtDNA (homoplasmy), but heteroplasmy was detected in approximately 12% of individuals. Overall, however, approximately 33% of families with LHON had at least one heteroplasmic individual. The high incidence of heteroplasmy in pedigrees with LHON raises the possibility that a closely related maternal relative of an index case may not harbor the mtDNA mutation, highlighting the importance of molecular genetic testing for each maternal family member seeking advice about their risks of visual failure. Available as a free download COMMENT: An important paper on the prevalence of LHON in the UK. Back ----------------------------------------------------------------------------------------------------------------------- PAPERS DISCUSSING RARE LHON VARIANTS ==================================== ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2009 Jun 5;383(3):286-92. Epub 2009 Mar 24. Leber's hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation. Liang M, Guan M, Zhao F, Zhou X, Yuan M, Tong Y, Yang L, Wei QP, Sun YH, Lu F, Qu J, Guan MX. Wenzhou Medical College, Zhejiang, China. We report here the clinical, genetic and molecular characterization of four Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T3394C (Y30H) mutation, which localized at a highly conserved tyrosine at position 30 of ND1, and distinct sets of mtDNA polymorphisms belonging to haplogroups D4b and M9a. The occurrence of T3394C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. However, there was the absence of functionally significant mtDNA mutations in these four Chinese pedigrees carrying the T3394C mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated T3394C mutation. Available as a free download COMMENT: Discusses the rare variant T3394C. Back ------------------------------------------------------------------------------------------------------------------------ J Transl Med. 2012 Mar 9;10:43. Mitochondrial DNA mutation m.10680G > A is associated with Leber hereditary optic neuropathy in Chinese patients. Zhang AM, Jia X, Guo X, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C). Rare pathogenic mutations have been occasionally reported in LHON patients. METHODS: We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR). Patients with m.10680G > A were further determined entire mtDNA genome sequence. RESULTS: The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330) were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients) identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784) was significantly higher than that of the general populations (0/9277) (P = 0.0005). CONCLUSION: Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis. Available as a free download COMMENT: The LHON variant G10680A. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2012 Jul 9;53(8):4586-94. Leber's hereditary optic neuropathy is associated with the T3866C mutation in mitochondrial ND1 gene in three Han Chinese Families. Zhou X, Qian Y, Zhang J, Tong Y, Jiang P, Liang M, Dai X, Zhou H, Zhao F, Ji Y, Mo JQ, Qu J, Guan MX. School of Ophthalmology and Optometry, Wenzhou Medical College, Zhejiang, China. PURPOSE: To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON). METHODS: Seventy-one subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included the measurements of the rates of endogenous, substrate-dependent respirations, the adenosine triphosphate (ATP) production and generation of reactive oxygen species using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects. RESULTS: Ten of 41 matrilineal relatives exhibited variable severity and age at onset of optic neuropathy. The average age at onset of optic neuropathy in matrilineal relatives of the three families was 5, 11, and 24 years, respectively. Molecular analysis identified the ND1 T3866C (I187T) mutation and distinct sets of polymorphisms belonging to the Eastern Asian haplogroups D4a, M10a, and R, respectively. The I187T mutation is localized at the highly conserved isoleucine at a transmembrane domain of the ND1 polypeptide. The marked reductions in the rate of endogenous, malate/glutamate-promoted and succinate/glycerol-3-phosphate-promoted respiration were observed in mutant cell lines carrying the T3866C mutation. The deficient respiration is responsible for the reduced ATP synthesis and increased generation of reactive oxygen species. CONCLUSIONS: Our data convincingly show that the ND1 T3866C mutation leads to LHON. This mutation may be insufficient to produce a clinical phenotype. Other modifier factors may contribute to the phenotypic manifestation of the T3866C mutation. The T3866C mutation should be added to the list of inherited factors for molecular diagnosis of LHON. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON. COMMENT: A paper that discusses the LHON mutation T3866C in China. Back ----------------------------------------------------------------------------------------------------------------------- Proc Natl Acad Sci U S A. 2012 May 8;109(19):7391-6. Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans. Ji F, Sharpley MS, Derbeneva O, Alves LS, Qian P, Wang Y, Chalkia D, Lvova M, Xu J, Yao W, Simon M, Platt J, Xu S, Angelin A, Davila A, Huang T, Wang PH, Chuang LM, Moore LG, Qian G, Wallace DC. lnstitute of Human Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease. Available as a free download COMMENT: The variant T3394C in Tibet. Back ----------------------------------------------------------------------------------------------------------------------- Brain. 2007 Jul;130(Pt 7):1894-904. Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy. Malfatti E, Bugiani M, Invernizzi F, de Souza CF, Farina L, Carrara F, Lamantea E, Antozzi C, Confalonieri P, Sanseverino MT, Giugliani R, Uziel G, Zeviani M. Unit of Molecular Neurogenetics, Neurological Institute C. Besta Foundation IRCCS, via Libero Temolo 4, 20126 Milano, Italy. Isolated Complex I (CI) deficiency, the most frequent cause of mitochondrial disease, is a clinically and genetically heterogeneous condition. Complex I is a giant multiheteromeric enzyme composed of seven ND subunits encoded by mitochondrial DNA (mtDNA) genes, and at least 38 subunits encoded by nuclear genes. To establish the contribution to human mitochondrial encephalopathy of ND versus nuclear gene mutations, we have been undertaking a systematic analysis of CI genes in a cohort of 46 adult and paediatric patients with biochemically defined CI defect. Sequence analysis of the entire mtDNA let us identify six patients with mutations in ND genes. The clinical presentations varied, from infantile Leigh syndrome, to childhood MELAS, to adult-onset encephalopathic syndromes of variable severity. Three of the mutations were not previously reported (3481G > A, 14600G > A and 13063G > A, in ND1, ND6 and ND5 genes, respectively) and were further investigated in mutant transmitochondrial cybrids. Tight correlation between mutation load and decrease in CI activity was observed in each of the three mutant cybrid lines, supporting the pathogenic role of the novel mutations. Structural studies on mutant cybrids showed impaired assembly or reduced stability of the holoenzyme complex. In our experience ND gene mutations are relatively common in CI-defective mitochondrial encephalopathy of both children and adults. Available as a free download COMMENT: An important paper that discusses rare variants. Back ----------------------------------------------------------------------------------------------------------------------- Ann Neurol. 2004 Nov;56(5):631-41. The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. Valentino ML, Barboni P, Ghelli A, Bucchi L, Rengo C, Achilli A, Torroni A, Lugaresi A, Lodi R, Barbiroli B, Dotti M, Federico A, Baruzzi A, Carelli V. Dipartimento di Scienze Neurologiche, Università di Bologna, Italy. A novel mitochondrial DNA (mtDNA) transition (3733G-->A) inducing the E143 K amino acid change at a very conserved site of the NADH dehydrogenase subunit 1 (ND1) was identified in a family with six maternally related individuals with Leber's hereditary optic neuropathy (LHON) and in an unrelated sporadic case, all negative for known mutations and presenting with the canonical phenotype. The transition was not detected in 1,082 control mtDNAs and was heteroplasmic in several individuals from both pedigrees. In addition, the mtDNAs of the two families were found to belong to different haplogroups (H and X), thus confirming that the 3733G-->A mutation occurred twice independently. Phosphorus magnetic resonance spectroscopy disclosed an in vivo brain and skeletal muscle energy metabolism deficit in the four examined patients. Muscle biopsy from two patients showed slight mitochondrial proliferation with abnormal mitochondria. Biochemical investigations in platelets showed partially insensitive complex I to rotenone inhibition. We conclude that the 3733G-->A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families. This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON. COMMENT: The minor variant G3733A in Italy. Back ----------------------------------------------------------------------------------------------------------------------- Graefes Arch Clin Exp Ophthalmol. 1999 Sep;237(9):745-52. Leber's hereditary optic neuropathy: clinical and molecular genetic findings in a patient with a new mutation in the ND6 gene. Besch D, Leo-Kottler B, Zrenner E, Wissinger B. Abteilung für Pathophysiologie des Sehens und Neuroophthalmologie, Universitäts-Augenklinik, Schleichstrasse 12, D-72076 Tübingen, Germany, dorothea.besch@uni-tuebingen.de BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited ocular disease associated with mutations in the mitochondrial DNA (mtDNA). We describe the clinical and molecular genetic findings in a LHON patient and his family with a new mtDNA mutation at np14568 in the ND6 gene. METHODS: Ophthalmological examination was performed in one affected male and two maternal relatives. Direct sequence analysis of the complete mtDNA protein coding region was initiated in the affected patient. Four unaffected maternal relatives also underwent molecular genetic evaluation. RESULTS: Clinical examination of the affected male showed typical features of LHON. In his unaffected mother slight peripapillary microangiopathy was found. Molecular analysis did not show any of the common LHON mutations. A nucleotide exchange was detected at position 14568 replacing a glycine by serine in the ND6 gene. This mutation was the only new mutation found within the entire protein and tRNA coding region of the patient's mitochondrial genome. This novel mutation was also present in four non-affected maternal family members, but absent in 60 other LHON lineages and 175 unrelated controls. CONCLUSION: The new mutation at nucleotide position 14568 lies in the close vicinity of other LHON-related mutations (np14459, np14484, np14498, np14596) within the evolutionarily most conserved region of the ND6 gene. Since no other mutation was detected throughout the mtDNA coding region and the new alteration was excluded in controls, our clinical and molecular genetic findings suggest that the novel point mutation at np14568 is responsible for LHON in this family. Available as a free download COMMENT: Discusses the rare variant C14568T in Germany. Back ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 1998 Jan;62(1):196-202. mtDNA mutations that cause optic neuropathy: how do we know? Howell N, Bogolin C, Jamieson R, Marenda DR, Mackey DA. Available as a free download COMMENT: Discusses the rare variant C14482G. Back ------------------------------------------------------------------------------------------------------------------------ PAPERS THAT ACCOMPANY mtDNA SEQUENCES ON GENBANK ================================================ ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 2006 Apr;78(4):564-74. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Carelli V, Achilli A, Valentino ML, Rengo C, Semino O, Pala M, Olivieri A, Mattiazzi M, Pallotti F, Carrara F, Zeviani M, Leuzzi V, Carducci C, Valle G, Simionati B, Mendieta L, Salomao S, Belfort R Jr, Sadun AA, Torroni A. Dipartimento di Scienze Neurologiche, Universita di Bologna, Bologna, Italy. The mitochondrial DNA (mtDNA) of 87 index cases with Leber hereditary optic neuropathy (LHON) sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, was evaluated in detail. Only seven pairs and three triplets of identical haplotypes were observed, attesting that the large majority of the LHON mutations were due to independent mutational events. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that two specific combinations of amino acid changes in the cytochrome b are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory-chain complexes I and III. The families with identical haplotypes were genealogically reinvestigated, which led to the reconnection into extended pedigrees of three pairs of families, including the Brazilian family with its Italian counterpart. The sequencing of entire mtDNA samples from the reconnected families confirmed the genealogical reconstruction but showed that the Brazilian family was heteroplasmic at two control-region positions. The survey of the two sites in 12 of the Brazilian subjects revealed triplasmy in most cases, but there was no evidence of the tetraplasmy that would be expected in the case of mtDNA recombination Available as a free download COMMENT: Accompanies GenBank sequences 'DQ341083-DQ341088' Back ------------------------------------------------------------------------------------------------------------------------ Neurology. 2008 Mar 4;70(10):762-70. Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. La Morgia C, Achilli A, Iommarini L, Barboni P, Pala M, Olivieri A, Zanna C, Vidoni S, Tonon C, Lodi R, Vetrugno R, Mostacci B, Liguori R, Carroccia R, Montagna P, Rugolo M, Torroni A, Carelli V. Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy. OBJECTIVE: To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON). METHODS: Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle ((31)P) and cerebral ((1)H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed. RESULTS: All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. (31)P-MRS was abnormal in five of six patients and (1)H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis. CONCLUSIONS: Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants. COMMENT: Accompanies GenBank sequences 'EF060363-EF060364' Back ----------------------------------------------------------------------------------------------------------------------- Mutat Res. 2008 Aug 25;643(1-2):48-53. Strikingly different penetrance of LHON in two Chinese families with primary mutation G11778A is independent of mtDNA haplogroup background and secondary mutation G13708A. Wang HW, Jia X, Ji Y, Kong QP, Zhang Q, Yao YG, Zhang YP. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences The penetrance of Leber's hereditary optic neuropathy (LHON) in families with primary mitochondrial DNA (mtDNA) mutations is very complex. Matrilineal and nuclear genetic background, as well as environmental factors, have been reported to be involved in different affected pedigrees. Here we describe two large Chinese families that show a striking difference in the penetrance of LHON, in which 53.3% and 15.0% of members were affected (P<0.02), respectively. Analysis of the complete mtDNA genome of the two families revealed the presence of the primary mutation G11778A and several other variants suggesting the same haplogroup status G2a. The family with higher penetrance contained a previously described secondary mutation G13708A, which presents a polymorphism in normal Chinese samples and does not affect in vivo mitochondrial oxidative metabolism as described in a previous study. Evolutionary analysis failed to indicate any putatively pathogenic mutation that cosegregated with G11778A in these two pedigrees. Our results suggest that the variable penetrance of LHON in the two Chinese families is independent of both their mtDNA haplotype background and a secondary mutation G13708A. As a result, it is likely that unknown nuclear gene involvement and/or other factors contribute to the strikingly different penetrance of LHON. COMMENT: Accompanies GenBank sequences 'EU545470-EU545472' Back ----------------------------------------------------------------------------------------------------------------------- Hum Genet. 2001 Jul;109(1):33-9. Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families. Brown MD, Zhadanov S, Allen JC, Hosseini S, Newman NJ, Atamonov VV, Mikhailovskaya IE, Sukernik RI, Wallace DC. Center for Molecular Medicine, Emory University School of Medicine, 420 B Dental Building, 1462 Clifton Road N.E., Atlanta, GA 30322, USA. Leber's hereditary optic neuropathy (LHON) is characterized by maternally transmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute polypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nucleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known as "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and biochemical analysis of five Russian families from the Novosibirsk region of Siberia manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete sequence analysis of proband mtDNA in the other two families has revealed novel complex I mutations at nps 3635A and 4640C, respectively. These mutations are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybrids demonstrated a respiration defect with complex-I-linked substrates, although the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russia is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression. COMMENT: Accompanies GenBank sequences 'EU807741-EU807742' Back ----------------------------------------------------------------------------------------------------------------------- Ann Hum Genet. 2005 Jan;69(Pt 1):67-89. Mitochondrial DNA diversity in indigenous populations of the southern extent of Siberia, and the origins of Native American haplogroups. Starikovskaya EB, Sukernik RI, Derbeneva OA, Volodko NV, Ruiz-Pesini E, Torroni A, Brown MD, Lott MT, Hosseini SH, Huoponen K, Wallace DC. Laboratory of Human Molecular Genetics, Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk 630090, Russia Federation. In search of the ancestors of Native American mitochondrial DNA (mtDNA) haplogroups, we analyzed the mtDNA of 531 individuals from nine indigenous populations in Siberia. All mtDNAs were subjected to high-resolution RFLP analysis, sequencing of the control-region hypervariable segment I (HVS-I), and surveyed for additional polymorphic markers in the coding region. Furthermore, the mtDNAs selected according to haplogroup/subhaplogroup status were completely sequenced. Phylogenetic analyses of the resulting data, combined with those from previously published Siberian arctic and sub-arctic populations, revealed that remnants of the ancient Siberian gene pool are still evident in Siberian populations, suggesting that the founding haplotypes of the Native American A-D branches originated in different parts of Siberia. Thus, lineage A complete sequences revealed in the Mansi of the Lower Ob and the Ket of the Lower Yenisei belong to A1, suggesting that A1 mtDNAs occasionally found in the remnants of hunting-gathering populations of northwestern and northern Siberia belonged to a common gene pool of the Siberian progenitors of Paleoindians. Moreover, lineage B1, which is the most closely related to the American B2, occurred in the Tubalar and Tuvan inhabiting the territory between the upper reaches of the Ob River in the west, to the Upper Yenisei region in the east. Finally, the sequence variants of haplogroups C and D, which are most similar to Native American C1 and D1, were detected in the Ulchi of the Lower Amur. Overall, our data suggest that the immediate ancestors of the Siberian/Beringian migrants who gave rise to ancient (pre-Clovis) Paleoindians have a common origin with aboriginal people of the area now designated the Altai-Sayan Upland, as well as the Lower Amur/Sea of Okhotsk region. COMMENT: Accompanies GenBank sequence 'EU828637' Back ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2008 Nov 7;376(1):221-4. Co-occurrence of A1555G and G11778A in a Chinese family with high penetrance of Leber's hereditary optic neuropathy. Zhang AM, Jia X, Yao YG, Zhang Q. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Jiaochang Donglu 32, Kunming, Yunnan 650223, China. Co-occurrence of double pathogenic mtDNA mutations with different claimed pathological roles in one mtDNA is infrequent. It is tentative to believe that each of these pathogenic mutations would have its own deleterious effect. Here we reported one three-generation Chinese family with a high penetrance of LHON (78.6%). Analysis of the complete mitochondrial genome in the proband revealed the presence of the LHON primary mutation G11778A in the NADH dehydrogenase 4 (ND4) gene and a deafness-associated mutation A1555G in the 12S rRNA gene. The other mtDNA variants in this family suggested a haplogroup status G2b. Although A1555G has long been confirmed to be a primary mutation for aminoglycoside-induced and non-syndromic hearing loss, none of the maternally related members in this family showed hearing impairment. It thus seems that the occurrence of A1555G in this family had no pathological manifestation. However, whether A1555G has a synergistic effect with G11778A and contribute to the high penetrance of LHON remained an open question. To our knowledge, this is the first report that identified the co-existence of a deafness mutation A1555G and a primary LHON mutation G11778A in one family. COMMENT: Accompanies GenBank sequence 'FJ015040' Back ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 2008 Dec;83(6):760-8. Mitochondrial DNA haplogroups M7b1'2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese families with the m.11778G-->a mutation. Ji Y, Zhang AM, Jia X, Zhang YP, Xiao X, Li S, Guo X, Bandelt HJ, Zhang Q, Yao YG. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Leber hereditary optic neuropathy (LHON) is the most extensively studied mitochondrial disease, with the majority of the cases being caused by one of three primary mitochondrial DNA (mtDNA) mutations. Incomplete disease penetrance and gender bias are two features of LHON and indicate involvement of additional genetic or environmental factors in the pathogenesis of the disorder. Haplogroups J, K, and H have been shown to influence the clinical expression of LHON in subjects harboring primary mutations in European families. However, whether mtDNA haplogroups would affect the penetrance of LHON in East Asian families has not been evaluated yet. By studying the penetrance of LHON in 1859 individuals from 182 Chinese families (including one from Cambodia) with the m.11778G-->A mutation, we found that haplogroup M7b1'2 significantly increases the risk of visual loss, whereas M8a has a protective effect. Analyses of the complete mtDNA sequences from LHON families with m.11778G-->A narrow the association of disease expression to m.12811T-->C (Y159H) in the NADH dehydrogenase 5 gene (MT-ND5) in haplogroup M7b1'2 and suggest that the specific combination of amino acid changes (A20T-T53I) in the ATP synthase 6 protein (MT-ATP6) caused by m.8584G-->A and m.8684C-->T might account for the beneficial background effect of M8a. Protein secondary-structure prediction for the MT-ATP6 with the two M8a-specific amino acid changes further supported our inferences. These findings will assist in further understanding the pathogenesis of LHON and guide future genetic counseling in East Asian patients with m.11778G-->A. COMMENT: Accompanies GenBank sequences 'FJ198214-FJ198228' Back ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2009 Sep 4;386(4):693-6. Novel A14841G mutation is associated with high penetrance of LHON/C4171A family. Yang J, Zhu Y, Chen L, Zhang H, Tong Y, Huang D, Zhang Z, Chen S, Han X, Ma X. Biomedical Engineering Center, Fujian Medical University, Fuzhou, Fujian, China. We report the clinical and genetic characterization of a Chinese LHON family carrying an ND1/C4171A mutation. This family has high penetrance of visual impairment and extremely low frequency of vision recovery, which is in marked contrast to previously reported results for Korean LHON families with the same mutation. Sequence analysis of the complete mtDNA in the partially defined East Asian haplogroup N9a1 revealed the presence of 29 other variants. A novel heteroplasmic A14841G mutation, one of the variants with a serine substituted for a highly conserved asparagine at amino acid 32 of Cytochrome b (Cytb), may play a synergistic role with the C4171A mutation, leading to significantly different clinical manifestations of LHON among these families. The study further confirmed that C4171A was a rare primary LHON mutation, and the mtDNA background could also contribute to the clinical manifestation of the LHON/C4171A mutation. COMMENT: Accompanies GenBank sequence 'FJ944094' Back ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2009 Aug 14;386(1):50-4. Confirmation of the mitochondrial ND1 gene mutation G3635A as a primary LHON mutation. Yang J, Zhu Y, Tong Y, Chen L, Liu L, Zhang Z, Wang X, Huang D, Qiu W, Zhuang S, Ma X. Biomedical Engineering Center, Fujian Medical University, Fuzhou, Fujian, China. We report the clinical and genetic characterization of two Chinese LHON families who do not carry the primary LHON-mutations. Mitochondrial genome sequence analysis revealed the presence of a homoplasmic ND1 G3635A mutation in both families. In Family LHON-001, 31 other variants belonging to the East Asian haplogroup R11a were identified and in Family LHON-019, 37 other variants belonging to the East Asian haplogroup D4g were determined. The ND1 G3635A mutation changes the conversed serine110 residue to asparagine. This mutation has been previously described in a single Russian LHON family and has been suggested to contribute to increased LHON expressivity. In addition, a mutation in cytochrome c oxidase subunit II at C7868T (COII/L95F) may act in synergy with G3635A, increasing LHON expressivity in Family LHON-001, which had a higher level of LHON penetrance than Family LHON-019. In summary, the G3635A mutation is confirmed as a rare primary pathogenic mutation for LHON. COMMENT: Accompanies GenBank sequences 'FJ969382-FJ969383' Back ----------------------------------------------------------------------------------------------------------------------- Mitochondrion. 2009 Jul;9(4):273-8. The novel G10680A mutation is associated with complete penetrance of the LHON/T14484C family. Yang J, Zhu Y, Tong Y, Zhang Z, Chen L, Chen S, Cao Z, Liu C, Xu J, Ma X. Biomedical Engineering Center, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian 350004, China. We report the clinical and genetic characterization of a Chinese Leber's hereditary optic neuropathy (LHON) family with complete penetrance and high percentage of recovery. Sequence analysis of the complete mitochondrial DNA revealed the presence of heteroplasmic ND6/T14484C mutation and 27 other variants, belonging to the East-Asian haplogroup B4b'd. Of those variants, a novel homoplasmic G10680A mutation substituted a threonine for a highly conserved alanine at ND4L amino acid 71, which was not found in unaffected family members and 100 normal controls. It indicated that G10680A may play a synergistic role with the primary mutation T14484C, leading to the complete penetrance of LHON in the presenting family. In addition, the other modifier factors including nuclear background, mitochondrial haplotypes and other environmental factors should account for the phenotypic variability of visual impairment in this family. COMMENT: Accompanies GenBank sequence 'FJ986465' Back ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2009 Aug 21;386(2):392-5. Mitochondrial DNA mutation m.3635G>A may be associated with Leber hereditary optic neuropathy in Chinese. Zhang AM, Zou Y, Guo X, Jia X, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. Leber hereditary optic neuropathy (LHON) was the first disease to be linked to the presence of a mitochondrial DNA (mtDNA) mutation. Nowadays over 95% of LHON cases are known to be caused by one of three primary mutations (m.11778G>A, m.14484T>C, and m.3460G>A). Reports for other (rare) primary mutations in LHON patients are not infrequent. Among those is the mutation m.3635G>A in the MT-ND1 gene which was reported to be pathogenic in a Russian LHON family. In this study, we report on a Chinese family with clinical features of LHON but without any of the three well-known primary mutations. Analysis of the complete mitochondrial genome in the proband revealed the presence of m.3635G>A and m.6228C>T, along with a full array of other variants that suggest the haplogroup M7b1. Evolutionary analysis indicates that site 3635, but not 6228, is highly conserved in vertebrates. Protein secondary-structure modeling for the MT-ND1 protein harboring amino acid change S110N indicates that mutant m.3635G>A decreases the protein hydrophobicity. Our current observations provide further support for a pathogenic role of m.3635G>A in patients with LHON. COMMENT: Accompanies GenBank sequence 'GQ202273' Back ----------------------------------------------------------------------------------------------------------------------- Neurogenetics. 2010 Jul;11(3):349-56. Molecular characterization of six Chinese families with m.3460G>A and Leber hereditary optic neuropathy. Yu D, Jia X, Zhang AM, Guo X, Zhang YP, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. The primary mutation m.3460G>A occurs with a very low frequency (approximately 1%) in Chinese patients with Leber hereditary optic neuropathy (LHON). Up to now, there is no comprehensive study of Chinese patients harboring this mutation. We characterized six unrelated probands with m.3460G>A in this study, which were identified from 1,626 patients with LHON or suspected with LHON. The overall penetrance of LHON (25.6% [10/39]) in four pedigrees with m.3460G>A was substantially lower than those families with m.11778G>A (33.3% [619/1859]) as reported in our previous study. Intriguingly, family Le688 with a heteroplasmic m.3460G>A presented a lower penetrance (12.5%) than the other three families with a homoplasmic mutation. There is an elevated gender bias (affected male to affected female = 4:1) in the four families with m.3460G>A compared to those LHON families with m.11778G>A (2.4:1). Complete mtDNA sequencing indicated that the six matrilines belonged to haplogroups B4d1, F2, A5b, M12a, D4b2b, and D4b2, respectively. We did not identify any potential secondary mutation(s) that will affect or be associated with the penetrance of LHON in the six probands by using an evolutionary analysis and protein secondary-structure prediction. Taken together, our results suggested that the m.3460G>A mutation occurred multiple times in Chinese LHON patients. The heteroplasmic status of mutation m.3460G>A might influence the penetrance of LHON in family Le688. COMMENT: Accompanies GenBank sequences 'GQ999958-GQ999963' Back ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2010 Aug 20;399(2):179-85. The MT-ND1 and MT-ND5 genes are mutational hotspots for Chinese families with clinical features of LHON but lacking the three primary mutations. Zou Y, Jia X, Zhang AM, Wang WZ, Li S, Guo X, Kong QP, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. LHON is one of the most common and primary causes of acute blindness in young male adults. Over 95% of LHON cases are caused by one of the three primary mutations (m.11778G>A, m.14484T>C, and m.3460G>A). In contrast to these genetically diagnosed LHON patients, there are many patients with clinical features of LHON but without the three primary mutations, and these patients have been insufficiently analyzed. We reported 10 suspected Chinese LHON families without the three primary mutations. The overall penetrance (53.4%) in these families is significantly higher than in those families with m.11778G>A (33.3%) or m.3460G>A (25.6%). Complete mtDNA genome sequencing of the 10 families showed that they belonged to different haplogroups and all identified variants (excluding m.12332A>G in mt-tRNA(Leu)) were previously reported. Eight of 12 private non-synonymous variants in the probands are located in the MT-ND1 and MT-ND5 genes, which is substantially higher than that of individuals from general Chinese populations. Comparison of the private variants in the 10 families and in 10 randomly selected mtDNAs from general Chinese populations using resampling simulation strategy further confirmed this pattern. Our results suggest that the MT-ND1 and MT-ND5 genes are mutational hotspots for Chinese families with suspected LHON lacking the common primary mutations. Variants m.3736G>A (p.V144I) in family Le1235 and m.10680G>A (p.A71T) in Le1107 can be the pathogenic mutations for LHON. COMMENT: Accompanies GenBank sequences 'GU377081-GU377090' Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2010 Oct 18;5(10):e13426. Mitochondrial DNA sequence variation and haplogroup distribution in Chinese patients with LHON and m.14484T>C. Yu D, Jia X, Zhang AM, Li S, Zou Y, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming BACKGROUND: Leber hereditary optic neuropathy (LHON, MIM 535000) is one of the most common mitochondrial genetic disorders caused by three primary mtDNA mutations (m.3460G>A, m.11778G>A and m. 14484T>C). The clinical expression of LHON is affected by many additional factors, e.g. mtDNA background, nuclear genes, and environmental factors. Hitherto, there is no comprehensive study of Chinese LHON patients with m.14484T>C. