Historically, LHON has been categorized into 3 distinct clinical groups: asymptomatic mutation carriers, patients with acute LHON (with disease duration of 1 year or less), and those with chronic LHON (with disease duration of more than 1 year) (9,11). More recently, the assessment by OCT of the different stages of LHON (10,22), in conjunction with the natural history (6,8) and established visual parameters, such as best-corrected visual acuity (BCVA) and visual fields, has provided new insights that have led to the subclassification of the acute stage into “subacute” and “dynamic” stages (Table 1, statement 1). Other phenotypic groups have been proposed, namely, childhood- and late-onset LHON (23,24), and the contribution of anatomic (25), environmental (26–30), and hormonal factors (31) have emerged as potential disease modifiers.
Clinical stages of LHON can be defined as follows, according to time from onset and clinical investigations:
The jury emphasized that for the clinical diagnosis, the following clinical investigations were important: visual acuity, color vision, fundus examination, visual field perimetry, and OCT imaging. The participants also noted that for childhood disease, the optic nerve head size was important. For late-onset LHON cases, the participants also felt that it was important to consider toxic exposure (smoking, drinking, and environmental factors) and hormonal factors (estrogens).
For the statement, there was strong consensus.
The diagnosis of LHON has been greatly improved by the availability of genetic testing (32). However, LHON remains a clinical diagnosis with recognizable clinical features and disease evolution (4,5), which is corroborated by the maternal inheritance of the disease, (33) when there is a family history, leading to Statement 2 (Table 1).
Diagnosis of LHON can usually be made based on patient and family clinical history as well as baseline investigations including neuro-ophthalmological examination and mtDNA genetic testing.
There was a strong consensus.
Despite the greatly improved recognition of LHON, there can still be considerable diagnostic delay, that is, compounded by variability in the initial findings and misinterpretation of the clinical picture, in particular with optic neuritis (34,35) or toxic optic neuropathy (36). A differential diagnosis remains an important point to consider, as noted in statements 3 and 4 (Table 1).
There was a strong consensus.
If further extraocular features are present, consider LHON “Plus”, including LHON/MS-like variant. Consider performing appropriate investigations including brain MRI and laboratory studies.
There was strong consensus.
Multiple reports on large LHON cohorts from different countries have defined some prognostic factors, which may impact the clinical course (23,25,37–39) and possibly the management of the disease, leading to statement 5 (Table 1).
However, prognostic factors do not affect management.
There was a strong consensus.
The standard clinical evaluation of LHON patients includes visual acuity and visual fields. OCT studies have proved to be a valuable tool in evaluating the clinical course of the disease (6,8,10,22). These considerations led to statement 6 (Table 1).
There was a strong consensus.
“Idebenone should be started as soon as possible at 900 mg/day in patients with disease less than 1 year.”
There was a strong consensus with 1 participant in partial disagreement.
There is not enough evidence to recommend treatment in chronic patients between 1 and 5 years (after the second eye onset), and no evidence to recommend treatment in chronic patients >5 years (after the second eye onset).
There was a strong consensus, but 2 participants disagreed.
There was a strong consensus.
There was strong consensus with 1 participant in partial disagreement.
“In subacute/dynamic patients, treatment at 900 mg/day should be continued for at least 1 year to assess the start of therapeutic response or until a plateau in terms of improvement is reached.”
There was strong consensus.
There was strong consensus, but 2 participants partially disagreed and 1 participant disagreed.
Consensus was not reached. Five participants did not vote.
Not voted because of lack of consensus on statement 13.
The following examinations should be performed to assess response during maintenance phase:
There was strong consensus.
There was strong disagreement, with 1 participant in agreement.
There was a strong consensus.
Similarly, the clinical evaluation and prophylactic treatment of unaffected LHON mutation carriers is a particularly relevant issue (9,10,25–27,29,39,44–47). This point has been developed in statements 18 and 19 (Table 1).
Eleven participants disagreed that all maternally related relatives should be screened. There was strong disagreement with 2 participants in agreement.
“Currently, treatment is not recommended for relatives of a LHON patient, but lifestyle counseling is recommended.”
There was a strong consensus.
Currently, there is no clinical prognostic factor that can be used.
There was strong consensus, with 1 participant in disagreement.
The jury unanimously endorsed the final version of all questions and statements (Table 1).
There was strong consensus for 16 statements, whereas for 3 statements, there was a lack of consensus (13, 16, and 18). For statements 8, 12, and 20, there was specific disagreement from 2, 1, and 1 participants, respectively. Specifically, for statement 8, the 2 participants believed that there was sufficient evidence to justify the use of idebenone for chronic cases. For statement 12, 1 participant believed that idebenone treatment could be continued for more than 1 year after plateau in patients who had shown a treatment response. For statement 20, 1 participant disagreed that there is no reliable predictive risk factor to assess the risk of disease conversion in a LHON carrier.
There was strong disagreement for statements 16 and 18. Eleven of 13 participants fully disagreed that idebenone should be continued with a maintenance dose in nonresponder patients. Also, 11 of 13 participants fully disagreed that it was necessary to clinically screen all maternal relatives including asymptomatic carriers.
Statements 1 to 6 and 9 pertained to the diagnosis and work-up of patients who presented with LHON for which there was strong consensus. The group debated the historical staging (9,11) of the disease and introduced a new distinction. Based on the currently available published evidence (6,8), the first year of the disease can be subdivided into subacute (less than 6 months) and dynamic (6–12 months) phases, based on both functional and structural changes. Visual acuity decreases throughout the subacute phase and then stabilizes at about 6 months. Thinning of the macular RGC layer measured by OCT is largely completed in 4–6 months, highlighting the severe cell loss of the cells originating the papillomacular bundle (8,49). RNFL thickness evaluated by OCT is characterized in the first 6 months by swelling, followed by progressive quadrant specific thinning (6). Thus, the dynamic stage, 6–12 months after onset, is characterized by still ongoing changes in RNFL as opposed to a substantial stability of RGC loss in the macula (8). Visual field defects may progress in this dynamic stage (50). Although the ideal therapeutic window for LHON remains unknown, it is possible that there is a greater potential for visual recovery in the subacute phase compared with the dynamic phase.