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed the mtDNA sequence variations and haplogroup distribution pattern of the largest number of Chinese LHON patients with m.14484T>C to date. We first determined the complete mtDNA sequences in eleven LHON probands with m.14484T>C, to discern the potentially pathogenic mutations that co-segregate with m.14484T>C. We then dissected the matrilineal structure of 52 patients with m.14484T>C (including 14 from unrelated families and 38 sporadic cases) and compared it with the reported Han Chinese from general populations. Complete mtDNA sequencing showed that the eleven matrilines belonged to nine haplogroups including Y2, C4a, M8a, M10a1a, G1a1, G2a1, G2b2, D5a2a1, and D5c. We did not identify putatively pathogenic mutation that was co-segregated with m.14484T>C in these lineages based on the evolutionary analysis. Compared with the reported Han Chinese from general populations, the LHON patients with m.14484T>C had significantly higher frequency of haplogroups C, G, M10, and Y, but a lower frequency of haplogroup F. Intriguingly, we also observed a lower prevalence of F lineages in LHON subjects with m.11778G>A in our previous study, suggesting that this haplogroup may enact similar role during the onset of LHON in the presence of m.14484T>C or m.11778G>A. CONCLUSIONS/SIGNIFICANCE: Our current study provided a comprehensive profile regarding the mtDNA variation and background of Chinese patients with LHON and m.14484T>C. Matrilineal background might affect the expression of LHON in Chinese patients with m.14484T>C. COMMENT: Accompanies GenBank sequences 'HM460791-HM460797' Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2011;6(10) Is mitochondrial tRNA(phe) variant m.593T>C a synergistically pathogenic mutation in Chinese LHON families with m.11778G>A? Zhang AM, Bandelt HJ, Jia X, Zhang W, Li S, Yu D, Wang D, Zhuang XY, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. Mitochondrial transfer RNA (mt-tRNA) mutations have been reported to be associated with a variety of diseases. In a previous paper that studied the mtDNA background effect on clinical expression of Leber's hereditary optic neuropathy (LHON) in 182 Chinese families with m.11778G>A, we found a strikingly high frequency (7/182) of m.593T>C in the mitochondrially encoded tRNA phenylalanine (MT-TF) gene in unrelated LHON patients. To determine the potential role of m.593T>C in LHON, we compared the frequency of this variant in 479 LHON patients with m.11778G>A, 843 patients with clinical features of LHON but without the three known primary mutations, and 2374 Han Chinese from the general populations. The frequency of m.593T>C was higher in LHON patients (14/479) than in suspected LHON subjects (12/843) or in general controls (49/2374), but the difference was not statistically significant. The overall penetrance of LHON in families with both m.11778G>A and m.593T>C (44.6%) was also substantially higher than that of families with only m.11778G>A (32.9%) (P?=?0.083). Secondary structure prediction of the MT-TF gene with the wild type or m.593T>C showed that this nucleotide change decreases the free energy. Electrophoretic mobility of the MT-TF genes with the wild type or m.593T>C transcribed in vitro further confirmed the change of secondary structure in the presence of this variant. Although our results could suggest a modest synergistic effect of variant m.593T>C on the LHON causing mutation m.11778G>A, the lack of statistical significance probably due to the relatively small sample size analyzed, makes necessary more studies to confirm this effect. Available as a free download COMMENT: Accompanies GenBank sequences 'JF896797-JF896801' Back ----------------------------------------------------------------------------------------------------------------------- Biochim Biophys Acta. 2012 Oct;1822(10):1535-43. Presence of mutation m.14484T>C in a Chinese family with maternally inherited essential hypertension but no expression of LHON. Guo H, Zhuang XY, Zhang AM, Zhang W, Yuan Y, Guo L, Yu D, Liu J, Yang DK, Yao YG. Chinese Academy of Science, Kunming Institute of Zoology, Kunming, China. Essential hypertension (EH, MIM 145500) is the most common cardiovascular disease and affects one-quarter of the world's adult population. Families with EH in a mode of maternal transmission have been occasionally observed in clinical settings and suggested an involvement of mitochondrial DNA (mtDNA) mutation. We aimed to characterize the role of mtDNA mutation in EH. We reported a large Han Chinese family with a maternally inherited EH and an extraordinarily high percentage of sudden death mainly in affected females. Analysis of the entire mtDNA genome of the proband identified a homoplasmic primary mutation m.14484T>C for Leber's hereditary optic neuropathy (LHON), along with several variants indicating haplogroup F1 status. Intriguingly, no maternal member in this family had LHON though they all harbored m.14484T>C. The arterial stiffness of the members carrying mutation m.14484T>C was significantly increased than that of non-maternal members without this mutation. No environmental factor (including age, sex, smoking, diabetes, hyperlipidemia) was correlated with the decreased aortic elastic properties observed in affected members. Mitochondrial respiration rate and membrane potential (??(m)) were significantly reduced in lymphoblastoid cell lines established from affected members carrying m.14484T>C when compared to control cell lines (P<0.05). There was an elevation of reactive oxygen species and a compensatory increase of mitochondrial mass in mutant cell lines. Our results suggest that m.14484T>C causes EH under certain circumstance. This study provides a paradigm for diverse phenotypes of the primary LHON mutation and suggests for the necessity of routine cardiac evaluation in patients with the primary LHON mutation. COMMENT: Accompanies GenBank sequences 'JN133516-JN133517' Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2011;6(11):e27750. Mitochondrial DNA haplogroup background affects LHON, but not suspected LHON, in Chinese patients. Zhang AM, Jia X, Bi R, Salas A, Li S, Xiao X, Wang P, Guo X, Kong QP, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, China. Recent studies have shown that mtDNA background could affect the clinical expression of Leber hereditary optic neuropathy (LHON). We analyzed the mitochondrial DNA (mtDNA) variation of 304 Chinese patients with m.11778G>A (sample #1) and of 843 suspected LHON patients who lack the three primary mutations (sample #2) to discern mtDNA haplogroup effect on disease onset. Haplogroup frequencies in the patient group was compared to frequencies in the general Han Chinese population (n?=?1,689; sample #3). The overall matrilineal composition of the suspected LHON population resembles that of the general Han Chinese population, suggesting no association with mtDNA haplogroup. In contrast, analysis of these LHON patients confirms mtDNA haplogroup effect on LHON. Specifically, the LHON sample significantly differs from the general Han Chinese and suspected LHON populations by harboring an extremely lower frequency of haplogroup R9, in particular of its main sub-haplogroup F (#1 vs. #3, P-value?=?1.46×10(-17), OR?=?0.051, 95% CI: 0.016-0.162; #1 vs. #2, P-value?=?4.44×10(-17), OR?=?0.049, 95% CI: 0.015-0.154; in both cases, adjusted P-value <10(-5)) and higher frequencies of M7b (#1 vs. #3, adjusted P-value?=?0.001 and #1 vs. #2, adjusted P-value?=?0.004). Our result shows that mtDNA background affects LHON in Chinese patients with m.11778G>A but not suspected LHON. Haplogroup F has a protective effect against LHON, while M7b is a risk factor. Available as a free download COMMENT: Accompanies GenBank sequences 'JN645818-JN645821' Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2012;7(8):e42242. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy. Achilli A, Iommarini L, Olivieri A, Pala M, Hooshiar Kashani B, Reynier P, La Morgia C, Valentino ML, Liguori R, Pizza F, Barboni P, Sadun F, De Negri AM, Zeviani M, Dollfus H, Moulignier A, Ducos G, Orssaud C, Bonneau D, Procaccio V, Leo-Kottler B, Fauser S, Wissinger B, Amati-Bonneau P, Torroni A, Carelli V. Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia, Italy. BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression. Available as a free download COMMENT: Accompanies GenBank sequences 'JN415470-JN415484' Back ----------------------------------------------------------------------------------------------------------------------- J Transl Med. 2012 Mar 9;10:43. Mitochondrial DNA mutation m.10680G > A is associated with Leber hereditary optic neuropathy in Chinese patients. Zhang AM, Jia X, Guo X, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C). Rare pathogenic mutations have been occasionally reported in LHON patients. METHODS: We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR). Patients with m.10680G > A were further determined entire mtDNA genome sequence. RESULTS: The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330) were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients) identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784) was significantly higher than that of the general populations (0/9277) (P = 0.0005). CONCLUSION: Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis. Available as a free download COMMENT: Accompanies GenBank sequences 'JN866818-JN866825' Back ----------------------------------------------------------------------------------------------------------------------- Biochim Biophys Acta. 2012 Dec 13. pii: S0925-4439(12)00287-6. Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions. Caporali L, Ghelli AM, Iommarini L, Maresca A, Valentino ML, La Morgia C, Liguori R, Zanna C, Barboni P, De Nardo V, Martinuzzi A, Rizzo G, Tonon C, Lodi R, Calvaruso MA, Cappelletti M, Porcelli AM, Achilli A, Pala M, Torroni A, Carelli V. IRCCS Istituto delle Scienze Neurologiche, Via Ugo Foscolo 7, 40123 Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy. Complex I (CI) deficiency is a frequent cause of mitochondrial disorders and, in most cases, is due to mutations in CI subunit genes encoded by mitochondrial DNA (mtDNA). In this study, we establish the pathogenic role of the heteroplasmic mtDNA m.3890G>A/MT-ND1 (p.R195Q) mutation, which affects an extremely conserved amino acid position in ND1 subunit of CI. This mutation was found in a young-adult male with optic atrophy resembling Leber's hereditary optic neuropathy (LHON) and bilateral brainstem lesions. The only previously reported case with this mutation was a girl with fatal infantile Leigh syndrome with bilateral brainstem lesions. Transfer of the mutant mtDNA in the cybrid cell system resulted in a marked reduction of CI activity and CI-dependent ATP synthesis in the presence of a normally assembled enzyme. These findings establish the pathogenicity of the m.3890G>A/MT-ND1 mutation and remark the link between CI mutations affecting the mtDNA-encoded ND subunits and LHON-like optic atrophy, which may be complicated by bilateral and symmetric lesions affecting the central nervous system. Peculiar to this mutation is the distribution of the brainstem lesions, with sparing of the striatum in both patients. COMMENT: Accompanies GenBank sequence 'JQ408982' Back ----------------------------------------------------------------------------------------------------------------------- Mol Vis. 2012;18:3087-94. Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy. Bi R, Zhang AM, Jia X, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China ; Graduate University of the Chinese Academy of Sciences, Beijing, China. PURPOSE: The majority of Leber hereditary optic neuropathy (LHON) cases are caused by one of three mitochondrial DNA (mtDNA) primary mutations (m.3460G>A, m.11778G>A, and m.14484T>C). In recent studies, we and others have shown that mutation m.3635G>A is a primary LHON mutation, particularly in Chinese. The purpose of this study was to perform a thorough analysis for the complete mtDNA genome sequence variation in Chinese patients with m.3635G>A and to identify potentially functional variants cosegregated with m.3635G>A. METHODS: The complete mtDNA genomes of five Chinese patients with LHON carrying m.3635G>A were determined. A phylogenetic tree was constructed to distinguish the private and ancestral mtDNA variants in each lineage. Previously unreported variants in each mtDNA were defined with a web-based and database search. mtDNA variants that changed the structure of the membrane-spanning region of the protein were also evaluated, together with evolutionary conservation analysis, to predict their potential pathogenicity. RESULTS: The five patients with LHON sequenced in this study belonged to haplogroups M7b4 (Le131), F1a (Le329 and Le337), B5b (Le569), and M7b6 (Le834), which suggested multiple origins of m.3635G>A. Private variants m.12811T>C, m.14063T>C, m.15237T>C, and m.9071C>T in these patients were predicted to change the structure of the membrane-spanning region of the respective proteins. CONCLUSIONS: Mutation m.3635G>A had multiple origins in Chinese patients with LHON. We also identified several potentially functional variants cosegregated with m.3635G>A. COMMENT: Accompanies GenBank sequences 'JX024564-JX024568' Back ----------------------------------------------------------------------------------------------------------------------- PAPERS DISCUSSING FACTORS THAT MIGHT CAUSE LHON DISEASE ============================================================ ----------------------------------------------------------------------------------------------------------------------- Brain. 2009 Sep;132(Pt 9):2317-26. Gene-environment interactions in Leber hereditary optic neuropathy. Kirkman MA, Yu-Wai-Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, Chinnery PF. Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK. Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake. Available as a free download COMMENT: Smoking predisposes to symptoms. Back ----------------------------------------------------------------------------------------------------------------------- Rinsho Shinkeigaku. 2011 Oct;51(10):781-3. Leber's hereditary optic neuropathy after head trauma: a case report Hayashi S, Okamoto K. Department of Neurology, Gunma University Graduate School of Medicine. A previously healthy 34-year-old man sustained multiple skull fractures in a traffic accident. Radiological findings and visual field examination did not detect any abnormality. Shortly after the accident, he noticed blurred vision in both eyes. Six months after the accident, he gradually developed disturbance of visual acuity in the right eye. His best corrected visual acuity (BCVA) was 0.8 OD and 1.2 OS and brain MRI did not show any abnormality, while Humphrey visual field analysis demonstrated right homonymous hemianopsia. Two months after the initial presentation, his BCVA showed 0.1 OD and 0.08 OS. Visual field examination suggested that both right homonymous hemianopsia and left blind spot had become enlarged. Mitochondrial DNA analysis demonstrated G11,778A mutation and a diagnosis of Leber's hereditary optic neuropathy (LHON) was made. A few reports have documented mild acute insult to the head or blunt optic trauma as triggers of optic neuropathy in subjects with LHON. Although, the precise mechanism of LHON following trauma remains unknown, it appears that an acute insult may be sufficient to precipitate neuropathy in the optic nerve already compromised by mitochondrial dysfunction. Asymptomatic carriers should be advised to avoid possible precipitating factors such as head trauma. COMMENT: Interesting, but is it cause and effect ? Back ----------------------------------------------------------------------------------------------------------------------- J Fr Ophtalmol. 2005 Dec;28(10):1095-100. Onset of Leber's hereditary optic neuropathy in association with borreliosis. Macarez R, Bazin S, Lagauche D, Soullié B, Giordano P, May F, Guigon B. Service d'Ophtalmologie, HIA Clermont Tonnerre, BP 41, 29240 Brest-Armées. INTRODUCTION: The diagnosis of Lyme disease in the presence of an acute optical neuritis always raises a difficult diagnostic problem. We present a case of Lyme-associated Leber's hereditary optic neuropathy (LHON). OBSERVATION: A 17-year-old Eurasian young man presented with left-eye visual impairment for 1 month. This loss of vision acuity in the left eye is related to an optic neuropathy. Mitochondrial DNA testing showed a G to A substitution at position 11778 confirming a diagnosis of LHON. The family history disclosed a case of LHON in a maternal cousin. The mother's family is Asian. Besides, serum examination of anti-Borrelia antibodies was performed and was positive against Borrelia burgdorferi garinii. The patient history indicated that he had been possessing a dog and was living in an endemic area of Lyme disease. But he did not recall receiving a tick bite nor having any erythema chronicum migrans. Initial examination showed bilateral green-red axis colour vision defects which made us fear bilateralisation of the optic neuropathy, which occurred 2 months later (that is 3 months after the onset of symptoms on the left eye). An antibiotic treatment by ceftriaxone was administered for 4 weeks all in all; and a long term ubidecarenone therapy was established. At present, after a 1-year follow up, the eyes' conditions remains unchanged. CONCLUSION: To our knowledge, this would be the first case reporting such an association, in which we can discuss the fortuitous character or the role of the infectious factor in the developing of the mitochondrial pathology. This observation also raises the problem of the positive diagnosis of Lyme disease when tick bite and erythema are absent or underestimated. COMMENT: A co-incidence, or cause and effect ? Back ----------------------------------------------------------------------------------------------------------------------- J Clin Psychiatry. 2012 Sep;73(9):e1158-9. Leber's hereditary optic neuropathy associated with schizophrenia. Boyer L, Guedj E, Dassa D, Lancon C. EA 3279-Self-Perceived Health Assessment Research Unit, School of Medicine, La Timone University, 13005 Marseille, France. COMMENT: G3460A LHON disease after treatment with Rispiridone. Back ----------------------------------------------------------------------------------------------------------------------- Eur Neurol. 2005;53(1):32-4. Leber hereditary optic neuropathy in 2 of 4 siblings with 11778 mtDNA mutation: clinical variability or effect of toxic environmental exposure? Rufa A, Dotti MT, Cardaioli E, Da Pozzo P, Federico A. Department of Neurological and Behavioral Sciences, Medical School, University of Siena, Siena, Italy. Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber's hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity. COMMENT: LHON and chemical exposure. Back ----------------------------------------------------------------------------------------------------------------------- Environ Health Perspect. 2007 Jan;115(1):113-5. Grand rounds: could occupational exposure to n-hexane and other solvents precipitate visual failure in leber hereditary optic neuropathy? Carelli V, Franceschini F, Venturi S, Barboni P, Savini G, Barbieri G, Pirro E, La Morgia C, Valentino ML, Zanardi F, Violante FS, Mattioli S. Dipartimento di Scienze Neurologiche, Alma Mater Studiorum-University of Bologna, Bologna, Italy. CONTEXT: Leber hereditary optic neuropathy (LHON) is a maternally inherited loss of central vision related to pathogenic mutations in the mitochondrial genome, which are a necessary but not sufficient condition to develop the disease. Investigation of precipitating environmental/occupational (and additional genetic) factors could be relevant for prevention. CASE PRESENTATION: After a 6-month period of occupational exposure to n-hexane and other organic solvents, a 27-year-old man (a moderate smoker) developed an optic neuropathy. The patient had a full ophthalmologic and neurologic investigation, including standardized cycloergometer test for serum lactic acid levels and a skeletal muscle biopsy. His exposure history was also detailed, and he underwent genetic testing for LHON mitochondrial DNA mutations. The patient suffered a sequential optic neuropathy with the hallmarks of LHON and tested positive for the homoplasmic 11778G--> A/ND4 mutation. Routine laboratory monitoring revealed increased concentrations of urinary 2.5 hexandione (n-hexane metabolite) and hippuric acid (toluene metabolite) in the period immediately preceding the visual loss. DISCUSSION: In a subject carrying an LHON mutation, the strict temporal sequence of prolonged appreciable occupational exposure followed by sudden onset of visual loss must raise a suspicion of causality (with a possible further interaction with tobacco smoke). RELEVANCE: In this article, we add to the candidate occupational/environmental triggers of LHON and highlight the need for appropriate case-control (and laboratory) studies to validate the causal effect of mixed toxic exposures. Available as a free download COMMENT: LHON precipitated by chemicals ? Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2009 Nov 19;4(11):e7922. doi: 10.1371/journal.pone.0007922. The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity. Ghelli A, Porcelli AM, Zanna C, Vidoni S, Mattioli S, Barbieri A, Iommarini L, Pala M, Achilli A, Torroni A, Rugolo M, Carelli V. Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna, Italy. annamaria.ghelli@unibo.it Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD) on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts) carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad implications for other neurodegenerative disorders such as Parkinson's disease. Available as a free download COMMENT: The effects of n-Hexane. Back ----------------------------------------------------------------------------------------------------------------------- Clin Experiment Ophthalmol. 2010 May;38(4):363-6. Antituberculosis medication as a possible epigenetic factor of Leber's hereditary optic neuropathy. Seo JH, Hwang JM, Park SS. Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea. PURPOSE: To investigate if antituberculosis medication including ethambutol could be a possible epigenetic factor in visual loss in Leber's hereditary optic neuropathy (LHON). METHODS: The authors reviewed the medical records of 46 patients registered at Bundang Seoul National University Hospital from 2002 to 2006, who developed the typical clinical neuro-ophthalmologic features of LHON and possessed a mtDNA mutation at nucleotide 11778, 14484, 3460 or 4171. RESULTS: Three of the 46 patients developed visual loss while taking antituberculosis medication. These three patients had the mtDNA 11778 mutation with a mean age of 32.7 years at the onset of visual loss, whereas the mean age of other 43 patients was 21.2 years. One of these three patients was female. CONCLUSION: Antituberculosis medication may be an epigenetic factor of LHON in patients with a primary LHON mutation. This risk should be recognized by physicians and LHON carriers. COMMENT: Does anti-tuberculosis medication precipitate LHON symptoms ? Back ----------------------------------------------------------------------------------------------------------------------- Graefes Arch Clin Exp Ophthalmol. 2006 Oct;244(10):1357-9. Leber's hereditary optic neuropathy and vitamin B12 deficiency. Pott JW, Wong KH. Department of Ophthalmology, University Medical Centre Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. j.w.r.pott@ohk.umcg.nl BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA (mtDNA). It is also believed that several epigenetic factors have an influence on the development of LHON. METHODS: A case series was observed. RESULTS: Three patients who developed bilateral optic neuropathy are presented. All patients had a primary LHON mutation in their mtDNA, but also a subnormal vitamin B12 serum level at the time of presentation. CONCLUSIONS: The clinical picture of optic neuropathy associated with vitamin B12 deficiency shows similarity to that of LHON. Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded. Available as as free download COMMENT: Does B12 deficiency precipitate symptoms ? Back ----------------------------------------------------------------------------------------------------------------------- Nihon Ganka Gakkai Zasshi. 2007 Nov;111(11):905-10. A case of Leber's hereditary optic neuropathy in a female patient with the recrudescence of hyperthyroidism. Kobayashi Y, Endo Y, Ito N, Iijima Y, Mizuki N. Department of Ophthalmology, Kanagawa Children's Medical Center, Minami-ku, Yokohama 232-8555, Japan. BACKGROUND: Thyroid hormone increases oxygen consumption and regulates mitochondrial biogenesis. On the other hand, in Leber's hereditary optic neuropathy(LHON), retinal ganglion cells are exposed to the oxidative stress generated during the process of adenosine 5'-triphosphate (ATP) synthesis, eventually leading to a loss of vision. Although there is a possibility that the thyroid hormone may have a role in the development or the course of LHON, no case has been reported indicating a relation between them. We report a female case with LHON who also presented exacerbation of hyperthyroidism during the course of the disease. CASE: The patient was a thirty-nine-year-old woman who complained of bilateral loss of vision. Her corrected visual acuity was 0.2 in the right eye, and 0.1 in the left. Fundus examination showed characteristic findings of LHON in both eyes. The blood free thyroxin(FT4) level at that time was abnormally high. The diagnosis of LHON was confirmed by the presence of mitochondrial DNA mutation at the nucleotide position 11778. Her visual acuity improved after one month of FT4 normalization. A year later, her corrected visual acuity recovered to 0.9 in the right eye and 1.0 in the left. COMMENT LHON and Hyperthryroidism. Back ------------------------------------------------------------------------------------------------------------------------ PAPERS DISCUSSING THE CUBAN EPIDEMIC OF OPTIC NEUROPATHY ======================================================== ----------------------------------------------------------------------------------------------------------------------- N Engl J Med. 1995 Nov 2;333(18):1176-82. Epidemic optic neuropathy in Cuba--clinical characterization and risk factors. The Cuba Neuropathy Field Investigation Team. BACKGROUND: From 1991 to 1993, epidemic optic and peripheral neuropathy affected more than 50,000 people in Cuba. The number of new cases decreased after the initiation of vitamin supplementation in the population. In September 1993, Cuban and U.S. investigators conducted a study to characterize and identify risk factors for the optic form of the syndrome. METHODS: We conducted ophthalmologic and neurologic examinations, assessed exposure to potential toxins, administered a semiquantitative food-frequency questionnaire, and assessed serum measures of nutritional status in 123 patients with severe optic neuropathy, matched for sex and age to randomly chosen normal subjects. RESULTS: In the case patients, prominent clinical features were subacute loss of visual acuity with field defects, diminished color vision, optic-nerve pallor, and decreased sensitivity to vibration and temperature in the legs. Tobacco use, particularly cigar smoking, was associated with an increased risk of optic neuropathy. The risk was reduced among subjects with higher dietary intakes of methionine, vitamin B12, riboflavin, and niacin and higher serum concentrations of antioxidant carotenoids. The risk was also reduced among subjects who raised chickens at home or had relatives living overseas--factors that may be indirect measures of increased food availability. CONCLUSIONS: The epidemic of optic and peripheral neuropathy in Cuba between 1991 and 1993 appears to be linked to reduced nutrient intake caused by the country's deteriorating economic situation and the high prevalence of tobacco use. Available as a free download COMMENT: Another paper about the Cuban epidemic. Back ------------------------------------------------------------------------------------------------------------------------- J Neuroophthalmol. 1994 Sep;14(3):130-4. Cuban epidemic optic neuropathy. Mitochondrial DNA analysis. Johns DR, Sadun AA. Department of Neurology, Harvard Medical School, Beth Israel Hospital, Massachusetts Eye and Ear Infirmary, Boston 02115. OBJECTIVE: To search for mitochondrial DNA (mtDNA) mutations previously associated with Leber's hereditary optic neuropathy (LHON) in patients with an optic neuropathy that appeared in epidemic form in Cuba. METHODS: Twelve Cuban patients underwent a comprehensive neuro-ophthalmologic examination and were found to have a characteristic optic neuropathy, Cuban epidemic optic neuropathy (CEON). At the same time, one patient was diagnosed with typical LHON that occurred during the epidemic Blood samples were taken from these patients as well as from 3 controls with normal neuro-ophthalmologic examinations. These samples were blindly analyzed for 9 LHON-associated mtDNA mutations by molecular genetic methods. RESULTS: CEON bore clinical and epidemiological similarity to LHON, however, family histories, systemic symptoms (especially weight loss and polyuria), and symptoms of peripheral neuropathy permitted a clinical distinction. None of the 12 patients with CEON or 3 controls had any of the LHON-associated mtDNA mutations. Only the patient with clinical LHON, who did not meet the case definition for CEON, harbored the 11778 mtDNA mutation. CONCLUSIONS: Known mtDNA mutations are not found frequently in CEON patients but they may contribute to some cases of Cuban optic neuropathy. CEON may represent an acquired variety of mitochondrial dysfunction induced by nutritional deficiencies, toxins, or both. Alternatively, CEON patients may also harbor as yet undiscovered mtDNA mutations that contribute to their genetic susceptibility. COMMENT: Another paper about the Cuban epidemic. Back ------------------------------------------------------------------------------------------------------------------------ MEDICC Rev. 2011 Jan;13(1):10-5. In the eye of the Cuban epidemic neuropathy storm: Rosaralis Santiesteban MD PhD, Neurology and Neurosurgery Institute. Interview by Christina Mills. When Cuba was hit by a neuropathy epidemic two decades ago, Dr Rosaralis Santiesteban was one of the Cuban health professionals who played a key role in its management, as reflected in a recent issue of Seminars in Ophthalmology. She was well prepared for her part: trained in medicine at the University of Havana before completing a residency in ophthalmology and eventually a doctorate in medical sciences, she has received multiple honors for her research, publishing and teaching. In 2007, she was named Distinguished Researcher by the Cuban Ministry of Science, Technology and the Environment. She has headed the Department of Neuro-ophthalmology at Cuba's Neurology and Neurosurgery Institute since 1977. Now called Cuban Epidemic Neuropathy, the 1990s epidemic that affected over 50,000 Cubans is the largest and best-documented of its kind in history. As researchers pressed to unravel the mystery of its etiology to hasten the epidemic's end, Dr Santiesteban recognized that similar outbreaks had occurred during Cuba's wars of independence in the late 1800s--described in her book, Epidemias y Endemias de neuropatía en Cuba. In the proverbial eye of the storm during the 1990s epidemic, she shares her reflections below on the context, causes, evolution and lessons learned from the challenge that put Cuba's health system to the test. Available as a free download COMMENT: A very good recent interview discussing the epidemic. Back ------------------------------------------------------------------------------------------------------------------------- Arch Ophthalmol. 1994 May;112(5):691-9. Epidemic optic neuropathy in Cuba. Eye findings. Sadun AA, Martone JF, Muci-Mendoza R, Reyes L, DuBois L, Silva JC, Roman G, Caballero B. ORBIS International, New York, NY. OBJECTIVE: To characterize and establish a clinical definition of the optic neuropathy that appeared in epidemic form in Cuba in 1992 and 1993. METHODS: At the invitation of the Cuban Ministry of Health, Havana, members of ORBIS International and the Pan American Health Organization, assembled teams that traveled to Cuba in May 1993. We were initially briefed by Cuban national experts in the areas of virology, nutrition, toxicology, ophthalmology, neurology, and public health. We then examined 20 patients on our own. Thirteen of these patients underwent a comprehensive neuro-ophthalmologic examination, including neurologic examination, ophthalmologic examination, visual fields, optic nerve function studies, contrast sensitivity studies, and funduscopy. We returned 4 months later to perform an additional 12 comprehensive neuro-ophthalmologic and follow-up examinations. RESULTS: Only seven of the 13 patients who were alleged to have the optic form of the epidemic and who were rigorously and systematically examined on the first visit demonstrated a bilateral optic neuropathy. These seven patients had several features that included decreased visual acuity, poor color vision, central scotomas, decreased contrast sensitivity, saccadic eye movements, and most prominent and distinctive of all, nerve fiber layer wedge defects of the papillomacular bundle. Our clinical definition was then implemented by the Cuban ophthalmologists and epidemiologists. On returning 4 months later, we found that all newly presented patients were correctly diagnosed to have the epidemic disease. With the new case definition and the application of a few simple psychophysical tests, the false-positive rate of diagnosis became much lower. After vitamin therapy, we reexamined the patients seen on our initial visit, and all showed marked improvement. CONCLUSIONS: The Cuban epidemic was characterized by an optic neuropathy with features that were similar to those of tobacco/alcohol amblyopia and Leber's optic atrophy. Recent political, economic, and social changes in Cuba may have contributed to the nutritional and/or toxic compromise of mitochondrial function of an acquired nature, which led to selective retinal ganglion cell damage. We have termed this condition Cuban epidemic optic neuropathy. COMMENT: A review of the Cuban epidemic. Back ------------------------------------------------------------------------------------------------------------------------ Int Ophthalmol. 1994-1995;18(6):373-8. Cuba: response of medical science to a crisis of optic and peripheral neuropathy. Sadun AA, Martone JF. Doheny Eye Institute, Los Angeles, CA 90033, USA. We made two trips to Cuba, as part of an invited international delegation, to investigate an epidemic of optic neuropathy-induced blindness. We worked closely with Cuban scientists and clinicians in their efforts to understand and then deal with 50,000 cases of blindness and an entire population at risk. This gave an unparalleled opportunity to understand the Cuban system of ophthalmologic health care and, in particular, to appreciate the responses of the scientific and health care communities to this crisis. Several features of the very different Cuban medical and scientific infrastructure were both problematic and advantageous as they affected the Cuban efforts to understand, contain and treat this remarkable epidemic. COMMENT: Another paper about the Cuban epidemic. Back ------------------------------------------------------------------------------------------------------------------------ Trans Am Ophthalmol Soc. 1998;96:881-923. Acquired mitochondrial impairment as a cause of optic nerve disease. Sadun A. Doheny Eye Institute, Department of Ophthalmology, University of Southern California School of Medicine, Los Angeles, USA. BACKGROUND: Blindness from an optic neuropathy recently occurred as an epidemic affecting 50,000 patients in Cuba (CEON) and had clinical features reminiscent of both tobacco-alcohol amblyopia (TAA) and Leber's hereditary optic neuropathy (Leber's; LHON). Selective damage to the papillomacular bundle was characteristic, and many patients also developed a peripheral neuropathy. Identified risk factors included vitamin deficiencies as well as exposure to methanol and cyanide. In all 3 syndromes, there is evidence that singular or combined insults to mitochondrial oxidative phosphorylation are associated with a clinically characteristic optic neuropathy. PURPOSE: First, to test the hypothesis that a common pathophysiologic mechanism involving impairment of mitochondria function and, consequently, axonal transport underlies both genetic optic nerve diseases such as Leber's and acquired toxic and nutritional deficiency optic neuropathies. According to this hypothesis, ATP depletion below a certain threshold leads to a blockage of orthograde axonal transport of mitochondria, which, in turn, leads to total ATP depletion and subsequent cell death. Second, to address several related questions, including (1) How does impaired energy production lead to optic neuropathy, particularly since it seems to relatively spare other metabolically active tissues, such as liver and heart? (2) Within the nervous system, why is the optic nerve, and most particularly the papillomacular bundle, so highly sensitive? Although there have been previous publications on the clinical features of the Cuban epidemic of blindness, the present hypothesis and the subsequent questions have not been previously addressed. METHODS: Patients in Cuba with epidemic optic neuropathy were personally evaluated through a comprehensive neuro-ophthalmologic examination. In addition, serum, lymphocytes for DNA analysis, cerebrospinal fluid (CSF), sural nerves, and eyes with attached optic nerves were obtained from Cuban patients, as well as from Leber's patients, for study. Finally, we developed an animal model to match the low serum folic acid and high serum formate levels found in the CEON patients, by administering to rats low doses of methanol after several months of a folic acid-deficient diet. Optic nerves and other tissues obtained from these rats were analyzed and compared with those from the Cuban patients. RESULTS: Patients from the Cuban epidemic of optic neuropathy with clinical evidence of a selective loss of the papillomacular bundle did much better once their nutritional status was corrected and exposure to toxins ceased. Patients with CEON often demonstrated low levels of folic acid and high levels of formate in their blood. Histopathologic studies demonstrated losses of the longest fibers (in the sural nerve) and those of smallest caliber (papillomacular bundle) in the optic nerve, with intra-axonal accumulations just anterior to the lamina cribrosa. Our animal model duplicated the serologic changes (low folic acid, high formate) as well as these histopathologic changes. Furthermore, ultrastructural examination of rat tissues demonstrated mitochondrial changes that further matched those seen on ultrastructural examination of tissues from patients with Leber's. CONCLUSION: Mitochondria can be impaired either genetically (as in Leber's) or through acquired insults (such as nutritional or toxic factors). Either may challenge energy production in all cells of the body. While this challenge may be met through certain compensatory mechanisms (such as in the size, shape, or number of the mitochondria), there exists in neurons a threshold which, once passed, leads to catastrophic changes. This threshold may be that point at which mitochondrial derangement leads to such ATP depletion that axonal transport is compromised, and decreased mitochondrial transport results in even further ATP depletion. Neurons are singularly dependent on the axonal transport of mitochondria. Available as a free download COMMENT: A review some years after the epidemic. Back ------------------------------------------------------------------------------------------------------------------------ Rev Neurol. 1999 Aug 16-31;29(4):289-96. Leber's hereditary optic neuropathy and its possible relation to a recent epidemic in Cuba]. Santiesteban-Freixas R, et al. Servicio de Neuroftalmología, Instituto de Neurología y Neurocirugía (INN), La Habana, Cuba. INTRODUCTION: This century, the greatest epidemic affecting the nervous system was notified in Cuba seven years ago. At the present time the epidemic continues although to a lesser extent. The clinical findings of the illness were mainly bilateral optic neuropathy sometimes accompanied by other symptoms and peripheral neuropathy. The similarity of the optic form of the illness with Leber's hereditary optic neuropathy, and their common risk factors, were obvious from the beginning. PATIENTS AND METHODS: Statistics from the national reference department of neuro-ophthalmology of the Instituto de Neurologia de Cuba were reviewed. From these it was evident that the number of cases of Leber's hereditary optic neuropathy had increased in recent years, coinciding with the period of epidemic and endemic Cuban neuropathy. Many of these patients had previously been diagnosed as having epidemic optic neuropathy. RESULTS: We describe the characteristics of a group of these patients and discuss the differences and possible relationship between the two conditions. In the case of epidemic optic neuropathy, there is strikingly simultaneous loss of vision, less visual changes with much smaller cecocentral scotomas, loss of ganglion fibres of the retina around the papillomacular bundle, a good response to multivitamin treatment, and increased frequency of association with peripheral sensory neuropathy. CONCLUSION: This analysis reinforces the hypothesis that many patients with Leber's hereditary optic neuropathy, which started at the time of the epidemic, were incorrectly classified as suffering from this, and also perhaps their condition worsened due to the toxic nutritional features common to both conditions. COMMENT: Another paper about the Cuban epidemic. Back ------------------------------------------------------------------------------------------------------------------------ Semin Ophthalmol. 2010 Jul;25(4):112-22. Cuban epidemic optic neuropathy and its relationship to toxic and hereditary optic neuropathy. Santiesteban-Freixas R, Mendoza-Santiesteban CE, Columbie-Garbey Y, Quevedo AG, Garcia AG, Rodríguez RC. Department of Neuro-ophthalmology, The Institute of Neurology and Neurosurgery, Havana, Cuba. The similarities and differences between toxic/nutritional and hereditary optic neuropathy and the pathophysiologic mechanisms that they have in common are described. This is based on data from the epidemic suffered in Cuba in 1992, which affected the optic nerves of many individuals and the experience of the authors in dealing with various toxic optic neuropathies, as well as Leber's hereditary optic neuropathy. COMMENT: A review some years after the epidemic. Back ------------------------------------------------------------------------------------------------------------------------- OLDER PAPERS DISCUSSING LHON ============================ ----------------------------------------------------------------------------------------------------------------------- Amer J Hum Genet 24:348-349, 1972 Leber's Optic Atrophy, a Possible Example of Maternal Inheritance ROBERT P. ERICKSON Available as a free download COMMENT: One of the very first papers to discuss LHON. Back ----------------------------------------------------------------------------------------------------------------------- Science. 1988 Dec 9;242(4884):1427-30. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322. Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease. COMMENT: The first paper to link LHON with the mutation G11778A. Back ------------------------------------------------------------------------------------------------------------------------ Am J Hum Genet. 1991 Jun;48(6):1147-53. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML. Department of Medical Genetics, University of Turku, Finland. A single base mutation at nucleotide position 3460 (nt 3460) in the ND1 gene in human mtDNA was found to be associated with Leber hereditary optic neuroretinopathy (LHON). The G-to-A mutation converts an alanine to a threonine at the 52d codon of the gene. The mutation also abolishes an AhaII restriction site and thus can be detected easily by RFLP analysis. The mutation was found in three independent Finnish LHON families but in none of the 60 controls. None of the families with the nt 3460 mutation in ND1 had the previously reported nt 11778 mutation in the ND4 gene. The G-to-A change at nt 3460 is the second mutation so far detected in LHON. Available as a free download COMMENT: The first report showing the LHON mutation G3460A. Back ------------------------------------------------------------------------------------------------------------------------ Am J Hum Genet. 1991 Mar;48(3):486-91. Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7. Vilkki J, Ott J, Savontaus ML, Aula P, Nikoskelainen EK. Department of Medical Genetics, University of Turku, Finland. Leber hereditary optic neuroretinopathy (LHON) is a maternally inherited disease, probably transmitted by mutations in mtDNA. The variation in the clinical expression of the disease among family members has remained unexplained, but pedigree data suggest an involvement of an X-chromosomal factor. We have studied genetic linkage of the liability to develop optic atrophy to 15 polymorphic markers on the X chromosome in six pedigrees with LHON. The results show evidence of linkage to the locus DXS7 on the proximal Xp. Tight linkage to the other marker loci was excluded. Multipoint linkage analysis placed the liability locus at DXS7 with a maximum lod score (Zmax) of 2.48 at a recombination fraction (theta) of .0 and with a Zmax - 1 support interval theta = .09 distal to theta = .07 proximal of DXS7. No evidence of heterogeneity was found among different types of families, with or without a known mtDNA mutation associated with LHON. Available as a free download COMMENT: An interesting paper from 1991. Back ------------------------------------------------------------------------------------------------------------------------ Genetics. 1992 Jan;130(1):163-73. Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Brown MD, Voljavec AS, Lott MT, Torroni A, Yang CC, Wallace DC. Center for Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322. Four new missense mutations have been identified through restriction analysis and sequencing of the mitochondrial DNAs (mtDNA) from Leber's hereditary optic neuropathy (LHON) patients who lacked the previously identified 11778 mutation. Each altered a conserved amino acid and correlated with the LHON phenotype in population and phylogenetic analyses. The nucleotide pair (np) 13708 mutation (G to A, ND5 gene) changed an alanine to a threonine and was found in 6/25 (24%) of non-11778 LHON pedigrees and in 5.0% of controls, the np 15257 mutation (G to A, cytochrome b gene) changed an aspartate to an asparagine and was found in 4 of the 13708-positive pedigrees and 0.3% of controls, the np 15812 mutation (G to A, cytochrome b gene) changed a valine to a methionine and was detected in two of the 15257-positive pedigrees and 0.1% of controls and the np 5244 mutation (G to A, ND2 gene) changed a glycine to a serine and was found in one of the 15812-positive patients and none of 2103 controls. The 15257 mutation altered a highly conserved amino acid in an extramembrane domain of cytochrome b that is associated with the ligation of the low potential b566 heme and the 5244 mutation altered a strongly evolutionarily conserved region of the ND2 polypeptide. The 13708 and 15812 mutations changed moderately conserved amino acids. Haplotype and phylogenetic analysis of the four np 15257 mtDNAs revealed that all harbored the same rare Caucasian haplotype and that the np 13708, np 15257, np 15812 and np 5244 mutations were added sequentially along this mtDNA lineage. Since the percentage of sighted controls decreases as these mutations accumulate, it appears that they interact synergistically, each increasing the probability of blindness. The involvement of both mitochondrial complex I (np 5244, 11778, 13708) and complex III (np 15257, 15812) mutations in LHON indicates that the clinical manifestations of this disease are the product of an overall decrease in mitochondrial energy production rather than a defect in a specific mitochondrial enzyme. Available as a free download" COMMENT: Important paper from 20 years ago. Back ------------------------------------------------------------------------------------------------------------------------ Am J Hum Genet. 1993 Jul;53(1):289-92. Reevaluation of the linkage of an optic atrophy susceptibility gene to X-chromosomal markers in Finnish families with Leber hereditary optic neuroretinopathy (LHON) Juvonen V, Vilkki J, Aula P, Nikoskelainen E, Savontaus ML. Available as a free download COMMENT: Further information on the X-Linkage. Back ------------------------------------------------------------------------------------------------------------------------ Biochem J. 1994 Jul 1;301 ( Pt 1):161-7. Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I). Degli Esposti M, Ghelli A, Ratta M, Cortes D, Estornell E. Dipartimento di Biologia, Università di Bologna, Italy. Natural products from the plants of the family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors of the NADH-ubiquinone reductase (Complex I) activity of mammalian mitochondria. The properties of five of such acetogenins are compared with those of rotenone and piericidin, classical potent inhibitors of Complex I. Rolliniastatin-1 and rolliniastatin-2 are more powerful than piericidin in terms of both their inhibitory constant and the protein-dependence of their titre in bovine submitochondrial particles. These acetogenins could be considered therefore the most potent inhibitors of mammalian Complex I. Squamocin and otivarin also have an inhibitory constant lower than that of piericidin, but display a larger protein-dependence of the titre. Squamocin and otivarin, contrary to the other acetogenins, behave qualitatively like rotenone. Rolliniastatin-2 shows unique properties as its interaction, although mutually exclusive to that of piericidin, appears to be mutually non-exclusive to that of rotenone. It is the first time that a potent inhibitor of Complex I is found not to overlap the active site of rotenone. Available as a free download COMMENT: A paper about Complex I inhibition. Back ----------------------------------------------------------------------------------------------------------------------- J Med Genet. 1995 Feb;32(2):81-7. Leber's hereditary optic neuropathy: the clinical relevance of different mitochondrial DNA mutations. Riordan-Eva P, Harding AE. Department of Neuro-Ophthalmology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Available as a free download COMMENT: A good review article from 1995. Back ----------------------------------------------------------------------------------------------------------------------- Br J Ophthalmol. 1996 Oct;80(10):915-7. Leber's hereditary optic neuropathy: heteroplasmy is likely to be significant in the expression of LHON in families with the 3460 ND1 mutation. Black GC, Morten K, Laborde A, Poulton J. Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford. AIM: To assess the effect of heteroplasmy on the expression of Leber's hereditary optic neuropathy (LHON) in a large family with the 3460 LHON mutation. METHODS: Mutation detection was performed by restriction enzyme digestion of polymerase chain reaction (PCR) products. Heteroplasmy was estimated by quantitation of wild type:mutant product ratios. RESULTS: There is a significant association between levels of mutant mtDNA and manifestation of the disease phenotype. CONCLUSION: As a high proportion of families with the 3460 mutation demonstrate heteroplasmy; this is likely to be a significant factor in disease expression. Available as a free download COMMENT: Heteroplasmy and the G3460A mutation. Back ----------------------------------------------------------------------------------------------------------------------- Eur J Hum Genet. 2002 Feb;10(2):141-4. Leigh disease associated with a novel mitochondrial DNA ND5 mutation. Taylor RW, Morris AA, Hutchinson M, Turnbull DM. Department of Neurology, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation. Available as a free download COMMENT: A mutation that causes Leigh's disease. Back ----------------------------------------------------------------------------------------------------------------------- RECENT PAPERS DISCUSSING LHON AND COMPLEX I =========================================== ----------------------------------------------------------------------------------------------------------------------- Biochem J. 2004 Nov 1;383(Pt. 3):491-9. Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin. Bourges I, Ramus C, Mousson de Camaret B, Beugnot R, Remacle C, Cardol P, Hofhaus G, Issartel JP. UMR 5090 CNRS-DRDC, CEA Grenoble, 38054 Grenoble cedex 9, France. Mitochondria-encoded ND (NADH dehydrogenase) subunits, as components of the hydrophobic part of complex I, are essential for NADH:ubiquinone oxidoreductase activity. Mutations or lack of expression of these subunits have significant pathogenic consequences in humans. However, the way these events affect complex I assembly is poorly documented. To understand the effects of particular mutations in ND subunits on complex I assembly, we studied four human cell lines: ND4 non-expressing cells, ND5 non-expressing cells, and rho degrees cells that do not express any ND subunits, in comparison with normal complex I control cells. In control cells, all the seven analysed nuclear-encoded complex I subunits were found to be attached to the mitochondrial inner membrane, except for the 24 kDa subunit, which was nearly equally partitioned between the membranes and the matrix. Absence of a single ND subunit, or even all the seven ND subunits, caused no major changes in the nuclear-encoded complex I subunit content of mitochondria. However, in cells lacking ND4 or ND5, very low amounts of 24 kDa subunit were found associated with the membranes, whereas most of the other nuclear-encoded subunits remained attached. In contrast, membrane association of most of the nuclear subunits was significantly reduced in the absence of all seven ND proteins. Immunopurification detected several subcomplexes. One of these, containing the 23, 30 and 49 kDa subunits, also contained prohibitin. This is the first description of prohibitin interaction with complex I subunits and suggests that this protein might play a role in the assembly or degradation of mitochondrial complex I. Available as free download COMMENT: ND4 & ND5 in COMPLEX I. Back ------------------------------------------------------------------------------------------------------------------------ Arch Neurol. 2005 May;62(5):730-6. Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids. Baracca A, Solaini G, Sgarbi G, Lenaz G, Baruzzi A, Schapira AH, Martinuzzi A, Carelli V. Dipartimento di Biochimica, University of Bologna, Italy. BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited form of central vision loss associated with mitochondrial DNA point mutations that affect the ND subunits of complex I. OBJECTIVE: To elucidate the bioenergetic consequences of complex I dysfunction in LHON. DESIGN: The biochemical phenotypes of LHON mutations have been investigated using the transmitochondrial cytoplasmic hybrid (cybrid) cell model derived from the osteocarcoma parental cell line 143B.TK-. SETTING: Research laboratories at neuroscience and biochemistry departments at the University of Bologna, Scientific Institute "E. Medea," and University of College Medical School. PARTICIPANTS: Fibroblast cell lines were obtained from patients affected with LHON, as defined by the presence of 1 pathogenic mutation, and from healthy volunteers as controls to construct cybrid cell lines. MAIN OUTCOME MEASURES: Complex I (glutamate-malate)- and complex II (succinate)-dependent adenosine triphosphate (ATP) synthesis, their respective respiratory rates, and total cellular ATP content were investigated using digitonin permeabilized cybrid cells. Multiple cybrid cell lines were constructed, introducing into osteosarcoma-derived rho(0) cells either wild-type or LHON mutant mitochondria carrying each of the 3 common mutations at positions 11778/ND4, 3460/ND1, and 14484/ND6. RESULTS: All 3 LHON mutations impaired ATP synthesis and the respiratory control ratio driven by complex I substrates. In contrast, succinate-driven ATP synthesis, respiration rates, and respiratory control ratios were not affected. However, the defective ATP synthesis with complex I substrates did not result in reduced ATP cellular content, indicating a compensatory mechanism. CONCLUSIONS: The LHON pathogenic mutations profoundly impair complex I-dependent synthesis of ATP, providing a common biochemical feature that may play a major role in LHON pathogenesis. Stratification of the results by mutation suggests that the 11778/ND4 mutation may induce an uncoupling of cybrid respiration, whereas the other 2 mutations impair the oxygen consumption rate. Available as a free download COMMENT: Discusses the link between LHON mutations and Complex I. Back ----------------------------------------------------------------------------------------------------------------------- Annu Rev Biochem. 2006;75:69-92. Energy converting NADH:quinone oxidoreductase (complex I). Brandt U. Universität Frankfurt, Fachbereich Medizin, Zentrum der Biologischen Chemie, D-60590 Frankfurt am Main, Germany. brandt@zbc.kgu.de NADH:quinone oxidoreductase (complex I) pumps protons across the inner membrane of mitochondria or the plasma membrane of many bacteria. Human complex I is involved in numerous pathological conditions and degenerative processes. With 14 central and up to 32 accessory subunits, complex I is among the largest membrane-bound protein assemblies. The peripheral arm of the L-shaped molecule contains flavine mononucleotide and eight or nine iron-sulfur clusters as redox prosthetic groups. Seven of the iron-sulfur clusters form a linear electron transfer chain between flavine and quinone. In most organisms, the seven most hydrophobic subunits forming the core of the membrane arm are encoded by the mitochondrial genome. Most central subunits have evolved from subunits of different hydrogenases and bacterial Na+/H+ antiporters. This evolutionary origin is reflected in three functional modules of complex I. The coupling mechanism of complex I most likely involves semiquinone intermediates that drive proton pumping through redox-linked conformational changes. COMMENT: Discusses the structure of Complex I Back ----------------------------------------------------------------------------------------------------------------------- J Biol Chem. 2006 Oct 27;281(43):32724-7. Bovine complex I is a complex of 45 different subunits. Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE. Dunn Human Nutrition Unit, The Medical Research Council, Hills Road, Cambridge CB2 2XY, United Kingdom. Mammalian mitochondrial complex I is a multisubunit membrane-bound assembly with a molecular mass approaching 1 MDa. By comprehensive analyses of the bovine complex and its constituent subcomplexes, 45 different subunits have been characterized previously. The presence of a 46th subunit was suspected from the consistent detection of a molecular mass of 10,566 by electrospray ionization mass spectrometry of subunits fractionated by reverse-phase high pressure liquid chromatography. The component was found associated with both the intact complex and subcomplex Ibeta, which represents most of the membrane arm of the complex, and it could not be resolved chromatographically from subunit SGDH (the subunit of bovine complex I with the N-terminal sequence Ser-Gly-Asp-His). It has now been characterized by tandem mass spectrometry of intact protein ions and shown to be a C-terminal fragment of subunit SGDH arising from a specific peptide bond cleavage between Ile-55 and Pro-56 during the electrospray ionization process. Thus, the subunit composition of bovine complex I has been established. It is a complex of 45 different proteins plus non-covalently bound FMN and eight iron-sulfur clusters. COMMENT: Determines there are 45 subunits making up Complex I. Back ----------------------------------------------------------------------------------------------------------------------- MITOCHONDRIAL DNA IN NEURONS AND ITS MODULATION BY NEUROTOXINS Maria Soledad Santos, Ph.D. thesis, University of Pittsburgh 2006. Available as a free download COMMENT: An extremely informative Ph.D. thesis discussing in detail mitochondria and the effects of 'rotenone'. Back ----------------------------------------------------------------------------------------------------------------------- EMBO J. 2007 Jul 11;26(13):3227-37. Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. Dunning CJ, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, Fletcher JM, Kirby DM, Thorburn DR, Ryan MT. Department of Biochemistry, La Trobe University, Melbourne, Australia. In humans, complex I of the respiratory chain is composed of seven mitochondrial DNA (mtDNA)-encoded and 38 nuclear-encoded subunits that assemble together in a process that is poorly defined. To date, only two complex I assembly factors have been identified and how each functions is not clear. Here, we show that the human complex I assembly factor CIA30 (complex I intermediate associated protein) associates with newly translated mtDNA-encoded complex I subunits at early stages in their assembly before dissociating at a later stage. Using antibodies we identified a CIA30-deficient patient who presented with cardioencephalomyopathy and reduced levels and activity of complex I. Genetic analysis revealed the patient had mutations in both alleles of the NDUFAF1 gene that encodes CIA30. Complex I assembly in patient cells was defective at early stages with subunits being degraded. Complementing the deficiency in patient fibroblasts with normal CIA30 using a novel lentiviral system restored steady-state complex I levels. Our results indicate that CIA30 is a crucial component in the early assembly of complex I and mutations in its gene can cause mitochondrial disease. Available as a free download Comment: A case of Complex I deficiency. Back ----------------------------------------------------------------------------------------------------------------------- Eur J Paediatr Neurol. 2007 Mar;11(2):115-8. Epub 2007 Jan 24. Atypical presentation of Leber's hereditary optic neuropathy associated to mtDNA 11778G>A point mutation --A case report. Grazina MM, Diogo LM, Garcia PC, Silva ED, Garcia TD, Robalo CB, Oliveira CR. Biochemistry Institute, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by bilateral loss of central vision, most frequently found in young adult males. In most patients there are no other neurological manifestations and cerebral neuroimaging is normal, but some rare cases of "LHON plus" have been described. Classical LHON is mainly associated to mitochondrial DNA (mtDNA) mutations 11778G>A, 3460G>A and 14484T>C, localized in the coding regions for ND4, ND1 and ND6 of the complex I subunits of mitochondrial respiratory chain (MRC), respectively. We report a 12-year-old girl who presented with reduced visual acuity secondary to optic atrophy at 8 months of age, which led to a clinical diagnosis of LHON. Psychomotor regression, refractory epilepsy and progressive neurological abnormalities developed subsequently. Skeletal muscle histology and biochemical MRC function were normal (evaluated by dual wavelength spectrophotometry). A 11778G>A mtDNA point mutation (investigated by standard PCR and automatic sequencing methods) was identified in lymphocytes isolated from peripheral blood, muscle biopsy and cultured skin fibroblasts. The mother and other maternal relatives are carriers for the same mutation. This case is unusual for age of onset, gender, associated neurological findings and evolution. Comment: The first report of a family with G11778A - see d'Almeida(2013) for more about this family. Back ----------------------------------------------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2007 Mar 30;355(1):181-7. The NDUFB11 gene is not a modifier in Leber hereditary optic neuropathy. Petruzzella V, Tessa A, Torraco A, Fattori F, Dotti MT, Bruno C, Cardaioli E, Papa S, Federico A, Santorelli FM. Department of Medical Biochemistry, Medical Biology and Medical Physics, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy. Over 95% of Leber hereditary optic neuropathy (LHON) cases are due to mutations in mitochondrial DNA-encoded subunits of NADH:ubiquinone oxidoreductase (E.C.1.6.5.3., complex I). A recessive X-linked susceptibility gene that acts synergistically with the primary mtDNA mutation to produce visual loss is suggested by the high male-to-female ratio among LHON patients. The ESSS protein is a recently isolated subunit of bovine heart mitochondrial complex I. We revisited the genomic sequence of NDUFB11, the human homolog mapping to chromosome Xp11.23, and identified two mRNA isoforms showing different expression profiles in human tissues. Cultured skin fibroblasts from four LHON patients showed a pattern of expression similar to normal controls. Moreover, NDUFB11 did not seem to influence risk and age at onset of visual loss in a total of 65 individuals from 35 Italian LHON families. Also, the gene was not affected in 11 children with a severe encephalopathy associated with decreased complex I activity in skeletal muscle. COMMENT: A study looking at LHON and the NDUFB11 gene. Back ----------------------------------------------------------------------------------------------------------------------- Biochim Biophys Acta. 2007 Oct;1767(10):1215-27. Human mitochondrial complex I assembly: a dynamic and versatile process. Vogel RO, Smeitink JA, Nijtmans LG. Nijmegen Centre for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands. One can but admire the intricate way in which biomolecular structures are formed and cooperate to allow proper cellular function. A prominent example of such intricacy is the assembly of the five inner membrane embedded enzymatic complexes of the mitochondrial oxidative phosphorylation (OXPHOS) system, which involves the stepwise combination of >80 subunits and prosthetic groups encoded by both the mitochondrial and nuclear genomes. This review will focus on the assembly of the most complicated OXPHOS structure: complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3). Recent studies into complex I assembly in human cells have resulted in several models elucidating a thus far enigmatic process. In this review, special attention will be given to the overlap between the various assembly models proposed in different organisms. Complex I being a complicated structure, its assembly must be prone to some form of coordination. This is where chaperone proteins come into play, some of which may relate complex I assembly to processes such as apoptosis and even immunity. COMMENT: An important paper about Complex I assembly Back ----------------------------------------------------------------------------------------------------------------------- J Biol Chem. 2008 Dec 12;283(50):34753-61. Subunits of mitochondrial complex I exist as part of matrix- and membrane-associated subcomplexes in living cells. Dieteren CE, Willems PH, Vogel RO, Swarts HG, Fransen J, Roepman R, Crienen G, Smeitink JA, Nijtmans LG, Koopman WJ. Department of Biochemistry, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Mitochondrial complex I (CI) is a large assembly of 45 different subunits, and defects in its biogenesis are the most frequent cause of mitochondrial disorders. In vitro evidence suggests a stepwise assembly process involving pre-assembled modules. However, whether these modules also exist in vivo is as yet unresolved. To answer this question, we here applied submitochondrial fluorescence recovery after photobleaching to HEK293 cells expressing 6 GFP-tagged subunits selected on the basis of current CI assembly models. We established that each subunit was partially present in a virtually immobile fraction, possibly representing the holo-enzyme. Four subunits (NDUFV1, NDUFV2, NDUFA2, and NDUFA12) were also present as highly mobile matrix-soluble monomers, whereas, in sharp contrast, the other two subunits (NDUFB6 and NDUFS3) were additionally present in a slowly mobile fraction. In the case of the integral membrane protein NDUFB6, this fraction most likely represented one or more membrane-bound subassemblies, whereas biochemical evidence suggested that for the NDUFS3 protein this fraction most probably corresponded to a matrix-soluble subassembly. Our results provide first time evidence for the existence of CI subassemblies in mitochondria of living cells. Available as a free download COMMENT: The structure of Complex I. Back ----------------------------------------------------------------------------------------------------------------------- J Fr Ophtalmol. 2008 Apr;31(4):409-15. Recurrent visual loss in Leber hereditary optic neuropathy: a case report, Momtchilova M, Pelosse B, Saliba M, Abdiche G, Doummar D, Laroche L, Billette De Villemeur T. Service d'Ophtalmologie, Hôpital d'Enfants Armand Trousseau, Paris. INTRODUCTION: We report an unusual case of Leber's hereditary optic neuropathy (LHON) in a 7-year-old boy with recurrent episodes of visual loss. OBSERVATION: A 7-year-old-boy developed acute severe bilateral optic neuropathy associated with mild optic disc edema. The patient was treated with high doses of systemic steroids followed by improvement in his vision. When the steroids were stopped his vision deteriorated. By the age of 14, this condition had recurred six times. At the age of 15, steroids were stopped and he was treated with azathioprin. At the age of 16, his visual acuity was 9/10 in his right eye and 8/10 in his left eye. Fundus examination showed bilateral optic atrophy. At the age of 15, his younger brother, 12 years old, developed severe visual loss in his left eye. Leber's hereditary optic neuropathy was suspected. Molecular genetic testing of their mother revealed the 11778 mtDNA mutation. DISCUSSION: In most patients with LHON, visual loss remains profound and permanent. However, recovery of even excellent central vision may occur years after visual deterioration. Recurrences of visual loss are extremely rare. LHON should be considered in any patient with acute bilateral optic neuropathy. In this patient, the visual improvement with corticosteroid treatment and no relapse with immunosuppressive treatment raises the problem of interrelated inflammatory optical neuropathy. COMMENT: A paper about a patient with recurrent LHON symptoms. Back ----------------------------------------------------------------------------------------------------------------------- Surv Ophthalmol. 2008 Jul-Aug;53(4):403-10. doi: 10.1016/j.survophthal.2008.04.003. You're too old for that. Shah VA, Randhawa S, Mizen T, Lee AG, Foroozan R. Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242-1091, USA. Leber hereditary optic neuropathy (LHON) produces a subacute and typically bilateral but sequential optic neuropathy. LHON is a mitochondrial disease and the most common mutations are at positions 11778, 14484 and 3460. LHON typically presents in young (age 20-40), healthy men but may occur in either sex and at any age. We report a case of LHON in a 72-year-old man and we emphasize the importance of testing for LHON in all cases of unexplained bilateral and sequential optic neuropathy with a ceco-central or central scotoma. COMMENT: LHON appearing in an older person. Back ----------------------------------------------------------------------------------------------------------------------- Am J Hum Genet. 2008 Oct;83(4):468-78. Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Sugiana C, Pagliarini DJ, McKenzie M, Kirby DM, Salemi R, Abu-Amero KK, Dahl HH, Hutchison WM, Vascotto KA, Smith SM, Newbold RF, Christodoulou J, Calvo S, Mootha VK, Ryan MT, Thorburn DR. Mitochondrial and Metabolic Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia. Complex I (NADH:ubiquinone oxidoreductase) is the first and largest multimeric complex of the mitochondrial respiratory chain. Human complex I comprises seven subunits encoded by mitochondrial DNA and 38 nuclear-encoded subunits that are assembled together in a process that is only partially understood. To date, mutations causing complex I deficiency have been described in all 14 core subunits, five supernumerary subunits, and four assembly factors. We describe complex I deficiency caused by mutation of the putative complex I assembly factor C20orf7. A candidate region for a lethal neonatal form of complex I deficiency was identified by homozygosity mapping of an Egyptian family with one affected child and two affected pregnancies predicted by enzyme-based prenatal diagnosis. The region was confirmed by microcell-mediated chromosome transfer, and 11 candidate genes encoding potential mitochondrial proteins were sequenced. A homozygous missense mutation in C20orf7 segregated with disease in the family. We show that C20orf7 is peripherally associated with the matrix face of the mitochondrial inner membrane and that silencing its expression with RNAi decreases complex I activity. C20orf7 patient fibroblasts showed an almost complete absence of complex I holoenzyme and were defective at an early stage of complex I assembly, but in a manner distinct from the assembly defects caused by mutations in the assembly factor NDUFAF1. Our results indicate that C20orf7 is crucial in the assembly of complex I and that mutations in C20orf7 cause mitochondrial disease. Available as a free download COMMENT: A case of Complex I deficiency Back ----------------------------------------------------------------------------------------------------------------------- Mol Vis. 2009;15:870-5. Genetic variation in the methylenetetrahydrofolate reductase gene, MTHFR, does not alter the risk of visual failure in Leber's hereditary optic neuropathy. Hudson G, Yu-Wai-Man P, Zeviani M, Chinnery PF. Mitochondrial Research Group, Institute of Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. PURPOSE: Focal neurodegeneration of the optic nerve in Leber hereditary optic neuropathy (LHON) is primarily due to a maternally inherited mitochondrial DNA mutation. However, the markedly reduced penetrance of LHON and segregation pattern of visual failure within families implicates an interacting nuclear genetic locus modulating the phenotype. Folate deficiency is known to cause bilateral optic neuropathy, and defects of folate metabolism have been associated with nonarteritic ischemic optic neuropathy. METHODS: Methylenetetrahydrofolate reductase (MTHFR) catalyzes a critical step in folate metabolism, and genetic variation in MTHFR has been associated with several late-onset neurodegenerative diseases. RESULTS: We therefore determined whether functional genetic variants in MTHFR could account for the reduced penetrance in LHON by studying 414 LHON mtDNA mutation carriers. We found no evidence of association between visual failure in LHON and MTHFR polymorphisms or the MTHFR haplotype. CONCLUSIONS: Genetic variation in MTHFR does not provide an explanation for the variable phenotype in LHON. Available as as free download COMMENT: A paper discussing the possible link of folate deficiency and LHON. Back ----------------------------------------------------------------------------------------------------------------------- J Biol Chem. 2009 Jan 23;284(4):2045-52. Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels. Porcelli AM, Angelin A, Ghelli A, Mariani E, Martinuzzi A, Carelli V, Petronilli V, Bernardi P, Rugolo M. Department of Evolutionary and Experimental Biology, University of Bologna, 40126 Bologna, Italy. Abstract We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an approximately 50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases. Available as a free download COMMENT: LHON mutations and Complex I. Back ------------------------------------------------------------------------------------------------------------------------ Am J Hum Genet. 2009 Jun;84(6):718-27. Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG. Metabolic Disease Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Mitochondrial complex I deficiency is the most prevalent and least understood disorder of the oxidative phosphorylation system. The genetic cause of many cases of isolated complex I deficiency is unknown because of insufficient understanding of the complex I assembly process and the factors involved. We performed homozygosity mapping and gene sequencing to identify the genetic defect in five complex I-deficient patients from three different families. All patients harbored mutations in the NDUFAF3 (C3ORF60) gene, of which the pathogenic nature was assessed by NDUFAF3-GFP baculovirus complementation in fibroblasts. We found that NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with complex I subunits. Furthermore, we show that NDUFAF3 tightly interacts with NDUFAF4 (C6ORF66), a protein previously implicated in complex I deficiency. Additional gene conservation analysis links NDUFAF3 to bacterial-membrane-insertion gene cluster SecF/SecD/YajC and to C8ORF38, also implicated in complex I deficiency. These data not only show that NDUFAF3 mutations cause complex I deficiency but also relate different complex I disease genes by the close cooperation of their encoded proteins during the assembly process. Available as a free download COMMENT: Disease caused by Complex I mutations Back ----------------------------------------------------------------------------------------------------------------------- Hum Mol Genet. 2009 May 15;18(10):1805-12. PGC-1alpha/beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Srivastava S, Diaz F, Iommarini L, Aure K, Lombes A, Moraes CT. Department of Neurology, University of Miami School of Medicine, Miami, FL 33136, USA. Members of the peroxisome proliferator-activated receptor gamma coactivator (PGC) family are potent inducers of mitochondrial biogenesis. We have tested the potential effect of increased mitochondrial biogenesis in cells derived from patients harboring oxidative phosphorylation defects due to either nuclear or mitochondrial DNA mutations. We found that the PGC-1alpha and/or PGC-1beta expression improved mitochondrial respiration in cells harboring a complex III or IV deficiency as well as in transmitochondrial cybrids harboring mitochondrial encephalomyopathy lactic acidosis and stroke A3243G tRNA((Leu)UUR) gene mutation. The respiratory function improvement was found to be associated with increased levels of mitochondrial components per cell, although this increase was not homogeneous. These results reinforce the concept that increased mitochondrial biogenesis is a promising venue for the treatment of mitochondrial diseases. Available as a free download COMMENT: PGC-1 alpha and mitochondrial biogenesis. Back ----------------------------------------------------------------------------------------------------------------------- Iran J Public Health. 2010;39(3):53-60. Leber hereditary optic neuropathy: do folate pathway gene alterations influence the expression of mitochondrial DNA mutation? Aleyasin A, Ghazanfari M, Houshmand M. Dept. of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran. BACKGROUND: Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy leading to the loss of central vision. The primary cause of vision loss is mutation in the mitochondrial DNA (mtDNA), however, unknown secondary genetic and/or epigenetic risk factors are suggested to influence its neuropathology. In this study folate gene polymorphisms were examined as a possible LHON secondary genetic risk factor in Iranian patients. METHODS: Common polymorphisms in the MTHFR (C677T and A1298C) and MTRR (A66G) genes were tested in 21 LHON patients and 150 normal controls. RESULTS: Strong associations were observed between the LHON syndrome and C677T (P= 0.00) and A66G (P= 0.00) polymorphisms. However, no significant association was found between A1298C (P =0.69) and the LHON syndrome. CONCLUSION: This is the first study that shows MTHFR C677T and MTRR A66G polymorphisms play a role in the etiology of the LHON syndrome. This finding may help in the better understanding of mechanisms involved in neural degeneration and vision loss by LHON and hence the better treatment of patients. Available as a free download COMMENT: LHON in Iran and its link to folic acid Back ----------------------------------------------------------------------------------------------------------------------- Clin Chim Acta. 2010 Nov 11;411(21-22):1671-4. Screening the three LHON primary mutations in the general Chinese population by using an optimized multiplex allele-specific PCR. Bi R, Zhang AM, Yu D, Chen D, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. BACKGROUND: Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial diseases, which is mainly caused by three mitochondrial DNA (mtDNA) mutations (m.3460G>A, m.11778G>A and m.14484T>C). Incomplete penetrance suggests that there might be asymptomatic carriers in general populations. These asymptomatic carriers are clinically important as they are potential future patients and the female carriers could transfer the pathogenic mutations to their offspring. Thus, screening the three LHON primary mutations in general populations is important for genetic counseling. METHODS: We optimized a multiplex allele-specific PCR method based on previous studies, and the sensitivity was evaluated. The three LHON primary mutations were screened by using this MAS-PCR method in 1571 subjects from general Chinese populations that are without symptoms or family history of optic neuropathy. RESULTS: The optimized MAS-PCR approach can detect a heteroplasmy level at 5%, 5%, and 20% for m.3460G>A, m.11778G>A and m.14484T>C, respectively. None of the three LHON primary mutations was detected in the 1571 subjects. CONCLUSION: The three LHON primary mutations are rare in general Chinese populations. The optimized MAS-PCR assay provides an easier, faster and more cost-effective method for detection of the three LHON primary mutations, making it practical for clinical diagnosis. COMMENT: Searching for carriers of LHON mutations. Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2010 Feb 18;5(2) Improved energy supply regulation in chronic hypoxic mouse counteracts hypoxia-induced altered cardiac energetics. Calmettes G, Deschodt-Arsac V, Gouspillou G, Miraux S, Muller B, Franconi JM, Thiaudiere E, Diolez P. Laboratoire de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS Université Bordeaux 2, Bordeaux, France. BACKGROUND: Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation. METHODOLOGY/PRINCIPAL FINDINGS: Swiss mice were exposed to a simulated altitude of 5500 m in a barochamber for 21 days. Isolated perfused hearts were used to study the effects of a decreased oxygen concentration in the perfusate on contractile performance (RPP) and phosphocreatine (PCr) concentration (assessed by (31)P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (-1.88+/-0.38 vs -0.89+/-0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply. CONCLUSIONS/SIGNIFICANCE: As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia. Available as a free download COMMENT: A Discussion on Energy Demand and Supply Back ----------------------------------------------------------------------------------------------------------------------- J Med Genet. 2010 Aug;47(8):507-12. Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome. Gerards M, Sluiter W, van den Bosch BJ, de Wit LE, Calis CM, Frentzen M, Akbari H, Schoonderwoerd K, Scholte HR, Jongbloed RJ, Hendrickx AT, de Coo IF, Smeets HJ. Department of Genetics and Cell Biology, Unit Clinical Genomics, Maastricht University, Maastricht, The Netherlands. BACKGROUND: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene. METHODS AND RESULTS: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers. CONCLUSIONS: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations. Available as a free download COMMENT: Another report of a case of Complex I deficiency. Back ----------------------------------------------------------------------------------------------------------------------- Science. 2010 Jul 23;329(5990):448-51. Epub 2010 Jul 1. Functional modules and structural basis of conformational coupling in mitochondrial complex I. Hunte C, Zickermann V, Brandt U. Institute for Biochemistry and Molecular Biology, Centre for Biological Signalling Studies (BIOSS), University of Freiburg, D-79104 Freiburg, Germany. Proton-pumping respiratory complex I is one of the largest and most complicated membrane protein complexes. Its function is critical for efficient energy supply in aerobic cells, and malfunctions are implicated in many neurodegenerative disorders. Here, we report an x-ray crystallographic analysis of mitochondrial complex I. The positions of all iron-sulfur clusters relative to the membrane arm were determined in the complete enzyme complex. The ubiquinone reduction site resides close to 30 angstroms above the membrane domain. The arrangement of functional modules suggests conformational coupling of redox chemistry with proton pumping and essentially excludes direct mechanisms. We suggest that a approximately 60-angstrom-long helical transmission element is critical for transducing conformational energy to proton-pumping elements in the distal module of the membrane arm. COMMENT: The x-ray crystallographic analysis of mitochondrial complex I Back ----------------------------------------------------------------------------------------------------------------------- Arch Ophthalmol. 2010 Sep;128(9):1129-35. Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. Lam BL, Feuer WJ, Abukhalil F, Porciatti V, Hauswirth WW, Guy J. Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. OBJECTIVE: To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use "allotopic expression" by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. METHODS: Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened for ND1, ND4, and ND6 mutations in mitochondrial DNA commonly associated with LHON. All patients and maternal relatives also underwent complete neuro-ophthalmic examination, automated visual field testing, pattern electroretinogram (PERG), and OCT3. RESULTS: Twenty-five subjects with LHON and 21 carriers positive for the G11778A mitochondrial DNA mutation were recruited. Three additional mutations in the ND4 gene, G11719A, G11947A, or G11914A, were detected. Mean retinal nerve fiber layer (RNFL) thickness was 78.3 ?m up to 32 months after visual loss. It was 63.5 ?m for all affected patients and 100.7 ?m for carriers (P < .01). Mean PERG amplitude was lower in affected patients (40% of normal) than in carriers (94% of normal) (P < .01). Four carriers with PERG amplitudes less than 75% of normal had Early Treatment Diabetic Retinopathy Study acuity more than 20/25, mean defect more than -2 dB, and average RNFL thickness more than 80 ?m. CONCLUSIONS: Potential candidates for future gene therapy may include affected patients, as late as 32 months after loss of vision, with mildly reduced RNFL thickness or carriers with low PERG amplitudes and normal RNFL thickness, if the PERG amplitude is a predictor of conversion to LHON in these carriers. Available as a free download COMMENT: A new trial of gene therapy using a viral vector. Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2010 Jul 8;5(7):e11472. Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model. Marella M, Seo BB, Thomas BB, Matsuno-Yagi A, Yagi T. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America. BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies. METHODOLOGY/PRINCIPAL FINDINGS: We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. Remarkably, even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects. CONCLUSIONS/SIGNIFICANCE: The present study reports successful manifestation of LHON-like symptoms in rats and demonstrates the potential of the NDI1 gene therapy on mitochondrial optic neuropathies. Our results indicate a window of opportunity for the gene therapy to be applied successfully after the onset of the disease symptoms. Available as a free download COMMENT: An interesting study that deals with an animal model. Back ----------------------------------------------------------------------------------------------------------------------- Dev Disabil Res Rev. 2010 Jun;16(2):183-8. Coenzyme Q and mitochondrial disease. Quinzii CM, Hirano M. Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA. Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies. Available as a free download COMMENT: A paper about the use of Coenzyme Q. Back ----------------------------------------------------------------------------------------------------------------------- Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1119-23. Genotype-phenotype correlations in Leber hereditary optic neuropathy. Tonska K, Kodron A, Bartnik E. Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Ul. Pawinskiego 5a, 02-106 Warsaw, Poland. Leber hereditary optic neuropathy (LHON), acute or subacute vision loss due to retinal ganglion cell death which in the long run leads to optic nerve atrophy is one of the most widely studied maternally inherited diseases caused by mutations in mitochondrial DNA. Although three common mutations, 11778G>A, 14484T>C or 3460G>A are responsible for over 90% of cases and affect genes encoding complex I subunits of the respiratory chain, their influence on bioenergetic properties of the cell is marginal and cannot fully explain the pathology of the disease. The following chain of events was proposed, based on biochemical and anatomical properties of retinal ganglion cells whose axons form the optic nerve: mitochondrial DNA mutations increase reactive oxygen species production in these sensitive cells, leading to caspase-independent apoptosis. As LHON is characterized by low penetrance and sex bias (men are affected about 5 times more frequently than women) the participation of the other factors-genetic and environmental-beside mtDNA mutations was studied. Mitochondrial haplogroups and smoking are some of the factors involved in the complex etiology of this disease. COMMENT: A paper discussing the causes of LHON disease. Back ------------------------------------------------------------------------------------------------------------------------ Brain. 2010 Oct;133(10):2952-63. The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. Tuppen HA, Hogan VE, He L, Blakely EL, Worgan L, Al-Dosary M, Saretzki G, Alston CL, Morris AA, Clarke M, Jones S, Devlin AM, Mansour S, Chrzanowska-Lightowlers ZM, Thorburn DR, McFarland R, Taylor RW. Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne, UK. Isolated complex I deficiency is the most frequently observed oxidative phosphorylation defect in children with mitochondrial disease, leading to a diverse range of clinical presentations, including Leigh syndrome. For most patients the genetic cause of the biochemical defect remains unknown due to incomplete understanding of the complex I assembly process. Nonetheless, a plethora of pathogenic mutations have been described to date in the seven mitochondrial-encoded subunits of complex I as well as in 12 of the nuclear-encoded subunits and in six assembly factors. Whilst several mitochondrial DNA mutations are recurrent, the majority of these mutations are reported in single families. We have sequenced core structural and functional nuclear-encoded subunits of complex I in a cohort of 34 paediatric patients with isolated complex I deficiency, identifying pathogenic mutations in 6 patients. These included a novel homozygous NDUFS1 mutation in an Asian child with Leigh syndrome, a previously identified NDUFS8 mutation (c.236C>T, p.P79L) in a second Asian child with Leigh-like syndrome and six novel, compound heterozygous NDUFS2 mutations in four white Caucasian patients with Leigh or Leigh-like syndrome. Three of these children harboured an identical NDUFS2 mutation (c.875T>C, p.M292T), which was also identified in conjunction with a novel NDUFS2 splice site mutation (c.866+4A>G) in a fourth Caucasian child who presented to a different diagnostic centre, with microsatellite and single nucleotide polymorphism analyses indicating that this was due to an ancient common founder event. Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes. Available as a free download COMMENT: A report of a case of Complex I deficiency. Back ----------------------------------------------------------------------------------------------------------------------- Hum Genet. 2010 Oct;128(4):465-8. No association between the SNPs (rs3749446 and rs1402000) in the PARL gene and LHON in Chinese patients with m.11778G>A. Zhang AM, Jia X, Zhang Q, Yao YG. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China. According to a recent genome-wide linkage scan and association study of families with m.11778G>A in Thailand, two single nucleotide polymorphisms (SNPs) (rs3749446 and rs1402000) in the presenilins-associated rhomboid-like (PARL) gene were found to be associated with Leber hereditary optic neuropathy (LHON). In order to verify this association in Chinese LHON patients, we genotyped three PARL gene variants (rs3749446, rs953419, and rs1402000) in 179 patients with m.11778G>A and 170 patients with suspected LHON, and compared them to a control population containing the HapMap Chinese and 58 normal individuals analyzed in this study. We identified no association between these PARL gene SNPs and LHON in Chinese patients with m.11778G>A (P>0.05). Haplotype analysis also showed no statistical difference among the three Chinese populations. COMMENT: No association between G11778A and the PARL gene Back ----------------------------------------------------------------------------------------------------------------------- Mol Genet Metab. 2010 Aug;100(4):379-84. Very high penetrance and occurrence of Leber's hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation. Zhou X, Zhang H, Zhao F, Ji Y, Tong Y, Zhang J, Zhang Y, Yang L, Qian Y, Lu F, Qu J, Guan MX. School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China. We report here the clinical, genetics and molecular characterization of a five-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). Strikingly, this family exhibits very high penetrance and occurrence of optic neuropathy. In particular, 25 (10 males/15 females) of 30 matrilineal relatives exhibited the variable severity, ranging from profound to mild of visual impairment. This penetrance of optic neuropathy in this Chinese family is much higher than those in many families with LHON worldwide. The age-at-onset for visual impairment in matrilineal relatives in this Chinese family varied from 7 to 24years old, with the average of 15 years old. Furthermore, the ratio between affected male and female matrilineal relatives is 1:1.5 in the Chinese family. This observation is in contrast with the typical features in LHON pedigrees that there was predominance of affected males in LHON in many families from different ethnic origins. Molecular analysis of mitochondrial genome identified the known ND4 G11778A mutation and 51 variants, belonging to Asian haplogroup C4a1. The absence of other known secondary LHON-associated and functionally significant mtDNA mutations in this Chinese family suggested that mitochondrial variants may not play an important role in the phenotypic manifestation of the G11778A mutation in this Chinese family. Therefore, nuclear modifier gene(s) may be responsible for very high penetrance and occurrence of optic neuropathy in this Chinese pedigree. Available as a free download COMMENT: G1178A LHON in China with very high penetrance. Back ------------------------------------------------------------------------------------------------------------------------ Biochem Soc Trans. 2011 Jun;39(3):799-806. doi: 10.1042/BST0390799. The mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease. Bridges HR, Birrell JA, Hirst J. Medical Research Council Mitochondrial Biology Unit, Cambridge, U.K. Complex I (NADH:ubiquinone oxidoreductase) is crucial to respiration in many aerobic organisms. The hydrophilic domain of complex I, containing nine or more redox cofactors, and comprising seven conserved core subunits, protrudes into the mitochondrial matrix or bacterial cytoplasm. The ?-helical membrane-bound hydrophobic domain contains a further seven core subunits that are mitochondrial-encoded in eukaryotes and named the ND subunits (ND1-ND6 and ND4L). Complex I couples the oxidation of NADH in the hydrophilic domain to ubiquinone reduction and proton translocation in the hydrophobic domain. Although the mechanisms of NADH oxidation and intramolecular electron transfer are increasingly well understood, the mechanisms of ubiquinone reduction and proton translocation remain only poorly defined. Recently, an ?-helical model of the hydrophobic domain of bacterial complex I [Efremov, Baradaran and Sazanov (2010) Nature 465, 441-447] revealed how the 63 transmembrane helices of the seven core subunits are arranged, and thus laid a foundation for the interpretation of functional data and the formulation of mechanistic proposals. In the present paper, we aim to correlate information from sequence analyses, site-directed mutagenesis studies and mutations that have been linked to human diseases, with information from the recent structural model. Thus we aim to identify and discuss residues in the ND subunits of mammalian complex I which are important in catalysis and for maintaining the enzyme's structural and functional integrity. COMMENT: A paper discussing Complex I Back ----------------------------------------------------------------------------------------------------------------------- Int J Dev Neurosci. 2011 May;29(3):311-24. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Clay HB, Sillivan S, Konradi C. Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA. Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders. Available as a free download COMMENT: An interesting paper discussing mitochondria and psychiatric conditions. Back ----------------------------------------------------------------------------------------------------------------------- PLoS Biol. 2011 Aug;9(8). Functional dissection of the proton pumping modules of mitochondrial complex I. Dröse S, Krack S, Sokolova L, Zwicker K, Barth HD, Morgner N, Heide H, Steger M, Nübel E, Zickermann V, Kerscher S, Brutschy B, Radermacher M, Brandt U. Molecular Bioenergetics Group, Medical School, Cluster of Excellence Frankfurt Macromolecular Complexes, Center for Membrane Proteomics, Johann Wolfgang Goethe-Universität, Frankfurt, Germany. Mitochondrial complex I, the largest and most complicated proton pump of the respiratory chain, links the electron transfer from NADH to ubiquinone to the pumping of four protons from the matrix into the intermembrane space. In humans, defects in complex I are involved in a wide range of degenerative disorders. Recent progress in the X-ray structural analysis of prokaryotic and eukaryotic complex I confirmed that the redox reactions are confined entirely to the hydrophilic peripheral arm of the L-shaped molecule and take place at a remarkable distance from the membrane domain. While this clearly implies that the proton pumping within the membrane arm of complex I is driven indirectly via long-range conformational coupling, the molecular mechanism and the number, identity, and localization of the pump-sites remains unclear. Here, we report that upon deletion of the gene for a small accessory subunit of the Yarrowia complex I, a stable subcomplex (nb8m?) is formed that lacks the distal part of the membrane domain as revealed by single particle analysis. The analysis of the subunit composition of holo and subcomplex by three complementary proteomic approaches revealed that two (ND4 and ND5) of the three subunits with homology to bacterial Mrp-type Na(+)/H(+) antiporters that have been discussed as prime candidates for harbouring the proton pumps were missing in nb8m?. Nevertheless, nb8m? still pumps protons at half the stoichiometry of the complete enzyme. Our results provide evidence that the membrane arm of complex I harbours two functionally distinct pump modules that are connected in series by the long helical transmission element recently identified by X-ray structural analysis. Available as a free download COMMENT: A paper showing NAD1, NAD2, NAD3, NAD4L & NAD6 form one proton pump, and NAD4 & NAD5 form a second. Back ----------------------------------------------------------------------------------------------------------------------- Brain. 2011 Jan;134(Pt 1):220-34. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, Sadun AA, d'Amati G, Carelli V. Dipartimento di Medicina Sperimentale e Patologia, Sapienza, Universita` di Roma, 00161 Rome, Italy. Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber's hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber's hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17ß-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber's hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17ß-oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17ß-oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor ß localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber's hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules Available as a free download COMMENT: A paper that suggest oestrogen protects against the effects of LHON. Back ----------------------------------------------------------------------------------------------------------------------- Cell Death Dis. 2011 Oct 27;2: Mitochondrial complex I and cell death: a semi-automatic shotgun model. Gonzalez-Halphen D, Ghelli A, Iommarini L, Carelli V, Esposti MD. Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México. Mitochondrial dysfunction often leads to cell death and disease. We can now draw correlations between the dysfunction of one of the most important mitochondrial enzymes, NADH:ubiquinone reductase or complex I, and its structural organization thanks to the recent advances in the X-ray structure of its bacterial homologs. The new structural information on bacterial complex I provide essential clues to finally understand how complex I may work. However, the same information remains difficult to interpret for many scientists working on mitochondrial complex I from different angles, especially in the field of cell death. Here, we present a novel way of interpreting the bacterial structural information in accessible terms. On the basis of the analogy to semi-automatic shotguns, we propose a novel functional model that incorporates recent structural information with previous evidence derived from studies on mitochondrial diseases, as well as functional bioenergetics. Available as a free download COMMENT: Complex I dysfunction - discusses LHON. Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2011;6(6) Accurate determination of the oxidative phosphorylation affinity for ADP in isolated mitochondria. Gouspillou G, Rouland R, Calmettes G, Deschodt-Arsac V, Franconi JM, Bourdel-Marchasson I, Diolez P. Laboratoire de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS-Université Victor Segalen Bordeaux 2, Bordeaux, France. BACKGROUND: Mitochondrial dysfunctions appear strongly implicated in a wide range of pathologies. Therefore, there is a growing need in the determination of the normal and pathological integrated response of oxidative phosphorylation to cellular ATP demand. The present study intends to address this issue by providing a method to investigate mitochondrial oxidative phosphorylation affinity for ADP in isolated mitochondria. METHODOLOGY/PRINCIPAL FINDINGS: The proposed method is based on the simultaneous monitoring of substrate oxidation (determined polarographically) and phosphorylation (determined using the glucose-hexokinase glucose-6-phosphate dehydrogenase-NADP(+) enzymatic system) rates, coupled to the determination of actual ADP and ATP concentrations by bioluminescent assay. This enzymatic system allows the study of oxidative phosphorylation during true steady states in a wide range of ADP concentrations. We demonstrate how the application of this method allows an accurate determination of mitochondrial affinity for ADP from both oxidation (K(mVox)) and phosphorylation (K(mVp)) rates. We also demonstrate that determination of K(mVox) leads to an important overestimation of the mitochondrial affinity for ADP, indicating that mitochondrial affinity for ADP should be determined using phosphorylation rate. Finally, we show how this method allows the direct and precise determination of the mitochondrial coupling efficiency. Data obtained from rat skeletal muscle and liver mitochondria illustrate the discriminating capabilities of this method. CONCLUSIONS/SIGNIFICANCE: Because the proposed method allows the accurate determination of mitochondrial oxidative phosphorylation affinity for ADP in isolated mitochondria, it also opens the route to a better understanding of functional consequences of mitochondrial adaptations/dysfunctions arising in various physiological/pathophysiological conditions. Available as a free download COMMENT: A Discussion about Energy Production Back ----------------------------------------------------------------------------------------------------------------------- Middle East Afr J Ophthalmol. 2011 Jan-Mar; 18(1): 67–70. Bilateral Progressive Visual Loss in an Epileptic, Mentally Retarded Boy Silvana Guerriero, Michele Vetrugno, Lorenza Ciracì, Lucia Artuso,1 Rosa Dell’Aglio,1 and Vittoria Petruzzella1,2 Leber’s hereditary optic neuropathy (LHON) is a maternally inherited, monosymptomatic disorder, characterized by severe central vision loss and optic atrophy that most frequently affects young men. The classic LHON phenotype is associated to three mitochondrial DNA mutations, mostly homoplasmic, in the Mt-ND4, Mt-ND6, and Mt-ND1 genes, encoding for complex I subunits of the mitochondrial respiratory chain. Rare cases have been described in the literature in association with variable central nervous system involvement in a syndromic form called LHON ‘plus.’ In the present study, we report the case of a 16-year-old boy with the 3460/ND1 mutation who presented with epilepsy, migraine, and mental retardation as non-ophthalmic features. We also investigated his relatives who all had the 3460/ND1 mutation. Available as a free download COMMENT: LHON with the 3460 mutation. Back ----------------------------------------------------------------------------------------------------------------------- Mitochondrion. 2011 Jul;11(4):620-2. Variation in MAPT is not a contributing factor to the incomplete penetrance in LHON. Hudson G, Yu-Wai-Man P, Griffiths PG, Horvath R, Carelli V, Zeviani M, Chinnery PF. Institute for Human Genetics, Newcastle University, Newcastle upon Tyne, UK. Leber's hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. LHON, which has an unexplained variable penetrance and pathology, is characterised by disruption of the mitochondrial respiratory chain ultimately resulting in degeneration of the retinal ganglion cells. Phosphorylation of the tau protein is known to cause neurodegeneration and variation in MAPT has been associated with a range of neurodegenerative disorders. Given the relationship between MAPT variation and altered mitochondrial respiratory chain function, we hypothesised that MAPT variation could contribute to the risk of blindness in LHON mtDNA mutation carriers. We studied MAPT variation in a large, well characterised LHON cohort, but were unable to find an association between MAPT genetic variation and visual failure in LHON mtDNA mutation carriers. Our findings suggest that genetic variation in MAPT is unlikely to make a major contribution to the risk of blindness among LHON mutation carriers. Available as a free download COMMENT: A paper trying to explain the features of LHON and failing. Back ----------------------------------------------------------------------------------------------------------------------- Brain. 2011 Sep;134(Pt 9):2677-86. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated. Available as a free download COMMENT: A paper supporting the use of Idebenone in some instances. Back ----------------------------------------------------------------------------------------------------------------------- J Ophthalmol. 2011;2011:179412. Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside. Koilkonda RD, Guy J. Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease. Available as a free download COMMENT: A review article discussing the causes of LHON and possible therapies. Back ----------------------------------------------------------------------------------------------------------------------- J Mol Biol. 2011 Dec 2;414(3):413-26. Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. McKenzie M, Tucker EJ, Compton AG, Lazarou M, George C, Thorburn DR, Ryan MT. Centre for Reproduction and Development, Monash Institute of Medical Research, Clayton 3168, Australia. The assembly of complex I (NADH-ubiquinone oxidoreductase) is a complicated process, requiring the integration of 45 subunits encoded by both nuclear and mitochondrial DNAs into a structure of approximately 1 MDa. A number of "assembly factors" that aid complex I biogenesis have recently been described, including C8orf38. This protein was identified as an assembly factor by its evolutionary conservation in organisms containing complex I and by a C8orf38 mutation in a patient presenting with Leigh syndrome and isolated complex I deficiency. In this report, we have undertaken the characterization of C8orf38 and its role in complex I assembly. Analysis of mitochondria from fibroblasts of a patient harboring a C8orf38 mutation showed almost undetectable levels of steady-state complex I and defective biogenesis of the mtDNA-encoded subunit ND1. Complementation with wild-type C8orf38 restored the levels of both ND1 and complex I, confirming the C8orf38 mutation as the cause of the complex I defect in the patient. In the absence of ND1 in patient cells, early- and mid-stage intermediate complexes were still formed; however, assembly of late-stage intermediates was impaired, indicating a convergence point in the assembly process. While C8orf38 appears to behave at a step in complex I biogenesis similar to that of the assembly factor C20orf7, complementation studies showed that both proteins are required for ND1 synthesis/stabilization. We conclude that C8orf38 is a crucial factor required for the translation and/or integration of ND1 into an early-stage assembly intermediate and that mutation of C8orf38 disrupts the initial stages of complex I biogenesis. COMMENT: A paper about C8orf38 and Complex I Back ----------------------------------------------------------------------------------------------------------------------- Brain. 2011 Sep;134(Pt 9):2447-50. Treatment of Leber hereditary optic neuropathy. Newman NJ. Department of Ophthalmology, Emory University, Atlanta, GA, USA. Available as a free download COMMENT: A review of present knowledge. Back ------------------------------------------------------------------------------------------------------------------------ PLoS One. 2011 Feb 10;6(2) Extra-visual functional and structural connection abnormalities in Leber's hereditary optic neuropathy. Rocca MA, Valsasina P, Pagani E, Bianchi-Marzoli S, Milesi J, Falini A, Comi G, Filippi M. Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits. Available as a free download COMMENT: A paper that shows LHON affects more than just the optic nerves. Back ----------------------------------------------------------------------------------------------------------------------- Eur J Hum Genet. 2011 Jul;19(7):769-75. Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. Swalwell H, Kirby DM, Blakely EL, Mitchell A, Salemi R, Sugiana C, Compton AG, Tucker EJ, Ke BX, Lamont PJ, Turnbull DM, McFarland R, Taylor RW, Thorburn DR. Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, UK. Defects of the mitochondrial respiratory chain are associated with a diverse spectrum of clinical phenotypes, and may be caused by mutations in either the nuclear or the mitochondrial genome (mitochondrial DNA (mtDNA)). Isolated complex I deficiency is the most common enzyme defect in mitochondrial disorders, particularly in children in whom family history is often consistent with sporadic or autosomal recessive inheritance, implicating a nuclear genetic cause. In contrast, although a number of recurrent, pathogenic mtDNA mutations have been described, historically, these have been perceived as rare causes of paediatric complex I deficiency. We reviewed the clinical and genetic findings in a large cohort of 109 paediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29 of 101 probands (29%), 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38 of 101 (38%) probands based on cell hybrid studies, mtDNA sequencing or mutation analysis (nuclear gene mutations were identified in 22 probands). Leigh or Leigh-like disease was the most common clinical presentation in both mtDNA and nuclear genetic defects. The median age at onset was higher in mtDNA patients (12 months) than in patients with a nuclear gene defect (3 months). However, considerable overlap existed, with onset varying from 0 to >60 months in both groups. Our findings confirm that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children. In the absence of parental consanguinity, we recommend whole mitochondrial genome sequencing as a key approach to elucidate the underlying molecular genetic abnormality. Available as a free download COMMENT: Discusses the serious conditions caused by mtDNA mutations. Back ----------------------------------------------------------------------------------------------------------------------- J Biol Chem. 2011 May 20;286(20):17579-84 A model of the proton translocation mechanism of complex I. Treberg JR, Brand MD. Buck Institute for Research on Aging, Novato, California 94945, USA Despite decades of speculation, the proton pumping mechanism of complex I (NADH-ubiquinone oxidoreductase) is unknown and continues to be controversial. Recent descriptions of the architecture of the hydrophobic region of complex I have resolved one vital issue: this region appears to have multiple proton transporters that are mechanically interlinked. Thus, transduction of conformational changes to drive the transmembrane transporters linked by a "connecting rod" during the reduction of ubiquinone (Q) can account for two or three of the four protons pumped per NADH oxidized. The remaining proton(s) must be pumped by direct coupling at the Q-binding site. Here, we present a mixed model based on a crucial constraint: the strong dependence on the pH gradient across the membrane (?pH) of superoxide generation at the Q-binding site of complex I. This model combines direct and indirect coupling mechanisms to account for the pumping of the four protons. It explains the observed properties of the semiquinone in the Q-binding site, the rapid superoxide production from this site during reverse electron transport, its low superoxide production during forward electron transport except in the presence of inhibitory Q-analogs and high protonmotive force, and the strong dependence of both modes of superoxide production on ?pH. Available as a free download COMMENT: Pumping of protons by Complex I. Back ----------------------------------------------------------------------------------------------------------------------- IUBMB Life. 2011 Sep;63(9):669-77. The molecular basis of human complex I deficiency. Tucker EJ, Compton AG, Calvo SE, Thorburn DR. Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia. ejtucker@student.unimelb.edu.au Disorders of oxidative phosphorylation (OXPHOS) have a birth prevalence of ?1/5,000 and are the most common inborn errors of metabolism. The most common OXPHOS disorder is complex I deficiency. Patients with complex I deficiency present with variable symptoms, such as muscle weakness, cardiomyopathy, developmental delay or regression, blindness, seizures, failure to thrive, liver dysfunction or ataxia. Molecular diagnosis of patients with complex I deficiency is a challenging task due to the clinical heterogeneity of patients and the large number of candidate disease genes, both nuclear-encoded and mitochondrial DNA (mtDNA)-encoded. In this review, we have thoroughly surveyed the literature to identify 149 patients described with both isolated complex I deficiency and pathogenic mutations within nuclear genes. In total, 115 different pathogenic mutations have been reported in 22 different nuclear genes encoding complex I subunits or assembly factors, highlighting the allelic and locus heterogeneity of this disorder. Missense mutations predominate in genes encoding core subunits and some assembly factors while null-type mutations are common in the genes encoding supernumerary subunits and other assembly factors. Despite developments in molecular technology, many patients do not receive molecular diagnosis and no gene has yet been identified that accounts for more than 5% of cases, suggesting that there are likely many disease genes that await discovery. COMMENT: A discussion about Complex I deficiency Back ----------------------------------------------------------------------------------------------------------------------- Eur J Ophthalmol. 2012 May 4;22(6):985-991. Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers. Barboni P, Savini G, Feuer WJ, Budenz DL, Carbonelli M, Chicani F, Ramos CD, Salomao SR, De Negri A, Parisi V, Carelli V, Sadun AA. Studio Oculistico d'Azeglio, Bologna - Italy; and Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna - Italy. Purpose. Recent investigations suggested that unaffected carriers of Leber hereditary optic neuropathy (LHON) may show subclinical visual alterations. Structural changes have also been detected by optical coherence tomography (OCT), which revealed a temporal thickening of the retinal nerve fiber layer (RNFL). These changes may reflect compensatory effects such as mitochondria accumulation within the RNFL axons. This study aimed to investigate whether the RNFL of LHON carriers shows greater than expected thickness variations, which may reflect transient subclinical changes, over the course of years. Methods. Using Stratus OCT, the RNFL thickness was measured yearly from 2005 to 2008 in 24 Brazilian LHON carriers, all with homoplasmic 11778/ND4 mtDNA mutation. An Italian sample of 20 healthy subjects served as a control. Data were compared also to a previously published sample (n=59) of glaucomatous eyes. Results. The LHON carriers showed test-retest standard deviations that were larger than normal controls in the temporal (p=0.004), superior (p<0.0001), and inferior quadrants (p=0.019). Compared to the glaucoma cases, no statistical differences were observed. Conclusions. The RNFL thickness in LHON carriers, when measured at different time points, has higher variability than in normal subjects. Transitory RNFL swelling may be caused either by compensatory mechanisms (increased mitochondrial biogenesis) or by axonal stasis preceding decompensation of retinal ganglion cells. In both situations, these changes may represent the origin of the visual alterations previously detected in LHON carriers. Alternatively, increased variability of RNFL thickness may be influenced by the LHON microangiopathy, as retinal blood vessels contribute to the OCT RNFL thickness measurements. Available as a free download COMMENT: Looking at the histology of optic nerves in LHON. Back ----------------------------------------------------------------------------------------------------------------------- BMC Genomics. 2012;13 Suppl 7:S5. doi: 10.1186/1471-2164-13-S7-S5. Quantitative assessment of mitochondrial DNA copies from whole genome sequencing. Chu HT, Hsiao WW, Tsao TT, Chang CM, Liu YW, Fan CC, Lin H, Chang HH, Yeh TJ, Chen JC, Huang DM, Chen CC, Kao CY. Department of Computer Science and Information Engineering, National Taiwan University, Taipei 10617, Taiwan. cykao@csie.ntu.edu.tw. BACKGROUND: Mitochondrial dysfunction is associated with various aging diseases. The copy number of mtDNA in human cells may therefore be a potential biomarker for diagnostics of aging. Here we propose a new computational method for the accurate assessment of mtDNA copies from whole genome sequencing data. RESULTS: Two families of the human whole genome sequencing datasets from the HapMap and the 1000 Genomes projects were used for the accurate counting of mitochondrial DNA copy numbers. The results revealed the parental mitochondrial DNA copy numbers are significantly lower than that of their children in these samples. There are 8%~21% more copies of mtDNA in samples from the children than from their parents. The experiment demonstrated the possible correlations between the quantity of mitochondrial DNA and aging-related diseases. CONCLUSIONS: Since the next-generation sequencing technology strives to deliver affordable and non-biased sequencing results, accurate assessment of mtDNA copy numbers can be achieved effectively from the output of whole genome sequencing. We implemented the method as a software package MitoCounter with the source code and user's guide available to the public at http://sourceforge.net/projects/mitocounter/. COMMENT: A paper showing mtDNA levels are highest in Childhood. Back ----------------------------------------------------------------------------------------------------------------------- Proteomics. 2012 May;12(9):1349-62. Impaired ubiquitin-proteasome-mediated PGC-1? protein turnover and induced mitochondrial biogenesis secondary to complex-I deficiency. Farhoud MH, Nijtmans LG, Wanders RJ, Wessels HJ, Lasonder E, Janssen AJ, Rodenburg RR, van den Heuvel LP, Smeitink JA. Nijmegen Center for Mitochondrial Disorders (NCMD), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.h.j.selman@lumc.nl Most eukaryotic cells depend on mitochondrial OXidative PHOSphorylation (OXPHOS) in their ATP supply. The cellular consequences of OXPHOS defects and the pathophysiological mechanisms in related disorders are incompletely understood. Using a quantitative proteomics approach we provide evidence that a genetic defect of complex-I of the OXPHOS system may associate with transcriptional derangements of mitochondrial biogenesis through stabilization of the master transcriptional regulator PPAR? co-activator 1? (PGC-1?) protein. Chronic oxidative stress suppresses the gene expression of PGC-1? but concomitant inhibition of the ubiquitin-proteasome system (UPS) can stabilize this co-activator protein, thereby inducing its downstream metabolic gene expression programs. Thus, mitochondrial biogenesis, which lays at the heart of the homeostatic control of energy metabolism, can be deregulated by secondary impairments of the protein turnover machinery. COMMENT: Another paper about Complex I Back ----------------------------------------------------------------------------------------------------------------------- J Med Genet. 2012 Sep;49(9):578-90. Complex I deficiency: clinical features, biochemistry and molecular genetics. Fassone E, Rahman S. Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK. Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ?25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis. Available as a free download COMMENT: An important paper that mentions LHON as one of the conditions caused by Complex I disorders. Back ----------------------------------------------------------------------------------------------------------------------- Biochim Biophys Acta. 2012 Feb;1817(2):363-9. The effects of idebenone on mitochondrial bioenergetics. Giorgio V, Petronilli V, Ghelli A, Carelli V, Rugolo M, Lenaz G, Bernardi P. Department of Biomedical Sciences, University of Padova, Padova, Italy. We have studied the effects of idebenone on mitochondrial function in cybrids derived from one normal donor (HQB17) and one patient harboring the G3460A/MT-ND1 mutation of Leber's Hereditary Optic Neuropathy (RJ206); and in XTC.UC1 cells bearing a premature stop codon at amino acid 101 of MT-ND1 that hampers complex I assembly. Addition of idebenone to HQB17 cells caused mitochondrial depolarization and NADH depletion, which were inhibited by cyclosporin (Cs) A and decylubiquinone, suggesting an involvement of the permeability transition pore (PTP). On the other hand, addition of dithiothreitol together with idebenone did not cause PTP opening and allowed maintenance of the mitochondrial membrane potential even in the presence of rotenone. Addition of dithiothreitol plus idebenone, or of idebenol, to HQB17, RJ206 and XTC.UC1 cells sustained membrane potential in intact cells and ATP synthesis in permeabilized cells even in the presence of rotenone and malonate, and restored a good level of coupled respiration in complex I-deficient XTC.UC1 cells. These findings demonstrate that idebenol can feed electrons at complex III. If the quinone is maintained in the reduced state, a task that in some cell types appears to be performed by dicoumarol-sensitive NAD(P)H:quinone oxidoreductase 1 [Haefeli et al. (2011) PLoS One 6, e17963], electron transfer to complex III may allow reoxidation of NADH in complex I deficiencies. Available as a free download" COMMENT: The effects of Idebenone Back ----------------------------------------------------------------------------------------------------------------------- Balkan Med J. 2012 Sep;29(3):306-9. Results of Mitochondrial DNA Sequence Analysis in Patients with Clinically Diagnosed Leber's Hereditary Optic Neuropathy. Gurkan H, Ozal SA, Esgin H. OBJECTIVE: To investigate possible mitochondrial DNA (mtDNA) mutations in patients with Leber's hereditary optic neuropathy (LHON) in order to provide a precise diagnosis and genetic counseling. MATERIAL AND METHODS: Between 1982 and 2007, ten patients were clinically diagnosed with LHON and six of these patients agreed to be involved in this study. Six healthy individuals were also included as a control group. mtDNA was isolated from peripheral blood samples and polymerase chain reaction and mtDNA sequence analysis were performed. RESULTS: In one of the six patients, a homoplasmic mutant m.11778G>A mutation was detected. All of the clinically diagnosed LHON patients and the control groups had the m.14212C>T and m.14580G>A single nucleotide polymorphisms (SNPs). The m.11719A>G SNP was detected in three of six patients and four of the controls. Two of the six patients had the m.3197T>C SNP and, in addition, the m.14258G>A SNP was found in one of these two patients, while neither of these mutations were present in the control group. CONCLUSION: The clinical diagnosis of LHON could be supported by molecular genetics only in one patient by the detection of one mutation. The m.3197T>C and m.14258G>A SNPs should be considered as potential mtDNA mutations due to the fact that they were detected in the patient group. These mutations should be investigated further in large case groups for suspected gene loci that could lead to optic neuropathy. Available as a free download COMMENT: LHON in the Balkans. Back ----------------------------------------------------------------------------------------------------------------------- J Med Genet. 2012 Apr;49(4):277-83. Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, Strecker V, Graf E, Mayr JA, Herberg U, Hennermann JB, Klopstock T, Kuhn KA, Ahting U, Sperl W, Wilichowski E, Hoffmann GF, Tesarova M, Hansikova H, Zeman J, Plecko B, Zeviani M, Wittig I, Strom TM, Schuelke M, Freisinger P, Meitinger T, Prokisch H. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. BACKGROUND: Next generation sequencing has become the core technology for gene discovery in rare inherited disorders. However, the interpretation of the numerous sequence variants identified remains challenging. We assessed the application of exome sequencing for diagnostics in complex I deficiency, a disease with vast genetic heterogeneity. METHODS: Ten unrelated individuals with complex I deficiency were selected for exome sequencing and sequential bioinformatic filtering. Cellular rescue experiments were performed to verify pathogenicity of novel disease alleles. RESULTS: The first filter criterion was 'Presence of known pathogenic complex I deficiency variants'. This revealed homozygous mutations in NDUFS3 and ACAD9 in two individuals. A second criterion was 'Presence of two novel potentially pathogenic variants in a structural gene of complex I', which discovered rare variants in NDUFS8 in two unrelated individuals and in NDUFB3 in a third. Expression of wild-type cDNA in mutant cell lines rescued complex I activity and assembly, thus providing a functional validation of their pathogenicity. Using the third criterion 'Presence of two potentially pathogenic variants in a gene encoding a mitochondrial protein', loss-of-function mutations in MTFMT were discovered in two patients. In three patients the molecular genetic correlate remained unclear and follow-up analysis is ongoing. CONCLUSION: Appropriate in silico filtering of exome sequencing data, coupled with functional validation of new disease alleles, is effective in rapidly identifying disease-causative variants in known and new complex I associated disease genes. COMMENT: Complex I and 'next generation sequencing'. Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2012;7(9):e45182. Idebenone Protects against Retinal Damage and Loss of Vision in a Mouse Model of Leber's Hereditary Optic Neuropathy. Heitz FD, Erb M, Anklin C, Robay D, Pernet V, Gueven N. Santhera Pharmaceuticals, Liestal, Switzerland. Leber's hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients. Available as a free download COMMENT: 'Idebenone' appears to protect against 'rotenone' induced optic nerve damage. Back ----------------------------------------------------------------------------------------------------------------------- BMC Struct Biol. 2012 Aug 3;12:19. A three-dimensional topology of complex I inferred from evolutionary correlations. Kensche PR, Duarte I, Huynen MA. Center for Molecular and Biomolecular Informatics/Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, Nijmegen, HB, 6500, The Netherlands. pkensche@cmbi.ru.nl BACKGROUND: The quaternary structure of eukaryotic NADH:ubiquinone oxidoreductase (complex I), the largest complex of the oxidative phosphorylation, is still mostly unresolved. Furthermore, it is unknown where transiently bound assembly factors interact with complex I. We therefore asked whether the evolution of complex I contains information about its 3D topology and the binding positions of its assembly factors. We approached these questions by correlating the evolutionary rates of eukaryotic complex I subunits using the mirror-tree method and mapping the results into a 3D representation by multidimensional scaling. RESULTS: More than 60% of the evolutionary correlation among the conserved seven subunits of the complex I matrix arm can be explained by the physical distance between the subunits. The three-dimensional evolutionary model of the eukaryotic conserved matrix arm has a striking similarity to the matrix arm quaternary structure in the bacterium Thermus thermophilus (rmsd=19 Å) and supports the previous finding that in eukaryotes the N-module is turned relative to the Q-module when compared to bacteria. By contrast, the evolutionary rates contained little information about the structure of the membrane arm. A large evolutionary model of 45 subunits and assembly factors allows to predict subunit positions and interactions (rmsd=52.6 Å). The model supports an interaction of NDUFAF3, C8orf38 and C2orf56 during the assembly of the proximal matrix arm and the membrane arm. The model further suggests a tight relationship between the assembly factor NUBPL and NDUFA2, which both have been linked to iron-sulfur cluster assembly, as well as between NDUFA12 and its paralog, the assembly factor NDUFAF2. CONCLUSIONS: The physical distance between subunits of complex I is a major correlate of the rate of protein evolution in the complex I matrix arm and is sufficient to infer parts of the complex's structure with high accuracy. The resulting evolutionary model predicts the positions of a number of subunits and assembly factors. Available as a free download COMMENT: An important paper about Complex I Back ----------------------------------------------------------------------------------------------------------------------- Mol Vis. 2012;18:2687-99. Clinical characterization and mitochondrial DNA sequence variations in Leber hereditary optic neuropathy. Kumar M, Kaur P, Kumar M, Saxena R, Sharma P, Dada R. Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. PURPOSE: Leber hereditary optic neuropathy (LHON), a maternally inherited disorder, results from point mutations in mitochondrial DNA (mtDNA). MtDNA is highly polymorphic in nature with very high mutation rate, 10-17 fold higher as compared to nuclear genome. Identification of new mtDNA sequence variations is necessary to establish a clean link with human disease. Thus this study was aimed to assess or evaluate LHON patients for novel mtDNA sequence variations. MATERIALS AND METHODS: Twenty LHON patients were selected from the neuro-ophthalmology clinic of the All India Institute of Medical Sciences, New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. For structural analysis (molecular modeling and simulation) the MODELER 9.2 program in Discovery Studio (DS 2.0) was used. RESULTS: MtDNA sequencing revealed a total of 47 nucleotide variations in the 20 LHON patients and 29 variations in 20 controls. Of 47 changes in patients 21.2% (10/47) were nonsynonymous and the remaining 78.72% (37/47) were synonymous. Five nonsynonymous changes, including primary LHON mutations (NADH dehydrogenase subunit 1 [ND1]:p.A52T, NADH dehydrogenase subunit 6 [ND6]:p.M64V, adenosine triphosphate [ATP] synthase subunit a (F-ATPase protein 6) [ATPase6]:p.M181T, NADH dehydrogenase subunit 4 [ND4]:p.R340H, and cytochrome B [CYB]:p.F181L), were found to be pathogenic. A greater number of changes were present in complex I (53.19%; 25/47), followed by complex III (19.14%; 9/47), then complex IV (19.14%; 9/47), then complex V (8.5%; 4/47). Nonsynonymous variations may impair respiratory chain and oxidative phosphorylation (OXPHOS) pathways, which results in low ATP production and elevated reactive oxygen species (ROS) levels. Oxidative stress is the underlying etiology in various diseases and also plays a crucial role in LHON. CONCLUSIONS: This study describes the role of mtDNA sequence variations in LHON patients. Primary LHON mutations of mtDNA are main variants leading to LHON, but mutations in other mitochondrial genes may also play an important role in pathogenesis of LHON as indicated in the present study. Certain alleles in certain haplogroups have protective or deleterious roles and hence there is a need to analyze a large number of cases for correlating phenotype and disease severity with mutation and mtDNA haplogroups. Available as a free download COMMENT: An important paper about Complex I Back ----------------------------------------------------------------------------------------------------------------------- Proc Natl Acad Sci U S A. 2012 Nov 5. Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, Ross-Cisneros FN, Baciu P, Sung E, McManus MJ, Pan BX, Gil DW, Macgregor GR, Wallace DC. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104. An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress. COMMENT: An interesting and potentially useful development of an animal model. Back ----------------------------------------------------------------------------------------------------------------------- Zhonghua Yan Ke Za Zhi. 2012 Oct;48(10):888-92. Measurement of retinal nerve fiber layer thickness in Leber hereditary optic neuropathy by optical coherence tomography. Liu Z, Sun CB, Tong Y, Zhang HJ, Zhao GJ, Qu J. Department of Ophthalmology, Zhejiang Provincial People's Hospital, Hangzhou 310014, China. OBJECTIVE: To evaluate retinal nerve fiber layer (RNFL) thickness in patients and unaffected carriers of Leber hereditary optic neuropathy (LHON) by optical coherence tomography (OCT). METHODS: This case-control study enrolled 42 LHON maternal family members with mitochondrial DNA G11778A mutation and 100 normal volunteers. RNFL thickness was measured by Stratus OCT in each participant. Mean RNFL thickness of each quadrant, as well as 360° average were calculated and compared in normal controls, LHON carries and LHON patients. RESULTS: Among LHON maternal family members, 15 cases were unaffected carriers who were subgrouped as normal-fundus-appearing carriers (10 cases) and preclinical carriers (5 cases). Twenty seven LHON patients included 9, 5, and 13 cases in the early, advancing and advanced stages, respectively. Normal fundus-appearing carriers showed normal RNFL thickness of each quadrant and 360° average. Preclinical carriers and early-staged patients showed no significant difference in RNFL thickness of each quadrant and 360° average (P = 0.138 to 0.645), yet both showed thicker RNFL in temporal, superior and inferior quadrant, as well as 360° average, if compared with normal controls (P = 0.000 to 0.018). Compared with normal controls, preclinical carriers and early-staged patients, advancing LHON patients showed thinner RNFL in temporal and inferior quadrant, as well as 360° average (P = 0.000 to 0.005). Advanced LHON patients showed thinner RNFL in each quadrant and 360° average, compared with normal controls, LHON carriers, and advancing cases (P = 0.000 to 0.037). CONCLUSIONS: RNFL thickness in LHON patients and unaffected carriers was characterized by OCT in this study, which would improve the understanding of the natural course of LHON. COMMENT: Retinal testing in LHON cases. Back ----------------------------------------------------------------------------------------------------------------------- Neuromuscul Disord. 2012 Dec;22 Suppl 3:S226-9. Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases. Mancuso M, Angelini C, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Zeviani M, Siciliano G; Nation-wide Italian Collaborative Network of Mitochondrial Diseases. Neurological Clinic, University of Pisa, Italy. mancusomichelangelo@gmail.com Fatigue and exercise intolerance are common symptoms of mitochondrial diseases, but difficult to be clinically assessed. New methods to quantify these rather common complaints are strongly needed in the clinical practice. Coenzyme Q10 administration and aerobic exercise may improve exercise intolerance, but more definite studies are still pending. Herein, we have revised "how to measure" and "how to treat" these symptoms of mitochondrial patients. Subsequently, we reviewed the clinical data of the 1164 confirmed mitochondrial patients present in the Italian nation-wide database of mitochondrial disease, with special regard to exercise intolerance. We observed that more of 20% of mitochondrial patients complain of exercise intolerance. This symptom seems to be frequently associated with specific patient groups and/or genotypes. Ragged red fibers and COX-negative fibers are more often present in subjects with exercise intolerance, whereas lactate levels could not predict this symptom. Multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases, and may represent the basis for more rigorous longitudinal studies. Available as a free download COMMENT: Exercise intolerance is not a feature of LHON. Back ----------------------------------------------------------------------------------------------------------------------- Gene. 2012 Dec 21. pii: S0378-1119(12)01534-X. Leigh Syndrome Associated with Mitochondrial Complex I Deficiency Due to Novel Mutations In NDUFV1 and NDUFS2. Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J, Tarnopolsky M. Department of Pediatrics, McMaster Children's Hospital, Hamilton, Ontario, Canada. Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. Mutations in genes encoding for subunits of the respiratory chain or assembly factors of respiratory chain complexes are often documented in LS cases. Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) enzyme deficiencies account for a significant proportion of mitochondrial disorders, including LS. In an attempt to expand the repertoire of known mutations accounting for LS, we describe the clinical, radiological, biochemical and molecular data of six patients with LS found to have novel mutations in two complex I subunits (NDUFV1 and NDUFS2). Two siblings were homozygous for the previously undescribed R386C mutation in NDUFV1, one patient was a compound heterozygote for the R386C mutation in NDUFV1 and a frameshift mutation in the same gene, one patient was a compound heterozygote for the R88G and R199P mutations in NDUFV1, and two siblings were compound heterozygotes for an undescribed E104A mutation in NDUFS2. After the novel mutations were identified, we employed prediction models using protein conservation analysis (SIFT, PolyPhen and UCSC genome browser) to determine pathogenicity. The R386C, R88G, R199P, and E104A mutations were found to be likely pathogenic, and thus presumably account for the LS phenotype. This case series broadens our understanding of the etiology of LS by identifying new molecular defects that can result in complex I deficiency and may assist in targeted diagnostics and/or prenatal diagnosis of LS in the future. COMMENT: A paper about disease caused by Complex I mutations. Back ----------------------------------------------------------------------------------------------------------------------- Brain. 2012 Jan;135(Pt 1):12-22. Assembly factors as a new class of disease genes for mitochondrial complex I deficiency: cause, pathology and treatment options. Nouws J, Nijtmans LG, Smeitink JA, Vogel RO. Nijmegen Centre for Mitochondrial Disorders at the Department of Paediatrics, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands. Complex I deficiency is the most frequent cause of oxidative phosphorylation disorders. The disease features a large diversity of clinical symptoms often leading to progressive encephalomyopathies with a fatal outcome. There is currently no cure, and although disease-causing mutations have been found in the genes encoding complex I subunits, half of the cases remain unexplained. However, in the past 5 years a new class of complex I disease genes has emerged with the finding of specific assembly factors. So far nine such genes have been described and it is believed that in the near future more will be found. In this review, we will address whether the functions of these chaperones point towards a general molecular mechanism of disease and whether this enables us to design a treatment for complex I deficiency. COMMENT: An review paper about Complex I Back ----------------------------------------------------------------------------------------------------------------------- Mol Genet Metab. 2012 Feb;105(2):163-72. Mitochondrial complex I deficiency of nuclear origin I. Structural genes. Pagniez-Mammeri H, Loublier S, Legrand A, Bénit P, Rustin P, Slama A. Laboratoire de Biochimie, APHP Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre cedex, France. Complex I (or NADH-ubiquinone oxidoreductase), is by far the largest respiratory chain complex with 38 subunits nuclearly encoded and 7 subunits encoded by the mitochondrial genome. Its deficiency is the most frequently encountered in mitochondrial disorders. Here, we summarize recent data obtained on architecture of complex I, and review the pathogenic mutations identified to date in nuclear structural complex I genes. The structural NDUFS1, NDUFS2, NDUFV1, and NDUFS4 genes are mutational hot spot genes for isolated complex I deficiency. The majority of the pathogenic mutations are private and the genotype-phenotype correlation is inconsistent in the rare recurrent mutations. COMMENT: A recent review of Complex I Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2012;7(11):e50230. doi: 10.1371/journal.pone.0050230. Secondary Post-Geniculate Involvement in Leber's Hereditary Optic Neuropathy. Rizzo G, et al. Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy ; "IRCCS Istituto delle Scienze Neurologiche", Bologna, Italy. Leber's hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B?=?0.002; P<0.05) and lack of recovery of visual acuity (B?=?0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons. Available as a free download COMMENT: A paper discussing the histological changes in LHON. Back ------------------------------------------------------------------------------------------------------------------------- J Biol Chem. 2012 Oct 5;287(41):34743-51. doi: 10.1074/jbc.M112.384560. Epub 2012 Aug 1. The deactive form of respiratory complex I from Mammalian mitochondria is a na+/h+ antiporter. Roberts PG, Hirst J. From The Medical Research Council Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, United Kingdom. In mitochondria, complex I (NADH:ubiquinone oxidoreductase) uses the redox potential energy from NADH oxidation by ubiquinone to transport protons across the inner membrane, contributing to the proton-motive force. However, in some prokaryotes, complex I may transport sodium ions instead, and three subunits in the membrane domain of complex I are closely related to subunits from the Mrp family of Na(+)/H(+) antiporters. Here, we define the relationship between complex I from Bos taurus heart mitochondria, a close model for the human enzyme, and sodium ion transport across the mitochondrial inner membrane. In accord with current consensus, we exclude the possibility of redox-coupled Na(+) transport by B. taurus complex I. Instead, we show that the "deactive" form of complex I, which is formed spontaneously when enzyme turnover is precluded by lack of substrates, is a Na(+)/H(+) antiporter. The antiporter activity is abolished upon reactivation by the addition of substrates and by the complex I inhibitor rotenone. It is specific for Na(+) over K(+), and it is not exhibited by complex I from the yeast Yarrowia lipolytica, which thus has a less extensive deactive transition. We propose that the functional connection between the redox and transporter modules of complex I is broken in the deactive state, allowing the transport module to assert its independent properties. The deactive state of complex I is formed during hypoxia, when respiratory chain turnover is slowed, and may contribute to determining the outcome of ischemia-reperfusion injury. Available as a free download COMMENT: A detailed paper on Complex I Back ----------------------------------------------------------------------------------------------------------------------- J Inherit Metab Dis. 2012 Jan;35(1):125-31. Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7. Saada A, Edvardson S, Shaag A, Chung WK, Segel R, Miller C, Jalas C, Elpeleg O. Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, POB 1200, 91120 Jerusalem, Israel. annsr@hadassah.org.il Defects of the mitochondrial oxidative phosphorylation (OXPHOS) system are frequent causes of neurological disorders in children. Linkage analysis and DNA sequencing identified a new founder p.G250V substitution in the C20ORF7 complex I chaperone in five Ashkenazi Jewish patients from two families with a combined OXPHOS complex I and IV defect presenting with Leigh's syndrome in infancy. Complementation with the wild type gene restored complex I, but only partially complex IV activity. Although the pathogenic mechanism remains elusive, a C20ORF7 defect should be considered not only in isolated complex I deficiency, but also in combination with decreased complex IV. Given the significant 1:290 carrier rate for the p.G250V mutation among Ashkenazi Jews, this mutation should be screened in all Ashkenazi patients with Leigh's syndrome prior to muscle biopsy. COMMENT: A case of Leigh's syndrome and C20orf7 Back ----------------------------------------------------------------------------------------------------------------------- Arch Neurol. 2012 Mar;69(3):331-8. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, Kubis K, Carelli V, Miller G. Doheny Eye Institute, Department of Ophthalmology, USC-Keck School of Medicine, 1450 San Pablo St, Los Angeles, CA 90089-0228, USA. asadun@usc.edu OBJECTIVE: To evaluate the safety and efficacy of a new therapeutic agent, EPI-743, in Leber hereditary optic neuropathy (LHON) using standard clinical, anatomic, and functional visual outcome measures. DESIGN: Open-label clinical trial. SETTING: University medical center. Patients Five patients with genetically confirmed LHON with acute loss of vision were consecutively enrolled and treated with the experimental therapeutic agent EPI-743 within 90 days of conversion. Intervention During the course of the study, 5 consecutive patients received EPI-743, by mouth, 3 times daily (100-400 mg per dose). MAIN OUTCOME MEASURES: Treatment effect was assessed by serial measurements of anatomic and functional visual indices over 6 to 18 months, including Snellen visual acuity, retinal nerve fiber layer thickness measured by optical coherence tomography, Humphrey visual fields (mean decibels and area with 1-log unit depression), and color vision. Treatment effect in this clinical proof of principle study was assessed by comparison of the prospective open-label treatment group with historical controls. RESULTS: Of 5 subjects treated with EPI-743, 4 demonstrated arrest of disease progression and reversal of visual loss. Two patients exhibited a total recovery of visual acuity. No drug-related adverse events were recorded. CONCLUSIONS: In a small open-label trial, EPI-743 arrested disease progression and reversed vision loss in all but 1 of the 5 consecutively treated patients with LHON. Given the known natural history of acute and rapid progression of LHON resulting in chronic and persistent bilateral blindness, these data suggest that the previously described irreversible priming to retinal ganglion cell loss may be reversed. COMMENT: An interesting trial of a drug to treat LHON. Back ----------------------------------------------------------------------------------------------------------------------- Doc Ophthalmol. 2012 Aug;125(1):71-4. Clinical and electrophysiological recovery in Leber hereditary optic neuropathy with G3460A mutation. Sharkawi E, Oleszczuk JD, Holder GE, Raina J. Jules-Gonin Eye Hospital, Avenue de France 15, Lausanne 1004, Switzerland. To report a case of clinical and electrophysiological recovery in Leber hereditary optic neuropathy (LHON) with G3460A Mutation. A 10-year-old boy with a three-month history of painless bilateral sequential visual loss upon presentation underwent visual acuity (diminished), anterior and posterior segment examination (normal), fluorescein angiography (normal), Goldman kinetic perimetry (bilateral central scotomata), genetic (a point G3460A mutation) and electrophysiological investigation (undetectable pattern visual evoked potentials (VEP); low amplitude, broadened and reduced flash VEPs and loss of the N95 component in the pattern electroretinograms). Diagnosis of LHON was made. Eighteen months later vision and electrophysiological tests results began spontaneously improving. Kinetic perimetry revealed reduced density and size of scotomata. Two years later, there had been further electrophysiological improvement. This report describes both clinical and electrophysiological improvement in LHON with G3460A mutation. COMMENT: A report showing spontaneous recover with 'LHON G3460A'. Back ----------------------------------------------------------------------------------------------------------------------- Curr Neurol Neurosci Rep. 2012 Jun;12(3):308-17. Disorders of the optic nerve in mitochondrial cytopathies: new ideas on pathogenesis and therapeutic targets. Sitarz KS, Chinnery PF, Yu-Wai-Man P. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle, UK. Mitochondrial cytopathies are a heterogeneous group of human disorders triggered by disturbed mitochondrial function. This can be due to primary mitochondrial DNA mutations or nuclear defects affecting key components of the mitochondrial machinery. Optic neuropathy is a frequent disease manifestation and the degree of visual failure can be profound, with a severe impact on the patient's quality of life. This review focuses on the major mitochondrial disorders exhibiting optic nerve involvement, either as the defining clinical feature or as an additional component of a more extensive phenotype. Over the past decade, significant progress has been achieved in our basic understanding of Leber hereditary optic neuropathy and autosomal-dominant optic atrophy--the two classical paradigms for these mitochondrial optic neuropathies. There are currently limited treatments for these blinding ocular disorders and, ultimately, the aim is to translate these major advances into tangible benefits for patients and their families. Available as a free download COMMENT: A recent review paper. Back ----------------------------------------------------------------------------------------------------------------------- Zhonghua Yan Ke Za Zhi. 2012 Dec;48(12):1065-8. A clinical study of Leber hereditary optic neuropathy Wei QP, Sun YH, Zhou XT, Zhou J, Gong XH, Jia XY. Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing 100078 OBJECTIVE: To investigate the clinical characteristics of Leber hereditary optic neurology (LHON) patients with different primary site mutation. METHODS: Four hundred and fourteen patients with optic neuropathy were divided into three groups: clinically diagnosed LHON group (group A), probable LHON group (group B), optic neuropathy of unknown reason group (group C). Visual acuity (VA), colour vision, Intraocular pressure (IOP), virual field and visual evoked potential (VEP) were tested for all the patients. Some (64 cases) had optical coherence tomography (OCT) measurement. Mutations of mtDNA were detected for all the groups, and clinical analysis were carried out emphatically in the patients with the 11778 mutation confirmed by gene assessment. T paired test was used to evaluate two group patients of different Mitochondrial DNA mutation. RESULTS: Gene mutations were found in 215 of the 414 patients (52%). Approximately 93% (199/255) of the patients were caused by the common primary mutations (11778, 14484, 3460 mutation), in which 100% mutation (106/106) in group A, 65% (91/139) in group B, and 11% (18/169) in group C. No cases were diagnosed with confirmed LHON in the patients with unilateral optic neuropathy. Fundus examination in 334 eyes of 167 cases showed pseudo papilledema (54 eyes), normal (67 eyes), pale disc or plae on the teperal side of the optic disc (213 eyes). On the basis data of OCT from 64 patients and 84 normal person, RNFL was found thickening at the early stage and thinning gradually at the later stage in the LHON patients. But, the RNFL thickness of patients with 1-2 years history was not significantly different from the patients with over 2 years history(P = 0.051), and there was no difference among the patients with different mitochondrial DNA mutations. The initial mean VA of patients with the 14484 mutation and 11778 mutation were 3.6 ± 0.65, 3.75 ± 0.54 (t = 0.536, P > 0.05), but the follow-up VA were 4.29 ± 0.55 (t = 4.034, P < 0.001) and 3.93 ± 0.49 respectively (t = 1.857, P > 0.05). CONCLUSIONS: The symptoms and fundus manifestation were similar in the LHOH patients with different primary site muation. Gene mutation analysis is helpful to assess the prognosis of visual acuity. COMMENT: LHON in China. Back ----------------------------------------------------------------------------------------------------------------------- Proc Natl Acad Sci U S A. 2012 May 15;109(20) Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model. Yu H, Koilkonda RD, Chou TH, Porciatti V, Ozdemir SS, Chiodo V, Boye SL, Boye SE, Hauswirth WW, Lewin AS, Guy J. Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. To introduce DNA into mitochondria efficiently, we fused adenoassociated virus capsid VP2 with a mitochondrial targeting sequence to carry the mitochondrial gene encoding the human NADH ubiquinone oxidoreductase subunit 4 (ND4). Expression of WT ND4 in cells with the G11778A mutation in ND4 led to restoration of defective ATP synthesis. Furthermore, with injection into the rodent eye, human ND4 DNA levels in mitochondria reached 80% of its mouse homolog. The construct expressed in most inner retinal neurons, and it also suppressed visual loss and optic atrophy induced by a mutant ND4 homolog. The adenoassociated virus cassette accommodates genes of up to ?5 kb in length, thus providing a platform for introduction of almost any mitochondrial gene and perhaps even allowing insertion of DNA encompassing large deletions of mtDNA, some associated with aging, into the organelle of adults. Available as a free download COMMENT: LHON suppression in Mouse Model. Back ------------------------------------------------------------------------------------------------------------------------ Curr Opin Neurol. 2013 Feb;26(1):52-8. Mitochondrial dysfunction in optic neuropathies: animal models and therapeutic options. Carelli V, La Morgia C, Sadun AA. Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna IRCCS Istituto di Scienze Neurologiche, Bologna, Italy Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. PURPOSE OF REVIEW: We review the recent advances in animal models generated to study the complexities of mitochondrial optic neuropathies and the therapeutic strategies proposed for these disorders. RECENT FINDINGS: We have recently witnessed a rapid proliferation of animal models attempting to recapitulate the clinical and pathogenic features of human genetic mitochondrial optic neuropathies, that is Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). Although the generation of an animal model of disorders due to nuclear gene defects is well established and technically feasible, for mitochondrial DNA (mtDNA)-based diseases, there have been major limitations. Notwithstanding these difficulties, various approaches circumvented the problem by proposing biochemical or tissue-specific delivery models of mutant mtDNA able to induce retinal ganglion cell disease, contextually providing gene therapy solutions. Recently, the first mito-mice model of LHON has also been reported. In addition to gene therapy, new generation quinone-derived molecules and other strategies based on pharmacological activation of mitochondrial biogenesis are currently being tested, with the first clinical trials being initiated in humans. SUMMARY: Major advancements have been achieved in delivering mtDNA to mitochondria and generating faithful animal models of mtDNA-based optic neuropathy. The availability of these approaches, including animal models of nuclear-encoded optic neuropathies, provides unprecedented opportunities to test therapies, both genetic and pharmacological, paving the road to clinical trials in humans. COMMENT: A new review paper. Back ----------------------------------------------------------------------------------------------------------------------- Discov Med. 2013 Mar;15(82):141-9. Novel therapeutic approaches for Leber's hereditary optic neuropathy. Iyer S. Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia 23284, USA. Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-to-treat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy. COMMENT: Future therapies ? Back ----------------------------------------------------------------------------------------------------------------------- Int Ophthalmol. 2013 Feb;33(1):75-7. Glaucoma progression associated with Leber's hereditary optic neuropathy. Nucci C, Martucci A, Mancino R, Cerulli L. Ophthalmological Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy. nucci@med.uniroma2.it The purpose of this article is to describe a case of open-angle glaucoma progression associated with Leber's hereditary optic neuropathy. Single case analysis method is used. A 53-year-old woman with a previous diagnosis of glaucoma presented with progressive visual field loss. Complete ophthalmological examination and blood tests were negative for other concomitant diseases. Genetic counseling revealed mitochondrial DNA mutation compatible with the diagnosis of Leber's hereditary optic neuropathy. In conclusion, the case describes the concomitant occurrence of open-angle glaucoma and Leber's optic neuropathy. We hypothesize that the two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the consequent rapid progression of visual impairment. Screening for mitochondrial DNA mutations may be requested in patients with glaucoma who, despite pharmacologically controlled intraocular pressure, show rapid progression of the disease. COMMENT: Associated with glaucoma ? Back ----------------------------------------------------------------------------------------------------------------------- PLoS ONE 8(5): e63446. doi:10.1371/journal.pone.0063446 Raised Intraocular Pressure as a Potential Risk Factor for Visual Loss in Leber Hereditary Optic Neuropathy. Thouin A, Griffiths PG, Hudson G, Chinnery PF, Yu-Wai-Man P Leber Hereditary Optic Neuropathy (LHON) is an important cause of inherited mitochondrial blindness among young adults. The majority of patients carry one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A and m.14484T>C, all of which affect critical complex I subunits of the mitochondrial respiratory chain. LHON is characterised by marked incomplete penetrance, clearly implying that the mtDNA mutation is insufficient on its own to trigger retinal ganglion cell dysfunction and visual loss. In this case series of three affected patients harbouring the m.11778G>A mutation, we provide evidence suggesting that raised intraocular pressure could be a risk factor triggering visual loss in at-risk LHON carriers. Available as a free download COMMENT: Associated with raised intraocular pressure ? Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2013 May 14. pii: iovs.13-11925v1. doi: 10.1167/iovs.13-11925. Haplogroup heterogeneity of LHON patients carrying m.14484T>C mutation in India. Khan NA, Govindaraj P, Soumittra N, Srilekha S, Ambika S, Vanniarajan A, Meena AK, Uppin MS, Sundaram C, Taly AB, Bindu PS, Gayathri N, Thangaraj K. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India. PURPOSE: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Leber hereditary optic neuropathy (LHON) in Indian patients carrying m.14484T>C mutation. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian families with LHON carrying m.14484T>C mutation. Haplogroup was constructed based on evolutionarily important mtDNA variants. RESULTS: In present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance was found to be 20.05% (16/76) in eight pedigrees with m.14484T>C mutation and showed substantially higher gender bias (ratio of affected male to female 13:3). The mtDNA haplogroup was constructed based on the complete mtDNA sequencing of probands and revealed that they belong to different haplogroups i.e F1c1, M31a, U2a, M*, I1, M6, M3a1, and R30a. In present study we did not find any association of specific haplogroup with m.14484T>C mutation in Indian population or any specific secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. CONCLUSIONS: Contrary to earlier reports showing preferential association of m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 sub-haplogroup background. The present study shows that m.14484T>C arose independently in different mtDNA haplogroup and ethnic background in Indian population, which may influence clinical expression of the disease. COMMENT: LHON and the T14484C mutation in India. Back ----------------------------------------------------------------------------------------------------------------------- Neuroimage. 2013 May 16. pii: S1053-8119(13)00526-0. doi: 10.1016/j.neuroimage.2013.05.032. Long term cortical plasticity in visual retinotopic areas in humans with silent retinal ganglion cell loss. d'Almeida OC, Mateus C, Reis A, Grazina MM, Castelo-Branco M. Visual Neuroscience Laboratory, IBILI, Faculty of Medicine, University of Coimbra, Portugal. Visual cortical plasticity induced by overt retinal lesions (scotomas) has remained a controversial phenomenon. Here we studied cortical plasticity in a silent model of retinal ganglion cell loss, documented by in vivo optical biopsy using coherence tomography. The cortical impact of non scotomatous subtle retinal ganglion cell functional and structural loss was investigated in carriers of the mitochondrial DNA 11778G>A mutation causing Leber's hereditary optic neuropathy. We used magnetic resonance imaging (MRI) to measure cortical thickness and fMRI to define retinotopic cortical visual areas V1, V2 and V3 in silent carriers and matched control groups. Repeated measures analysis of variance revealed a surprising increase in cortical thickness in the younger carrier group (below 21years of age). This effect dominated in extrastriate cortex, and notably V2. This form of structural plasticity suggests enhanced plastic developmental mechanisms in extrastriate retinotopic regions close to V1 and not receiving direct retinocortical input. COMMENT: Looking at cortical adaptations in carriers of a LHON mutation. See also Grazina(2007) Back ----------------------------------------------------------------------------------------------------------------------- Neurobiol Dis. 2013 May 20. pii: S0969-9961(13)00149-6. doi: 10.1016/j.nbd.2013.05.007. The mitochondrial disease associated protein Ndufaf2 is dispensable for Complex-1 assembly but critical for the regulation of oxidative stress. Schlehe JS, Journel MS, Taylor KP, Amodeo KD, Lavoie MJ. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston MA 02115, USA. Deficiency in human mitochondrial Complex-1 has been linked to a wide variety of neurological disorders. Homozygous deletion of the Complex-1 associated protein, Ndufaf2, leads to a severe juvenile onset encephalopathy involving degeneration of the substantia nigra and other sub-cortical regions resulting in adolescent lethality. To understand the precise role of Ndufaf2 in Complex-1 function and its links to neurologic disease, we studied the effects on Complex-1 assembly and function, as well as pathological consequences at the cellular level, in multiple in vitro models of Ndufaf2 deficiency. Using both Ndufaf2-deficient human neuroblastoma cells and primary fibroblasts cultured from Ndufaf2 knock-out mice we found that Ndufaf2-deficiency selectively reduces Complex-1 activity. While Ndufaf2 is traditionally referred to as an assembly factor of Complex-1, surprisingly, however, Ndufaf2-deficient cells were able to assemble a fully mature Complex-1 enzyme, albeit with reduced kinetics. Importantly, no evidence of intermediate or incomplete assembly was observed. Ndufaf2 deficiency resulted in significant increases in oxidative stress and mitochondrial DNA deletion, consistent with contemporary hypotheses regarding the pathophysiology of inherited mutations in Complex-1 disorders. These data suggest that Ndufaf2, unlike other Complex-1 assembly factors, may be more accurately described as a chaperone involved in proper folding during Complex-1 assembly, since it is dispensable for Complex-1 maturation but not its proper function. COMMENT: More about Complex-1 functioning. Back ----------------------------------------------------------------------------------------------------------------------- Mitochondrion. 2013 Jun 6. pii: S1567-7249(13)00092-5. Severe manifestation of Leber`s hereditary optic neuropathy due to 11778G>A mtDNA mutation in a female with hypoestrogenism due to Perrault syndrome. Badura-Stronka M, Wawrocka A, Zawieja K, Silska S, Krawczynski MR. Chair and Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland; Center for Medical Genetics GENESIS, Poznan, Poland. Perrault syndrome (PS) is a rare autosomal recessive condition with ovarian dysgenesis, hearing deficit and neurological abnormalities in female patients. The molecular basis of the syndrome is heterogeneous, mutations in the HSD17B4 gene have been identified in one family and mutations in the HARS2 gene have been found in another one. We have excluded pathogenic changes in the HSD17B4 gene and in the HARS2 gene by a direct sequencing of all coding exons in a female with clinical hallmarks of PS, ataxia and mild mental retardation. In addition, the patient suffers from severe Leber`s hereditary optic neuropathy (LHON) due to 11778G>A mtDNA mutation. This case is the first reported patient with PS and LHON. Possible influence of hypoestrogenism on the manifestation of optic neuropathy in this patient is discussed in the context of recent findings concerning the crucial role of estrogens in supporting the vision capacity in LHON-related mtDNA mutation carriers. COMMENT: LHON and low oestrogen. Back ----------------------------------------------------------------------------------------------------------------------- Mol Vis. 2013 Jun 11;19:1282-1289. Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy. Khan NA, Govindaraj P, Jyothi V, Meena AK, Thangaraj K. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India. BACKGROUND: Mitochondrial DNA (mtDNA) mutations are known to cause Leber hereditary optic neuropathy (LHON). However, the co-occurrence of double pathogenic mutations with different pathological significance in pedigrees is a rare event. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was performed for two Indian families with LHON. The haplogroup was constructed based on evolutionarily important mtDNA variants. RESULTS: We observed the existence of double pathogenic mutations (m.11778G>A and m.1555A>G) in two Indian LHON families, who are from different haplogroup backgrounds (M5a and U2e1), with different clinical penetrance of the disease (visual impairment). The m.11778G>A mutation in the MT-ND4 gene is associated primarily with LHON; whereas, m.1555A>G in the 12S rRNA gene has been reported with aminoglycoside-induced non-syndromic hearing loss. CONCLUSIONS: The absence of hearing abnormality and widely varying clinical expression of LHON suggest additional nuclear modifier genes, environmental factors, and population heterogeneity might play an important role in the expression of visual impairment in these families. Available as a free download COMMENT: LHON and the A1555G mutation occurring in the same persons. Back ----------------------------------------------------------------------------------------------------------------------- J Child Neurol. 2013 Jul 17. Uncommon Leber "Plus" Disease Associated With Mitochondrial Mutation m.11778G>A in a Premature Child. Paquay S, Benoit V, Wetzburger C, Cordonnier M, Meire F, Charon A, Roland D, Coster RV,Nassogne MC, Maystadt I. Service de Neurologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. Leber hereditary optic neuropathy is a well-known mitochondrial disorder that leads to bilateral subacute visual failure. Although visual impairment is often the sole clinical feature, additional and severe neurologic abnormalities also have been documented for this disease. We report on a 13-year-old boy who has presented with severe visual failure since early childhood in a context of prematurity. In the first years of his life, clinical features included delayed psychomotor development and ataxia. The clinical presentation, which was initially attributed to prematurity, worsened thereafter, and the child developed acute neurologic degradation with the typical radiological findings of Leigh syndrome. The mitochondrial DNA point mutation 11778G>A was identified in the ND4 gene. The probable influence of environmental background on clinical expression of Leber optic neuropathy, particularly those of prematurity and oxygen therapy, is discussed in our manuscript. COMMENT: LHON and prematurity. Back ----------------------------------------------------------------------------------------------------------------------- Hsu TK, Wang AG, Yen MY, Liu JH. Department of Ophthalmology, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China. We report a case of Leber's hereditary optic neuropathy (LHON) masquerading as optic neuritis with late visual recovery. A 28-year-old man had gradual visual loss in both eyes for two weeks. Visual acuity was 0.4 in the right eye and 0.7 in the left. Fundus examination revealed hyperaemic discs in each eye. Fluorescein angiography revealed dye leakage at both optic discs in the late phase. Static perimetry (Humphrey 30-2) revealed bilateral relative central scotomata. Magnetic resonance imaging of the optic nerves was normal and his lumbar puncture showed normal opening pressure. He received steroid pulse therapy for three days. Nevertheless, vision in his right eye deteriorated to 0.1 one month later and left vision worsened to 0.05 six months later. Fifteen months after onset, his vision began to improve. At 21 months, his vision recovered to 0.9?R and 1.0?L. Peripheral blood DNA sequencing revealed 14484 mutation of mitochondrial DNA (mtDNA). Visual recovery can occur in patients with Leber's hereditary optic neuropathy with mtDNA 14484 mutation. LHON could be misdiagnosed as optic neuritis in some cases. Molecular examination of mtDNA mutation can confirm the diagnosis of LHON in clinically controversial patients. We should keep in mind the diagnosis of LHON when optic neuritis shows poor response to pulse therapy. COMMENT: LHON and optic neuritis. Back ----------------------------------------------------------------------------------------------------------------------- Exp Eye Res. 2013 Aug 22;116C:55-57. Identification of the variants in PARL, the nuclear modifier gene, responsible for the expression of LHON patients in Thailand. Istikharah R, Tun AW, Kaewsutthi S, Aryal P, Kunhapan B, Katanyoo W, Chuenkongkaew W, Lertrit P. Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. The present study explored variation in the PARL gene as one of the potential nuclear modifiers in the pathogenesis of Leber hereditary optic neuropathy (LHON). Ten exons, their franking introns and 3' UTR of the PARL gene were analysed. Seventeen SNPs detected were investigated in 83 affected and 53 unaffected individuals from 47 independent Thai LHON pedigrees using MQLS statistics in order to minimize the influence of the family background. Three intronic SNPs (rs953419, rs3749446 and rs1402000) showed statistically significant results. Joint haplotypes were constructed based on the genotypes at 3 SNPs and 7 possible haplotypes were observed in the 136 subjects. Our findings that the frequency of the haplotype AAC, and AAT were significantly higher in the unaffected cases and the frequencies of haplotype GGT were significantly higher in LHON cases, indicate that it might have a role in the penetrance of this mitochondrial disease. COMMENT: The PARL gene & LHON. Back ----------------------------------------------------------------------------------------------------------------------- Mol Biol Rep. 2013 Oct 24. Fifteen novel mutations in the mitochondrial NADH dehydrogenase subunit 1, 2, 3, 4, 4L, 5 and 6 genes from Iranian patients with Leber's hereditary optic neuropathy (LHON). Rezvani Z, Didari E, Arastehkani A, Ghodsinejad V, Aryani O, Kamalidehghan B, Houshmand M. Department of Biotechnology, Faculty of Chemistry, University of Kashan, Kashan, Iran. Leber's hereditary optic neuropathy (LHON) is an optic nerve dysfunction resulting from mutations in mitochondrial DNA (mtDNA), which is transmitted in a maternal pattern of inheritance. It is caused by three primary point mutations: G11778A, G3460A and T14484C; in the mitochondrial genome. These mutations are sufficient to induce the disease, accounting for the majority of LHON cases, and affect genes that encode for the different subunits of mitochondrial complexes I and III of the mitochondrial respiratory chain. Other mutations are secondary mutations associated with the primary mutations. The purpose of this study was to determine MT-ND variations in Iranian patients with LHON. In order to determine the prevalence and distribution of mitochondrial mutations in the LHON patients, their DNA was studied using PCR and DNA sequencing analysis. Sequencing of MT-ND genes from 35 LHON patients revealed a total of 44 nucleotide variations, in which fifteen novel variations-A14020G, A13663G, C10399T, C4932A, C3893G, C10557A, C12012A, C13934T, G4596A, T12851A, T4539A, T4941A, T13255A, T14353C and del A 4513-were observed in 27 LHON patients. However, eight patients showed no variation in the ND genes. These mutations contribute to the current database of mtDNA polymorphisms in LHON patients and may facilitate the definition of disease-related mutations in human mtDNA. This research may help to understand the disease mechanism and open up new diagnostic opportunities for LHON. COMMENT: LHON in Iran. Back ----------------------------------------------------------------------------------------------------------------------- J Fr Ophtalmol. 2013 Oct 22. pii: S0181-5512(13)00248-9. Hereditary optic neuropathies: From clinical signs to diagnosis. Meunier I, Lenaers G, Hamel C, Defoort-Dhellemmes S. Centre national de référence maladies rares, affections sensorielles génétiques, service d'ophtalmologie, hôpital Gui-de-Chauliac, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France. Inherited optic atrophy must be considered when working up any optic nerve involvement and any systemic disease with signs of optic atrophy, even with a negative family history. There are two classical forms: dominant optic atrophy, characterized by insidious, bilateral, slowly progressive visual loss and temporal disc pallor, and Leber's optic atrophy, characterized by acute loss of central vision followed by the same event in the fellow eye within a few weeks to months, with disc hyperemia in the acute phase. Family history is critical for diagnosis. In the absence of family history, the clinician must rule out an identifiable acquired cause, i.e. toxic, inflammatory, perinatal injury, traumatic or tumoral, with orbital and brain imaging (MRI). Recessive optic atrophies are more rare and more severe and occur as part of multisystemic disorders, particularly Wolfram syndrome (diabetes mellitus, diabetes insipidus, and hearing loss). Effective treatments are limited; alcohol and smoking should be avoided. A cyclosporine trial (taken immediately upon visual loss in the first eye) is in progress in Leber's optic atrophy to prevent involvement of the fellow eye. COMMENT: A trial of cyclosporine in LHON. Back ----------------------------------------------------------------------------------------------------------------------- Neurology. 2013 Nov 6. Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations. Pfeffer G, Burke A, Yu-Wai-Man P, Compston DA, Chinnery PF. Institute of Genetic Medicine (G.P., P.Y.-W.-M., P.F.C.), Newcastle; Institute of Neurology (A.B.), University College London; and Department of Clinical Neurosciences (D.A.S.C.), University of Cambridge, UK. OBJECTIVE: To determine whether the association between multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) (known as "Harding disease") is a chance finding, or the 2 disorders are mechanistically linked. METHODS: We performed a United Kingdom-wide prospective cohort study of prevalent cases of MS with LHON mitochondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mutations to find evidence of a genetic association. RESULTS: Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data. CONCLUSIONS: Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded. COMMENT: LHON and MS. Back ----------------------------------------------------------------------------------------------------------------------- Mol Vis. 2013 Nov 21;19:2343-2351. Point mutations associated with Leber hereditary optic neuropathy in a Latvian population. Aitullina A, Baumane K, Zalite S, Ranka R, Zole E, Pole I, Sepetiene S, Laganovska G, Baumanis V, Pliss L. Riga Stradins University, Riga, Latvia ; Latvian Biomedical Research and Study Centre, Riga, Latvia. PURPOSE: To study mutations associated with Leber hereditary optic neuropathy (LHON) in patients suspected of having this mitochondrial disorder in a Latvian population. Additional aims were to determine the heteroplasmy status of all non-synonymous polymorphisms identified in the current study and to identify the mitochondrial haplogroups of the studied participants because these factors may contribute to the manifestation of LHON. METHODS: Twelve patients, including patients in two families, were enrolled in the current study. LHON was suspected based on the findings of ophthalmologic examinations. In clinically affected individuals, the presence of all previously reported LHON-associated mutations was assessed with sequencing analysis. Additionally, the SURVEYOR endonuclease assay was used to detect heteroplasmy. The mitochondrial haplogroups were identified with restriction analysis and the sequencing of hypervariable segment 1. RESULTS: In one family (mother and son), there was one primary LHON-associated mutation, G11778A. In addition, one rare previously reported LHON-associated polymorphism, A13637G, was detected in two unrelated patients. A non-synonymous polymorphism at T6253C was found in one individual. This mutation was reported in the background of the 3460 mutation among LHON patients in a Chinese population. No non-synonymous point mutations in mitochondrial DNA were found in five of the study participants. CONCLUSIONS: Molecular analysis of 12 patients with suspected LHON confirmed the diagnosis in four patients and allowed the use of appropriate prophylactic measures and treatment. Further investigations and additional studies of different populations are necessary to confirm the role of the non-synonymous polymorphisms A13637G and T6253C in the manifestation of LHON and the associations of these polymorphisms with mitochondrial haplogroups and heteroplasmy. COMMENT: LHON in Latvia. Back ----------------------------------------------------------------------------------------------------------------------- http://www.biorxiv.org/content/early/2013/11/25/000935 Ian S Logan The-LHON-Enigma: explaining the behaviour of Leber’s Hereditary Optic Neuropathy by the use of a simple computer model Leber's Hereditary Optic Neuropathy (LHON) appears as an enigmatic condition; affecting only certain families and often causing a severe loss of vision seemingly at random amongst family members. The first breakthrough came in 1988 with the linking of the condition to a mutation in the mitochondrial DNA (mtDNA). Now it is known that about 90% of cases are linked to 3 mutations. In this paper the hypothesis is suggested that a LHON mutation decreases the function of the mitochondrial enzyme, Complex I, by 50% and this alone critically endangers the survival of cells - especially the fragile cells of the optic nerves. A computer model has been written to illustrate how the hypothesis can produce a natural history for the condition of LHON that has features similar to those observed in practice; thereby successfully explaining the behaviour of this enigmatic condition Available as a free download COMMENT: A computer model of LHON. Back ----------------------------------------------------------------------------------------------------------------------- Brain. 2013 Dec 24. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy. Giordano C, Iommarini L, Giordano L, Maresca A, Pisano A, Valentino ML, Caporali L, Liguori R, Deceglie S, Roberti M, Fanelli F, Fracasso F, Ross-Cisneros FN, D'Adamo P, Hudson G, Pyle A, Yu-Wai-Man P, Chinnery PF, Zeviani M, Salomao SR, Berezovsky A, Belfort R Jr, Ventura DF, Moraes M, Moraes Filho M, Barboni P, Sadun F, De Negri A, Sadun AA, Tancredi A, Mancini M, d'Amati G, Loguercio Polosa P, Cantatore P, Carelli V. Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies. COMMENT: Mitochondrial biogensis and LHON. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2014 Jan 7. pii: iovs.13-13011v1. Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber hereditary optic neuropathy. Liang M, Jiang P, Li F, Zhang J, Ji Y, He Y, Xu M, Zhu J, Meng X, Zhao F, Tong Y, Liu X, Sun Y, Zhou X, Mo JQ, Qu J, Guan MX. Purpose: To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families. Methods: A cohort of 1218 Han Chinese subjects with LHON and 316 control subjects underwent the clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. Results: The age at onset of optic neuropathy in these subjects ranged from 5 to 55 years, with the average of 18 years. Mutational analysis of ND6 gene identified 92 (73 known and 19 novel) variants in these subjects. These variants included 29 (9 novel and 20 known) missense mutations and 63 silence variants. A total of 94 subjects carrying one of known T14484C, T14502C and G14459A mutations accounted for 7.7% cases of this cohort, particularly 4.4% for T14484C mutation. Furthermore, 8 putative LHON-associated ND6 mutations accounted for 1.1% case of this cohort. Thus, 106 subjects carrying one of ND6 mutations accounted for 8.7% cases of this cohort. Low penetrance of optic neuropathy in pedigrees carrying one of 8 putative mutations indicated that the mutation(s) is necessary but itself insufficient to produce a clinical phenotype. mtDNAs in 98 probands carrying the ND6 mtuation(s) were widely dispersed among 10 Eastern Asian subhaplogroups. In particular, the occurrences of haplogroups M9, M10, M11 and H2 in patients carrying the ND6 mutations were higher than those in controls. Conclusions: These data further support that the ND6 gene is the hot spot for mutations associated with LHON. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of LHON. COMMENT: ND6 and LHON. Back ----------------------------------------------------------------------------------------------------------------------- Ophthalmic Genet. 2014 Jan 13. Leber's Hereditary Optic Neuropathy is Associated with Compound Primary Mutations of Mitochondrial ND1 m.3635G>A and ND6 m.14502 T>C. Jin X, Wang L, Gong Y, Chen B, Wang Y, Chen T, Wei S. Purpose: To describe the clinical and molecular characteristics of a Chinese Leber hereditary optic neuropathy (LHON) pedigree with compound mitochondrial DNA (mtDNA) mutations of m.3635G>A and m.14502T>C. Methods: A total of 22 individuals (2 affected, 20 unaffected) from a five-generation Chinese family with LHON underwent comprehensive ophthalmic examination, including visual acuity, slit lamp examination, fundoscopy, visual field examination and visual evoked potentials (VEP). The complete mtDNA genome of the two patients were amplified by polymerase chain reaction, sequenced using a Bigdye terminator v3.1 cycle sequencing kit and analyzed on an ABI 3700XL Genetic Analyzer. Results: Two LHON patients in the family presented typical features of LHON: painless and progressive deterioration of bilateral vision, bilateral optic atrophy, centrocecal scotomata in both eyes and significant prolonged P100 latency and low amplitude potential in VEP. Compound primary mtDNA mutations of m.3635G>A and m.14502T>C were identified in these two patients and another 12 living matrilineal members of the pedigree. Haplogroup analysis showed the patients in this LHON family belonged to the N9b1 haplogroup. Modeled mutant structure showed the mutations altered the molecular local space conformation on the surface of ND1 and ND6. Conclusions: Compound mtDNA mutations of m.3635G>A and m.14502T>C presented with low penetration, and the patients with these compound mutations exhibited mild visual impairment. The biological information analysis suggested that m.14502T>C might play a protective role in LHON associated with m.3635G>A. The haplogroup analysis indicated that the mtDNA haplogroup might be an important factor affecting the expression of LHON associated with m.3635G>A and/or m.14502T>C. COMMENT: T14502C and LHON. Back ----------------------------------------------------------------------------------------------------------------------- J Hum Genet. 2014 Jan 16. Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated ND1 G3460A mutation in Chinese families. Ji Y, Liang M, Zhang J, Zhang M, Zhu J, Meng X, Zhang S, Gao M, Zhao F, Wei QP, Jiang P, Tong Y, Liu X, Qin Mo J, Guan MX. To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON), a cohort of 1164 Han Chinese subjects with LHON were screened for ND1 G3460A mutation. A total of 295 subjects from 16 Han Chinese families carrying the G3460A mutation underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The incidence of G3460A mutation was 1.4% in this cohort of Chinese subjects with LHON. Twenty-seven (20 males/7 females) of 109 matrilineal relatives among 10 Chinese pedigrees carrying this mutation exhibited a wide range of severity and age-at-onset in visual impairment. Penetrances of optic neuropathy ranged from 7.1% to 50%, with the average of 24.5%. The age-at-onset of 27 affected matrilineal relatives varied from 10 to 40 years, with the average of 22 years. Molecular analysis identified the homoplasmic G3460A mutation and distinct sets of variants belonging to eight haplogroups. Haplogroup M with G3460A mutation was of higher frequency than those in controls. The penetrances of visual loss in families carrying mitochondrial DNA haplogroups A, B and M were higher than those in other families. Furthermore, haplogroup-specific variants tRNASer(AGY) A12223G, tRNAThr G15927A and tRNAGlu A14693G may enhance the penetrance of visual loss in these families. The G3460A mutation occurred through recurrent origins and founder events in Chinese population. Mitochondrial modifiers may modulate the penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the G3460A mutation. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON. COMMENT: The G3460A mutation in China Back ----------------------------------------------------------------------------------------------------------------------- JAMA Ophthalmol. 2014 Jan 23. Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial. Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J. IMPORTANCE We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. OBJECTIVE To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTING In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. EXPOSURE Ocular infection with recombinant adeno-associated viral vectors containing a wild-type allotopic human ND4 gene. MAIN OUTCOMES AND MEASURES Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4. RESULTS We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions. CONCLUSIONS AND RELEVANCE Expression of our allotopic ND4 vector in the ex vivo human eye, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitochondrial DNA in our patients COMMENT: Gene therapy and LHON. Back ----------------------------------------------------------------------------------------------------------------------- Eur J Paediatr Neurol. 2014 Jan 25. pii: S1090-3798(14)00011-7. Leber hereditary optic neuropathy in the population of Serbia. Jancic J, Dejanovic I, Samardzic J, Radovanovic S, Pepic A, Kosanovic-Jakovic N, Cetkovic M, Kostic V. BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. However, few countries have published their population-based findings related to this multisystemic disease. THE AIM: In order to get a better insight into the epidemiological and clinical picture of this maternally inherited disorder, we performed the first population-based clinical and molecular-genetic study of LHON in the Serbian population. METHODS: Prospective study included patients who were diagnosed with LHON after detailed medical examination and molecular-genetic confirmation. RESULTS: We identified 41 individuals from 12 genealogically unrelated families, carrying one of the three "primary" mitochondrial (mt) DNA point mutations associated with LHON. Fourteen of them were clinically affected, giving a minimum point prevalence of 1.9 per 1 000 000. The minimum point prevalence for mtDNA LHON mutations was 5.2 per 1 000 000. Male to female ratio was 6:1. Only one affected patient harboured mutant mtDNA in heteroplasmic condition. All patients were presented with common clinical findings. CONCLUSION: We observed significantly lower prevalence and higher gender ratio than expected. However, frequencies of primary mutations, incidence of heteroplasmy and clinical findings are in accordance with other studies in Caucasoid populations. Our results might be a consequence of poor recognition and misdiagnosis due to lack of diagnostic possibilities of the entity in different region of our country or less likely be in part due to specific haplotype background of Serbian population which should be further investigated. COMMENT: LHON in Serbia. Back ----------------------------------------------------------------------------------------------------------------------- Br J Ophthalmol. 2014 Feb 25. ND4L gene concurrent 10609T>C and 10663T>C mutations are associated with Leber's hereditary optic neuropathy in a large pedigree from Kuwait. Behbehani R, Melhem M, Alghanim G, Behbehani K, Alsmadi O. BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a condition characterised by a rapid bilateral central vision loss due to death of the retinal ganglion cells, leading to visual impairment commonly occurring during young adulthood. The disease manifests itself more in male patients than female patients. The mtDNA mutations m.11778G>A, m.3460G>A and m.14484T>C are by far more frequent in LHON than any other mutation. In this report, a multi-generational Arab family from Kuwait with 14 male members with LHON was investigated. METHODS: Complete mtDNA mutational analysis by direct Sanger's sequencing was carried out to detect pathogenic mutations, polymorphisms and haplogrouping. RESULTS: All maternally related subjects from this study who were examined expressed the L3 haplotype background, with two concurrent mtDNA mutations, 10609T>C and 10663T>C, that led to non-conservative amino acid changes of Ile47Thr and Val65Ala, respectively. The two variations were absent in 144 normal and ethnicity-matched controls. CONCLUSIONS: The two identified mutations associated with LHON in this family may exert their pathogenicity through a cumulative or haplogroup effect. This is the first report of the presence of two concurrent mutations in the ND4L gene in individuals with LHON who carry the L3 haplogroup. COMMENT: LHON in a Kuwaiti family. Back ----------------------------------------------------------------------------------------------------------------------- Mol Vis. 2014 Mar 14;20:334-40. Pan-American mDNA haplogroups in Chilean patients with Leber's hereditary optic neuropathy. Romero P, Fernández V, Slabaugh M, Seleme N, Reyes N, Gallardo P, Herrera L, Peña L, Pezo P, Moraga M. PURPOSE: The clinical impact of mDNA mutations on the development of Leber hereditary optic neuropathy (LHON) may be modulated by mitochondrial haplogroups, which vary across populations. The aim of this research was to determine the clinical spectrum and molecular characteristics, including the haplogroup, of 15 South American families with LHON. METHODS: This study was a prospective, observational study conducted between March 2006 and August 2012. All patients were referred to the Clinical Hospital of the University of Chile, where the clinical study was conducted. Molecular studies were conducted at the Biomedical Sciences Institute (ICBM) of the University of Chile. Fifteen index cases were identified with molecular analysis after initial neuroophthalmic examination at different centers throughout Chile. Clinical features of patients with LHON and maternal relatives of the 15 families (75 individuals: 26 affected and 49 healthy carriers) were evaluated. The primary mDNA mutations (m.3460G>A, m.11778G>A, or m.14484T>C) were determined with restriction fragment length polymorphism analysis in all individuals. Mitochondrial haplogroups were determined with direct sequencing of two hypervariable regions (HV1 and HV2) and compared with reference sequences. RESULTS: The m.11778G>A mutation was found in 59 subjects (78.7%), the m.14484T>C mutation was found in 12 subjects (16.0%), and the m.3460G>A mutation was found in four (5.3%) subjects. The average age of onset of symptoms in affected subjects was 22.2 years old (range 3 to 53 years); 21 (80.7%) were male, and five (19.3%) were female. Twelve families (80%) had Amerindian haplogroups: One family had the A2 haplogroup, four families had the B2i2 haplogroup, six families had the C1b haplogroup, and one family had the D1g haplogroup. CONCLUSIONS: In this limited sample size, the Amerindian haplogroup A2 was associated with delayed onset of disease in this population. Patients with haplogroup C retained better vision than the patients with other haplogroups in this population. Disease in subjects with haplogroup D appeared to be underrepresented compared to the population at large. Available as a free download COMMENT: LHON in Chile. Back ----------------------------------------------------------------------------------------------------------------------- J Clin Pathol. 2014 Apr 19. m.3635G>A mutation as a cause of Leber hereditary optic neuropathy. Kodrol A, Krawczy?ski MR, To?ska K, Bartnik E. Over 90% of Leber's hereditary optic neuropathy (LHON) is caused by one of three mtDNA mutations (m.11778A>G, m.3460G>A, m.14484T>C). The remaining cases are due to rare mutations in different genes encoding subunits of the respiratory chain. The proband is a 17-year-old male with symptoms of optic nerve atrophy. No common LHON mutations were found, but detailed sequencing identified a rare, homoplasmic mutation m.3635G>A in the ND1 gene. COMMENT: A paper describing the LHON mutation G3635A Back ----------------------------------------------------------------------------------------------------------------------- Yi Chuan. 2014 Apr;36(4):336-45. The analysis of mitochondrial DNA haplogroups and variants for Leber's hereditary optic neuropathy in Chinese families carrying the m.14484T >C mutation. Meng X, Zhu J, Gao M, Zhang S, Zhao F, Zhang J, Liu X, Wei Q, Tong Y, Zhang M, Qu J, Guan M. The m.14484T>C mutation in mitochondrial ND6 gene (MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy (LHON), but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were significantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average penetrance (46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those car-rying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss. COMMENT: The LHON mutation T14485C in China. Back ----------------------------------------------------------------------------------------------------------------------- Clin Experiment Ophthalmol. 2014 May 7. New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy. Martinez-Romero I, Herrero-Martin MD, Llobet L, Emperador S, Martin-Navarro A, Narberhaus B, Ascaso FJ, Lopez-Gallardo E, Montoya J, Ruiz-Pesini E. BACKGROUND: Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harboring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations. METHODS: The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced and the candidate mutation was analyzed in more than 18,000 individuals around the world, its conservation index was estimated in more than 3,100 species from protists to mammals, its position was modeled in the crystal structure of a bacteria ortholog subunit and its functional consequences were studied in a cybrid model. RESULTS: Genetic analysis revealed an m.3472T>C transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiologic factor for the disorder. CONCLUSIONS: This mutation expands the spectrum of deleterious changes in mitochondrial DNA-encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients. COMMENT: A new mutation in LHON T3472C Back ----------------------------------------------------------------------------------------------------------------------- Yi Chuan. 2014 Apr;36(4):336-45. The analysis of mitochondrial DNA haplogroups and variants for Leber's hereditary optic neuropathy in Chinese families carrying the m.14484T>C mutation. Xiangjuan M, Jinping Z, Min G, Sai Z, Fuxin Z, Juanjuan Z, Xiaoling L, Qiping W, Yi T, Minglian Z, Jia Q, Minxin G. The m.14484T>C mutation in mitochondrial ND6 gene (MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy (LHON) , but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were significantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average penetrance (46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those carrying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss. COMMENT: Haplogroup M10a and LHON. Back ----------------------------------------------------------------------------------------------------------------------- BMC Neurol. 2014 May 28;14(1):116. Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. La Morgia C, Caporali L, Gandini F, Olivieri A, Toni F, Nassetti S, Brunetto D, Stipa C, Scaduto C, Parmeggiani A, Tonon C, Lodi R, Torroni A, Carelli V. BACKGROUND: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. CASE PRESENTATION: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. CONCLUSION: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation. COMMENT: C4171A and LHON. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2014 Sep 9. pii: IOVS-14-14953. Mutation screening of mitochondrial DNA as well as OPA1 and OPA3 in a Chinese cohort with suspected hereditary optic atrophy. Chen J, Xu K, Zhang X, Jiang F, Liu LJ, Dong B, Ren Y, Li Y. Purpose: Leber's hereditary optic atrophy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common forms. The objective of this study was to define the fractional prevalence of LHON and DOA in a cohort of Chinese patients with suspected hereditary optic neuropathy. Participants: 520 unrelated patients with bilateral optic atrophy were recruited for genetic analysis: 174 patients had a positive family history of visual failure and 346 were sporadic cases. Methods: Fourteen primary LHON-causing mtDNA mutations were screened by PCR-based sequencing methods for all patients except the individuals with a paternal family history. All coding exons and exon-intron boundaries of the OPA1 and OPA3 gene were screened for mutations by PCR-based DNA sequencing for all patients with paternal family history and for the LHON-negative patients. A large genomic DNA arrangement of the OPA1 gene was further detected by multiplex ligation probe amplification (MLPA) assay for the patients with paternal family history, but results were negative for the OPA1 and OPA3 mutation screenings. Results: We found molecular defect in 323 (62%) of the 520 probands screened. Among these, 271 patients (83.9%) had an mtDNA mutation, 50 patients (15.5%) carried an OPA1 mutation, and 2 patients (0.6%) had an OPA3 mutation. Co-existence m.3460 G>A and m.11778G>A was found in one patient. Forty intragenic mutations and six large genomic DNA arrangements of the OPA1 gene were identified, 23 of which were novel. Conclusions: LHON-mtDNA mutations are the most common genetic defects, followed by the OPA1 mutations, in this Chinese cohort. COMMENT: Screening for LHON in China. Back ----------------------------------------------------------------------------------------------------------------------- Mitochondrion. 2014 Sep 4. Leber's hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families. Zhang J, Jiang P, Jin X, Liu X, Zhang M, Xie S, Gao M, Zhang S, Sun YH, Zhu J, Ji Y, Wei QP, Tong Y, Guan MX. In this report, we investigated the molecular mechanism underlying Leber's hereditary optic neuropathy (LHON) -associated mitochondrial m.3635G>A (p.S110N, ND1) mutation. In a mutational screening of ND1 gene in a cohort of 1070 Han Chinese subjects LHON identified the m.3635G>A mutation in nine Chinese families with suggestively maternally transmitted LHON. Thirty-eight (22 males/16 females) of 162 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. Molecular analysis of their mitochondrial genomes identified the homoplasmic m.3635G>A mutation and distinct sets of polymorphisms belonging to the Asian haplogroups G2a1, R11a, D4, R11a, M7b2, G1a, F1a1, B4, and N9a3, respectively. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from one Chinese family into mtDNA-less (?0) cells, we showed ~27% decrease in the activity of NADH:ubiquinone oxidoreductase (complex I) in mutant cybrids carrying the m.3635G>A mutation, compared with control cybrids. The respiratory deficiency caused by the m.3635G>A mutation results in decreased efficiency of mitochondrial ATP synthesis. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cybrids. The data provide the direct evidence for the m.3635G>A mutation leading to LHON. Our findings may provide new insights into the understanding of pathophysiology of LHON. COMMENT: The LHON mutation G3635A in China. Back ----------------------------------------------------------------------------------------------------------------------- PLoS One. 2014 Sep 12;9(9) Profiling the Mitochondrial Proteome of Leber's Hereditary Optic Neuropathy (LHON) in Thailand: Down-Regulation of Bioenergetics and Mitochondrial Protein Quality Control Pathways in Fibroblasts with the 11778G>A Mutation. Aung Win Tun, Sakdithep Chaiyarit, Supannee Kaewsutthi, Wanphen Katanyoo Wanicha Chuenkongkaew, Masayoshi Kuwano, Takeshi Tomonaga, Chayanon Peerapittayamongkol, Visith Thongboonkerd, Patcharee Lertrit Leber's Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead to the development of LHON in synergy with the primary mtDNA mutation Available as a free download COMMENT: LHON in Thailand. Back ----------------------------------------------------------------------------------------------------------------------- Orphanet J Rare Dis. 2014 Oct 23;9(1):158. Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients. Dimitriadis K, Leonhardt M, Yu-Wai-Man P, Kirkman M, Korsten A, De Coo IF, Chinnery P, Klopstock T. Background Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON). Methods From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann¿Whitney-U-Test for two independent groups of sampled data. Results The proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m.11778G > A and m.3460G > A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m.11778G > A, m.3460G > A and m.14484 T > C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset- and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset.ConclusionAs already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients. Available as a free download COMMENT: Late onset LHON disease. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2014 Oct 23. Pathogenic Mitochondrial DNA Mutations and Associated Clinical Features in Korean Patients with Leber's Hereditary Optic Neuropathy. Yum HR, Chae H, Shin SY, Kim Y, Kim M, Park SH. Abstract Purpose: To identify the spectrum of pathogenic mitochondrial DNA (mtDNA) mutations and clinical features in Korean patients with genetically confirmed Leber's hereditary optic neuropathy (LHON). Methods: The medical records of 34 unrelated genetically confirmed LHON patients were reviewed. Total genomic DNA was isolated from the peripheral blood leukocytes of the patients with suspected LHON, and primary or secondary mtDNA mutations were identified by direct sequencing. We analyzed the visual acuity (VA), color vision, RNFL thickness, and visual field at the final visit from 20 patients who were followed up for more than 6 months after the onset of LHON. Results: Among 34 patients, 21 (61.8%) had the homoplasmic primary mutation, 11 (32.4%) had the homoplasmic secondary mutation and 2 (5.9%) had the heteroplasmic primary mutation along with the homoplasmic secondary mutation. Analysis of mtDNA sequences revealed six different types of LHON-associated mutations: two primary LHON-associated primary mutations, m.11778G>A (20 patients, 58.8%) and m.14484T>C (3 patients, 8.8%), and four secondary LHON-associated mutations, which were m.3394T>C (3 patients, 8.8%), m.3497C>T (4 patients, 11.8%), m.11696G>A (4 patients, 11.8%), and m.14502T>C (2 patients, 5.9%). Secondary mutation-carrying patients demonstrated a decreased in RNFL thickness, similar to those in primary mutation-carrying LHON patients. These patients had a higher female ratio (p=0.019), better VA (p=0.043) and color vision (p=0.005), as well as better visual field. Conclusions: In addition to common primary LHON-associated mutations, our study identified secondary mtDNA mutations which should be considered when evaluating patients with optic atrophy. COMMENT: LHON disease in Korea. Back ----------------------------------------------------------------------------------------------------------------------- Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015 Apr 10;32(2):198-203. Identification of mitochondrial DNA ND1 T3866C mutation in three ethnic Han Chinese families affected with Leber's hereditary optic neuropathy. Zhang S, Gao M, Zhang Z, Liu X, Guan M. Abstract OBJECTIVE: To report on the clinical, genetic and molecular characteristics of three ethnic Han Chinese families affected with Leber's hereditary optic neuropathy (LHON). METHODS: The three families were all diagnosed with LHON. Ophthalmologic examinations were conducted on the probands. The ND1, ND4 and ND6 genes of the mitochondrial DNA (mtDNA) were amplified with PCR respectively for the screening of three primary mutations G3460A, G11778A and T14484C. The entire mtDNA of the probands were also amplified by PCR. RESULTS: Analysis of mtDNA in the three pedigrees has failed to find the presence of the three LHON associated mutations but presence of a homoplastic ND1 T3866C mutation in all probands and their matrilineal relatives. The probands had different levels of visual impairment. The penetrance in the three families has been calculated as 12.5%, 11.1% and 33.3%, respectively. The T3866C mutation has resulted in replacement of isoleucine at position 187 with theronine. The isoleucine at position 187 is located at one of the transmembrane domains of ND1 polypeptide. CONCLUSION: Above results have suggested that the ND1 T3866C mutation might have been involved in the pathogenesis of LHON in the three Chinese families studied. COMMENT: LHON mutation T3866C. Back ----------------------------------------------------------------------------------------------------------------------- Mol Med Rep. 2015 May 4 Two families with Leber's hereditary optic neuropathy carrying G11778A and T14502C mutations with haplogroup H2a2a1 in mitochondrial DNA. Qiao C, Wei T, Hu B, Peng C, Qiu X, Wei L, Yan M. The mitochondrial haplogroup has been reported to affect the clinical expression of Leber's hereditary optic neuropathy (LHON). The present study aimed to investigate the interaction between mutations and the haplogroup of mitochondrial DNA (mtDNA) in families. Two unrelated families with LHON were enrolled in the study, and clinical, genetic and molecular characterizations were determined in the affected and unaffected family members. Polymerase chain reaction direct sequencing was performed using 24 pairs of overlapping primers for whole mtDNA to screen for mutations and haplogroup. Bioinformatics analysis was performed to evaluate the pathogenic effect of these mtDNA mutations and the haplogroup. The G11778A mutation was identified in the two families. In addition, the members of family 2 exhibited the T14502C mutation and those in family 1 exhibited the T3394C and T14502C mutations, which were regarded as secondary mutations. The penetrance of visual loss in families 1 and 2 were 30.8 and 33.3%, respectively. In addition, the two families were found to be in the H2a2a1 haplogroup. In this limited sample size, it was demonstrated that the H2a2a1 haplogroup had a possible protective effect against LHON. Additional modifying factors, including environmental factors, lifestyle, estrogen levels and nuclear genes may also be important in LHON. COMMENT: LHON in Haplogroup H2a2a1. Back ----------------------------------------------------------------------------------------------------------------------- Mol Ther Methods Clin Dev. 2015 Feb 25;2:15003. Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Cwerman-Thibault H, Augustin S, Lechauve C, Ayache J, Ellouze S, Sahel JA, Corral-Debrinski M. Abstract Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome. COMMENT: LHON therapy with an adeno-associated viral vector. Back ----------------------------------------------------------------------------------------------------------------------- Invest Ophthalmol Vis Sci. 2015 Jul 1;56(8):4778-4788. Prevalence of Mitochondrial ND4 Mutations in 1281 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy. Jiang P, Liang M, Zhang J, Gao Y, He Z, Yu H, Zhao F, Ji Y, Liu X, Zhang M, Fu Q, Tong Y, Sun Y, Zhou X, Huang T, Qu J, Guan MX. Abstract Purpose: To investigate the prevalence and spectrum of mitochondrial ND4 mutations in subjects with Leber's hereditary optic neuropathy (LHON). Methods: A cohort of 1281 Chinese Han probands and 478 control subjects underwent clinical and genetic evaluation, and sequence analysis of mitochondrial (mt) DNA, as well as enzymatic assay of NADH:ubiquinone oxidoreductase. Results: In this cohort, 503 probands had a family history of optic neuropathy and 778 subjects were sporadic cases. Mutational analysis of ND4 gene identified 149 (102 known and 47 novel) variants. The prevalence of known m.11778G>A mutation was 35.36%. Furthermore, we identified the known m.11696G>A and m.11253T>C mutations and five novel putative LHON-associated mutations. These mutations accounted for 2.74% of cases of LHON subjects. By enzymatic assay, we showed a mild decrease in the activity of NADH:ubiquinone oxidoreductase in mutant cell lines carrying only one putative mtDNA mutation. The low penetrance of optic neuropathy and mild biochemical defects in these pedigrees carrying only m.11696G>A mutation and one putative LHON-associated mutation suggested that the mutation(s) is(are) necessary but is(are) itself(themselves) insufficient to produce a visual failure. Moreover, mtDNAs in 169 probands carrying the LHON-associated mutation(s) were widely dispersed among 13 Eastern Asian haplogroups. In particular, the frequencies of haplogroups D, M8, M10, M11, and H in probands carrying the LHON-associated mtDNA mutation(s) were higher than those in Chinese controls. Conclusions: These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON. COMMENT: LHON in China. Back ----------------------------------------------------------------------------------------------------------------------- Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015 Aug 10;32(4):485-489. A novel mutation T8821G in mitochondrial DNA may be associated with Leber's hereditary optic neuropathy Gao M, Zhang S, Zhang Z, Zhao F, Zhang J, Liang M, Liu X, Wei Q, Tong Y, Qu J, Guan M. Abstract OBJECTIVE: To report on clinical, genetic and molecular characterization of two Chinese families with Leber's hereditary optic neuropathy. METHODS: Ophthalmological examinations have revealed variable severity and age at onset of visual loss among the probands and other matrilineal relatives of both families. The entire mitochondrial genome of the two probands was amplified with PCR in 24 overlapping fragments using sets of oligonucleotide primers. RESULTS: The ophthalmological examinations showed that penetrance was 12.5% and 30.0% respectively in the two families. Sequence analysis of the complete mitochondrial genomes in these pedigrees has identified unreported homoplasmic T8821G mutation in the ATPase 6 gene and distinct sets of polymorphisms belonging to haplogroups M10a. The T8821G mutation has occurred at the extremely conserved nucleotide (conventional position 99) of the ATPase6. Thus, this mutation may alter structural formation of ATPase6, thereby leading to failure in the synthesis of ATP involved in visual impairment. CONCLUSION: Above observations have suggested that the ATPase6 T8821G mutation may be involved in the pathogenesis of optic neuropathy in these families. COMMENT: LHON mutation T8821G. Back ----------------------------------------------------------------------------------------------------------------------- Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Ophthalmology. 2015 Nov 19. pii: S0161-6420(15)01210-5 Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. Abstract PURPOSE: Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN: In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 109 vg), and the fourth participant was treated at the medium dose (2.46 × 1010 vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS: Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES: Loss of visual acuity. RESULTS: Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS: No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations. COMMENT: Trial of gene therapy Back ----------------------------------------------------------------------------------------------------------------------- Jiang P, et al. Hum Mol Genet. 2015 Dec 8. pii: The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation Abstract Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations, and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNATyr were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNATyr metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complex I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 worsens mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2. COMMENT: Effect of mutations in the YARS2 gene Back ----------------------------------------------------------------------------------------------------------------------- Cruz-Bermúdez A, Vicente-Blanco RJ, Hernández-Sierra R, Montero M, Alvarez J, González Manrique M, Blázquez A, Martín MA, Ayuso C, Garesse R, Fernández-Moreno MA. PLoS One. 2016 Jan 19;11(1) Functional Characterization of Three Concomitant MtDNA LHON Mutations Shows No Synergistic Effect on Mitochondrial Activity. The presence of more than one non-severe pathogenic mutation in the same mitochondrial DNA (mtDNA) molecule is very rare. Moreover, it is unclear whether their co-occurrence results in an additive impact on mitochondrial function relative to single mutation effects. Here we describe the first example of a mtDNA molecule harboring three Leber's hereditary optic neuropathy (LHON)-associated mutations (m.11778G>A, m.14484T>C, m.11253T>C) and the analysis of its genetic, biochemical and molecular characterization in transmitochondrial cells (cybrids). Extensive characterization of cybrid cell lines harboring either the 3 mutations or the single classic m.11778G>A and m.14484T>C mutations revealed no differences in mitochondrial function, demonstrating the absence of a synergistic effect in this model system. These molecular results are in agreement with the ophthalmological characteristics found in the triple mutant patient, which were similar to those carrying single mtDNA LHON mutations. COMMENT: Triple LHON mutations found in the same person. Back ----------------------------------------------------------------------------------------------------------------------- Wan X, etal. Sci Rep. 2016 Feb 19;6:21587. Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy. Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON. COMMENT: Virus treatment Back ----------------------------------------------------------------------------------------------------------------------- Kolarova, et al. Ophthalmic Genet. 2016 Feb 19:1-5. Unique presentation of LHON/MELAS overlap syndrome caused by m.13046T>C in MTND5. BACKGROUND: Leber hereditary optic neuropathy (LHON) and mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) syndromes are mitochondrially inherited disorders characterized by acute visual failure and variable multiorgan system presentation, respectively. MATERIALS AND METHODS: A 12-year-old girl with otherwise unremarkable medical history presented with abrupt, painless loss of vision. Over the next few months, she developed moderate sensorineural hearing loss, vertigo, migraines, anhedonia and thyroiditis. Ocular examination confirmed bilateral optic nerve atrophy. Metabolic workup documented elevated cerebrospinal fluid lactate. Initial genetic analyses excluded the three most common LHON mutations. Subsequently, Sanger sequencing of the entire mitochondrial DNA (mtDNA) genome was performed. RESULTS: Whole mtDNA sequencing revealed a pathogenic heteroplasmic mutation m.13046T>C in MTND5 encoding the ND5 subunit of complex I. This particular variant has previously been described in a single case report of MELAS/Leigh syndrome (subacute necrotizing encephalopathy). Based on the constellation of clinical symptoms in our patient, we diagnose the condition as LHON/MELAS overlap syndrome. CONCLUSIONS: We describe a unique presentation of LHON/MELAS overlap syndrome resulting from a m.13046T>C mutation in a 12-year-old girl. In patients with sudden vision loss in which three of the most prevalent LHON mitochondrial mutations have been ruled out, molecular genetic examination should be extended to other mtDNA-encoded subunits of MTND5 complex I. Furthermore, atypical clinical presentations must be considered, even in well-described phenotypes. COMMENT: MELAS and LHON Back ----------------------------------------------------------------------------------------------------------------------- Rosenberg T, Nørby S, Schwartz M, Saillard J, Magalhães PJ, Leroy D, Kann EC, Duno M. Invest Ophthalmol Vis Sci. 2016 Mar 1;57(3):1370-1375. doi: 10.1167/iovs.15-18306. Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population. Abstract Purpose: In Denmark, the occurrence of Leber hereditary optic neuropathy (LHON) has continuously been monitored since 1944. We provide here a summary of 70 years of data collection including registered lines and subjects by the end of 2012. Methods: Affected individuals were identified from a national register of hereditary eye diseases at the National Eye Clinic (NEC), a tertiary low vision rehabilitation center for the entire Danish population. The assembling of LHON pedigrees was based on the reconstruction of published families and newly diagnosed cases from 1980 to 2012 identified in the files of NEC. Genealogic follow-up on the maternal ancestry of all affected individuals was performed to identify a possible relation to an already known maternal line. A full genotypic characterization of the nation-based LHON cohort is provided. Results: Forty different lines were identified. The number of live affected individuals with a verified mitochondrial DNA mutation was 104 on January 1, 2013, which translates to a prevalence rate of 1:54,000 in the Danish population. Conclusions: Haplogroup distribution as well as mutational spectrum of the Danish LHON cohort do not deviate from those of other European populations. The genealogic follow-up reveals a relatively high turnover among families with approximately 15 newly affected families per century and the dying out of earlier maternal lines. COMMENT: LHON in Denmark Back ----------------------------------------------------------------------------------------------------------------------- Xie S, Zhang J, Sun J, Zhang M, Zhao F, Wei QP, Tong Y, Liu X, Zhou X, Jiang P, Ji Y, Guan MX Mitochondrial DNA A DNA MappSeq Anal. 2016 Jan 22:1-8. Mitochondrial haplogroup D4j specific variant m.11696G>a(MT-ND4) may increase the penetrance and expressivity of the LHON-associated m.11778G>A mutation in Chinese pedigrees. Abstract Leber's hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders. We report here the clinical, genetic and molecular analysis of mitochondrial DNA (mtDNA) in eight Han Chinese families carrying the known mitochondrial 11778G>A(MT-ND4) mutation. Thirty-seven (26 males/11 females) of 77 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. The penetrances were from 25% to 75%, with the average of 42%, and the age-at-onset for visual impairment varied from 10 to 25 years, with the average of 17 in these Chinese pedigrees. Molecular analysis of their mtDNA identified distinct sets of variants belonging to the Eastern Asian haplogroupD4j. Except the known m.11778G>A mutation, the m.11696G>A(MT-ND4) mutation caused the substitution of an isoleucine for valine at amino acid position 313, located in a predicted transmembrane region of ND4. And, it is reported that the m.11696G>A mutation was associated with LHON, and appeared to contribute to higher penetrance in these nine Chinese families than other Chinese families carrying only the m.11778G?>?A mutation. Therefore, the mitochondrial haplogroup D4j specific m.11696G>A mutation may act in synergy with the primary LHON-associated m.11778G>A mutation, thereby increasing the penetrance and expressivity of visual loss in these Chinese families. COMMENT: LHON and G11696A Back ----------------------------------------------------------------------------------------------------------------------- Ji Y, Liang M, Zhang J, Zhu L, Zhang Z, Fu R, Liu X, Zhang M, Fu Q, Zhao F, Tong Y, Sun Y, Jiang P, Guan MX. Invest Ophthalmol Vis Sci. 2016 May 1;57(6):2377-89. Mitochondrial ND1 Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy. Abstract PURPOSE: The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON). METHODS: A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt)DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls. RESULTS: Mutational analysis identified 178 (70 missense and 108 silent) variants in the MT-ND1 gene. The incidences of known m.3460G>A, m.3635G>A, m.3733G>A, m.3866T>C, and m.3394T>C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls. CONCLUSIONS: These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON. COMMENT: LHON and ND1 mutations Back ----------------------------------------------------------------------------------------------------------------------- Jiang P, et al. Hum Mol Genet. 2016 Jul 17. pii Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation. Abstract Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T>C, p. 58I>V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G>A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T>C and m.11778G>A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G>A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ?o cells with enucleated cells from LHON patients carrying both m.11778G>A and m.14502T>C mutations, only m.14502T>C or m.11778G>A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T>C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G>A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T>C and m.11778G>A mutations than those carrying only m.11778G>A or m.14502T>C mutation. In particular, the m.14502T>C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G>A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T>C and m.11778G>A mutation than those carrying only 11778G>A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations. COMMENT: LHON and the T14502C mutation Back ----------------------------------------------------------------------------------------------------------------------- Chao de la Barca JM, et al. Brain. 2016 Sep 15. pii The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress. Abstract Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q2 cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2?, as well as the greater expression of C/EBP homologous protein and the increased XBP1 splicing, in fibroblasts from affected patients, all these changes being reversed by the endoplasmic reticulum stress inhibitor, TUDCA (tauroursodeoxycholic acid). Thus, our metabolomic analysis reveals a pharmacologically-reversible endoplasmic reticulum stress in complex I-related Leber's hereditary optic neuropathy fibroblasts, a finding that may open up new therapeutic perspectives for the treatment of Leber's hereditary optic neuropathy with endoplasmic reticulum-targeting drugs. COMMENT: An important metabolomic study. Back ----------------------------------------------------------------------------------------------------------------------- Catarino CB, et al. Mitochondrion. 2016 Oct 6. pii: S1567-7249(16)30205-7. Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA. Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient. COMMENT: Dual LHON mutations. Back ----------------------------------------------------------------------------------------------------------------------- Bi R, Logan I, Yao YG. Handb Exp Pharmacol. 2016 Oct 28. Leber Hereditary Optic Neuropathy: A Mitochondrial Disease Unique in Many Ways. Leber hereditary optic neuropathy (LHON) was the first mitochondrial disease to be identified as being caused by mutations in the mitochondrial DNA (mtDNA). This disease has been studied extensively in the past two decades, particularly in Brazilian, Chinese and European populations; and many primary mutations have been reported. However, the disease is enigmatic with many unique features, and there still are several important questions to be resolved. The incomplete penetrance, the male-biased disease expression and the prevalence in young adults all defy a proper explanation. It has been reported that the development of LHON is affected by the interaction between mtDNA mutations, mtDNA haplogroup background, nuclear genes, environmental factors and epigenetics. Furthermore, with the help of new animal models for LHON that have been created in recent years, we are continuing to learn more about the mechanism of this disease. The stage has now been reached at which there is a good understanding of both the genetic basis of the disease and its epidemiology, but just how the blindness that follows from the death of cells in the optic nerve can be prevented remains to be a pharmacological challenge. In this chapter, we summarize the progress that has been made in various recent studies on LHON, focusing on the molecular pathogenic mechanisms, clinical features, biochemical effects, the pharmacology and its treatment. COMMENT: Dual LHON review. Back ----------------------------------------------------------------------------------------------------------------------- Li Y, Li J, Jia X, Xiao X, Li S, Guo X. PLoS One. 2017 Jan 12;12(1):e0170090. doi: 10.1371/journal.pone.0170090. eCollection 2017. Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy. Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes) and to analyze the genotype-phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA) (m.3460G>A, m.11778G>A and m.14484T>C). All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3%) primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations), four at m.3460 (4/89, 4.5%) and nine at m.14484 (9/89, 10.1%). This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age. COMMENT: LHON in children. Back ----------------------------------------------------------------------------------------------------------------------- Soldath P, Wegener M, Sander B, Rosenberg T, Duno M, Wibrand F, Vissing J Ophthalmic Genet. 2017 Jan 31:1-6. Leber hereditary optic neuropathy due to a new ND1 mutation. Soldath P, Wegener M, Sander B, Rosenberg T, Duno M, Wibrand F, Vissing J We report a proband with Leber hereditary optic neuropathy (LHON), in whom we have identified a novel homoplasmic m.3,395A>G mutation in the ND1 gene. The mutation alters a highly conserved amino acid in codon 30 which previously has been associated with LHON and leads to a severe selective complex I deficiency. By providing further evidence for pathogenicity we conclude that m.3,395A>G is pathogenic. High definition optical coherence tomography of the retina and peripapillary retinal nerve fiber layer (pRNFL) confirms recent reports that retinal ganglion cell loss precedes axonal loss in LHON and is present in the early stage of the disease. Furthermore, evaluation of two unaffected mutation carriers disclosed asymptomatic borderline ganglion cell loss and thin pRNFL in one. COMMENT: LHON mutation A3395G. Back ----------------------------------------------------------------------------------------------------------------------- Hwang TJ, et al. Ophthalmology. 2017 Feb 10. pii: S0161-6420(16)30848-X. Natural History of Conversion of Leber's Hereditary Optic Neuropathy: A Prospective Case Series. PURPOSE: To illustrate the natural history of Leber's hereditary optic neuropathy (LHON). DESIGN: Prospective observational case series. PARTICIPANTS: The Soave-Brazil pedigree of m.11778G>A/ND4 mitochondrial DNA LHON mutation. METHODS: A prospectively acquired database of the Soave-Brazil pedigree was reviewed. Data from 285 individuals were included in the database over a 15-year period. The pedigree was reviewed for unaffected mutation carriers who converted to affected status, 6 patients with LHON were identified. The medical records were reviewed 1 year preconversion to 1 year postconversion for visual acuity (logarithm of the minimum angle of resolution [logMAR]), Humphrey Visual Field (HVF) mean deviation (MD), and retinal nerve fiber layer (RNFL) thickness, as measured by Cirrus (Carl Zeiss, Oberkochen, Germany) optic coherence tomography (OCT). The RNFL thickness values were normalized for age. Visual acuity, HVF, and processed RNFL data from each of the 12 eyes were then sorted into 2-month time periods relative to the date of conversion, within which they were averaged. MAIN OUTCOME MEASURES: The main outcome measures were visual acuity, HVF MD, and RNFL thickness. RESULTS: Decreased visual acuity preceded conversion by up to 2 months and then declined up to 8 months postconversion. Decrease in HVF MD occurred at least 4 months preceding conversion, after which values decreased until plateau at 6 to 8 months. Average RNFL thickness was above normal baseline thickness in all 4 quadrants as measured by OCT at the time of conversion. Increase in RNFL thickness preceded conversion as early as 4 to 6 months, peaked at conversion, and decreased until individual plateaus. The temporal quadrant was first to be involved, then the inferior and superior quadrants, and the nasal quadrant showed the latest and least changes. CONCLUSIONS: Subclinical changes preceded the date of conversion and may reflect the complicated nature of identifying the date of conversion in LHON. Early increases in RNFL preceding conversion suggest that structural changes precede clinically significant vision loss. Asynchronous quadrant involvement supports a previously published mathematical model. The natural history of LHON is not a subacute process, as previously believed, but progresses more slowly, taking up to 8 months to plateau. COMMENT: Development of LHON disease. Back ----------------------------------------------------------------------------------------------------------------------- Wallace DC, Lott MT. Handb Exp Pharmacol. 2017 Feb 24. doi: 10.1007/164_2017_2. Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease. Abstract The report in 1988 that Leber Hereditary Optic Neuropathy (LHON) was the product of mitochondrial DNA (mtDNA) mutations provided the first demonstration of the clinical relevance of inherited mtDNA variation. From LHON studies, the medical importance was demonstrated for the mtDNA showing its coding for the most important energy genes, its maternal inheritance, its high mutation rate, its presence in hundreds to thousands of copies per cell, its quantitatively segregation of biallelic genotypes during both mitosis and meiosis, its preferential effect on the most energetic tissues including the eye and brain, its wide range of functional polymorphisms that predispose to common diseases, and its accumulation of mutations within somatic tissues providing the aging clock. These features of mtDNA genetics, in combination with the genetics of the 1-2000 nuclear DNA (nDNA) coded mitochondrial genes, is not only explaining the genetics of LHON but also providing a model for understanding the complexity of many common diseases. With the maturation of LHON biology and genetics, novel animal models for complex disease have been developed and new therapeutic targets and strategies envisioned, both pharmacological and genetic. Multiple somatic gene therapy approaches are being developed for LHON which are applicable to other mtDNA diseases. Moreover, the unique cytoplasmic genetics of the mtDNA has permitted the first successful human germline gene therapy via spindle nDNA transfer from mtDNA mutant oocytes to enucleated normal mtDNA oocytes. Such LHON lessons are actively being applied to common ophthalmological diseases like glaucoma and neurological diseases like Parkinsonism. COMMENT: Review of LHON disease. Back ----------------------------------------------------------------------------------------------------------------------- Majander A, et al. Br J Ophthalmol. 2017 Mar 17. pii: Childhood-onset Leber hereditary optic neuropathy. Abstract BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12?years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15?years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ?0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor. COMMENT: LHON in childhood. Back ----------------------------------------------------------------------------------------------------------------------- Ueda K, et al. J Epidemiol. 2017 Apr 6. pii: S0917-5040(17)30074-6. Nationwide epidemiological survey of Leber hereditary optic neuropathy in Japan. Abstract BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy that leads to central loss of vision, predominantly in young males. Most LHON cases have one of three primary point mutations in mitochondrial DNA (mtDNA). The annual incidence and prevalence of LHON in Japan are not known. Thus, we estimated the annual incidence of molecularly confirmed LHON in Japan during 2014. METHODS: Sequential questionnaires were sent to 1397 facilities, which included all of the university hospitals in Japan, and they were certified by either the Japanese Ophthalmological Society or the Japanese Neuro-Ophthalmological Society. We calculated the incidence number (Ir) as the number of patients who developed LHON in 2014 and its 95% confidence interval. RESULTS: We received 861 responses to the first questionnaire, where 49 facilities reported 72 cases (67 were male and 5 were female) of newly developed LHON during 2014. It was calculated as 117, and the 95% confidence interval ranged from 81 to 153. For the second questionnaire, responses were received from 30 facilities, where the median age at onset was 38 years for males and 30 years for females, and 86.5% of cases possessed the mtDNA ND4/G11778A mutation. CONCLUSION: Approximately 120 cases of newly developed LHON were reported during 2014 in Japan, and 93.2% were males. COMMENT: LHON in Japan. Back ----------------------------------------------------------------------------------------------------------------------- Bianco A, et al Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):2193-2197. High Mitochondrial DNA Copy Number Is a Protective Factor From Vision Loss in Heteroplasmic Leber's Hereditary Optic Neuropathy (LHON). Abstract Purpose: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance. Methods: We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated. Results: The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected. Conclusions: The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON. COMMENT: LHON mtDNA copy number. Back ----------------------------------------------------------------------------------------------------------------------- Khan NA, et al. Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):3923-3930. Leber's Hereditary Optic Neuropathy-Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India. Abstract Purpose: Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation. Methods: Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations. Results: A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected. Conclusions: The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations. COMMENT: LHON in India. Back ----------------------------------------------------------------------------------------------------------------------- PAPERS DISCUSSING COMPLEX I and the RARE TUMOUR - the ONCOCYTOMA ================================================================= ----------------------------------------------------------------------------------------------------------------------- Carcinogenesis. 2003 Sep;24(9):1461-6. Mitochondrial complex I is deficient in renal oncocytomas. Simonnet H, Demont J, Pfeiffer K, Guenaneche L, Bouvier R, Brandt U, Schagger H, Godinot C. CGMC (Center of Molecular and Cell Genetics), Unit 5534 of the CNRS and the University Lyon 1 Claude Bernard, Villeurbanne, France. simonnet@univ-lyon1.fr Renal oncocytomas are benign tumors characterized by dense accumulation of mitochondria the cause of which remains unknown so far. Consistently, mitochondrial DNA content and the amounts and catalytic activities of several oxidative phosphorylation (OXPHOS) complexes were known to be increased in these tumors, but it was not ascertained that the OXPHOS system was functional. Here we investigated mitochondrial complex I and found that its NADH dehydrogenase activity and protein content were specifically decreased in oncocytomas, in stark contrast with the parallel decrease of all respiratory chain complexes in other, malignant, renal tumors. We conclude that deficiency of complex I in oncocytomas might be the early event causing the increased mitochondrial biogenesis, attempting to compensate for the loss of OXPHOS function. Since other tumors were found to be linked to mitochondrial deficiencies like genetic alterations of fumarate hydratase or succinate dehydrogenase, oncocytoma could be the third type of benign tumor associated with impairment of mitochondrial ATP production in an oxidative, quiescent tissue. Besides, complex I enzyme activity was moderately decreased in the vicinity of oncocytomas, when compared with normal tissue adjacent to other renal tumors. This suggested that oncocytomas are the result of at least two serial modifications altering the mitochondrial respiratory chain. Available as a free download COMMENT: Complex I and oncocytomas Back ----------------------------------------------------------------------------------------------------------------------- Hum Mol Genet. 2008 Apr 1;17(7):986-95. Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma. Gasparre G, Hervouet E, de Laplanche E, Demont J, Pennisi LF, Colombel M, Mège-Lechevallier F, Scoazec JY, Bonora E, Smeets R, Smeitink J, Lazar V, Lespinasse J, Giraud S, Godinot C, Romeo G, Simonnet H. Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy. Mutations in mitochondrial DNA (mtDNA) are frequent in cancers but it is not yet clearly established whether they are modifier events involved in cancer progression or whether they are a consequence of tumorigenesis. Here we show a benign tumor type in which mtDNA mutations that lead to complex I (CI) enzyme deficiency are found in all tumors and are the only genetic alteration detected. Actually renal oncocytomas are homogeneous tumors characterized by dense accumulation of mitochondria and we had found that they are deficient in electron transport chain complex I (CI, NADH-ubiquinone oxidoreductase). In this work total sequencing of mtDNA showed that 9/9 tumors harbored point mutations in mtDNA, seven in CI genes, one in complex III, and one in the control region. 7/8 mutations were somatic. All tumors were somatically deficient for CI. The clonal amplification of mutated mtDNA in 8/9 tumors demonstrates that these alterations are selected and therefore favor or trigger growth. No nuclear DNA rearrangement was detected beside mtDNA defects. We hypothesize that functional deficiency of the oxidative phosphorylation CI could create a loop of amplification of mitochondria during cell division, impair substrates oxidation and increase intermediary metabolites availability. Available as a free download COMMENT: More on Complex I and the oncocytoma. Back ----------------------------------------------------------------------------------------------------------------------- BMC Med Genomics. 2010 Dec 16;3:59. Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, Sääf A, Zickert P, Aly M, Bergerheim U, Nordenskjöld M, Gad S, Giraud S, Denoux Y, Yonneau L, Méjean A, Vasiliu V, Richard S, MacKeigan JP, Teh BT, Furge KA. Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, MI, USA. BACKGROUND: Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied. METHODS: BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets. RESULTS: Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1?-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression. CONCLUSIONS: Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1?-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function. Available as a free download COMMENT: More on mitochondrial function and oncocytomas Back -----------------------------------------------------------------------------------------------------------------------