Statements 7, 8, and 10–16 pertained to the use of idebenone in LHON. The group reached consensus that idebenone was indicated in subacute and dynamic patients at 900 mg/day dosage (16), starting the treatment as soon as possible (17). There was also consensus about the continuation of the treatment in responders based on the established outcome measures of BCVA and visual fields, and the criteria for defining a clinically relevant response (17). The group strongly disagreed with the use of idebenone as a maintenance dose in nonresponders who have received treatment for 1 year. Concerning patients in the chronic stage (>1 year), it was determined that there was not enough evidence to support treatment for those patients with disease duration of 1–5 years, and no evidence for treatment after 5 years of disease. As a consequence, there was no consensus on statement 13 and the jury unanimously agreed not to vote on statement 14. The group based its judgment strictly on the existing data on clinical administration of idebenone in patients, as derived from the published literature (14–20,40–43) and the unpublished information publicly available at the EMA website, including the European public assessment report ([EPAR]; ema.europa.eu/Find medicine/Human medicines/EPARs) and the summary of the opinion of the Committee for Orphan Medicinal Products for Raxone (ema.europa.eu/Find medicine/Human medicines/Rare disease designation). Preclinical research also was considered (51–55), as was the fact that the effectiveness and mechanisms of action of idebenone are still a subject of debate.
Statements 17–20 pertained to the proband's maternally related relatives and specifically unaffected carriers. The group agreed that the unaffected mutation carriers did not require routine genetic or clinical testing. However, as best practice with any genetic disease, genetic counseling is offered to the patient who has the right to refuse any wider family involvement. Furthermore, the group reached a strong consensus that treatment is not recommended for asymptomatic carriers, and that there is currently no prognostic measure to predict disease conversion.
The diagnosis of LHON should be based on a careful history, evaluation of key structural and functional visual parameters, and on a molecular confirmation of a pathogenic mtDNA mutation. The management of LHON includes genetic counseling, informing the patient about potentially preventable lifestyle risk factors and, for subacute and dynamic cases, the use of idebenone at the currently approved dose. Idebenone should be discontinued in nonresponder patients and is currently not recommended in patients in the chronic stages of the disease. These guidelines and recommendations are based on a consensus developed on the current state of the literature. Further investigations and clinical trials are needed to lead to better disease-modifying treatments and to improve the management of patients with LHON.
The authors are particularly grateful to Dr. Maria Lucia Cascavilla, Dr. Anna Maria De Negri, Dr. Arturo Carta, Dr. Michelangelo Mancuso, Dr. Costanza Lamperti, and Prof. Antonio Toscano for their comments and critical review of the manuscript.
Jury members of the first Consensus Conference on clinical and therapeutic management of Leber's Hereditary Optic Neuropathy: Piero Barboni, Michele Carbonelli, Valerio Carelli, Irenaus de Coo, Thomas Klopstock, Wolf Lagrèze, Chiara La Morgia, Nancy J. Newman, Christine Orssaud, Jan Willem Pott, Alfredo A. Sadun, Judith van Everdingen, Patrick Yu-Wai-Man, Additional experts contributing to the statements, Aki Kawasaki, Catherine Vignal-Clermont, Marcela Votruba.
1. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988;242:1427–1430.
2. Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015;77:753–759.
3. Mascialino B, Leinonen M, Meier T. Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe. Eur J Ophthalmol. 2012;22:461–465.
4. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004;23:53–89.
5. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114.
6. Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A, Salomao SR, Carelli V, Sadun AA. Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology. 2010;117:623–627.
7. Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao SR, Moraes-Filho MN, Moraes MN, Berezovsky A, Belfort R Jr, Sadun AA. Mathematically modeling the involvement of axons in Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2012;53:7608–7617.
8. Balducci N, Savini G, Cascavilla ML, La Morgia C, Triolo G, Giglio R, Carbonelli M, Parisi V, Sadun AA, Bandello F, Carelli V, Barboni P. Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy. Br J Ophthalmol. 2016;100:1232–1237.
9. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy. I. Fundus findings in asymptomatic family members. Arch Ophthalmol. 1982;100:1597–1602.
10. Savini G, Barboni P, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, Carelli V. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber's hereditary optic neuropathy mutations. Ophthalmology. 2005;112:127–131.
11. Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber's hereditary optic neuropathy. II. The fundus findings in the affected family members. Arch Ophthalmol. 1983;101:1059–1068.
12. Stone EM, Newman NJ, Miller NR, Johns DR, Lott MT, Wallace DC. Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin Neuroophthalmol. 1992;12:10–14.
13. 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. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy. PLoS One. 2012;7:e42242.
14. Newman NJ. Treatment of hereditary optic neuropathies. Nat Rev Neurol. 2012;8:545–556.
15. Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). 2014;28:521–537.
16. 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. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011;134:2677–2686.
17. Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni P. Idebenone treatment in Leber's hereditary optic neuropathy. Brain. 2011;134:e188.
18. Newman NJ. Treatment of Leber hereditary optic neuropathy. Brain. 2011;134:2447–2450.
19. Klopstock T, Metz G, Yu-Wai-Man P, Büchner B, Gallenmüller C, Bailie M, Nwali N, Griffiths PG, von Livonius B, Reznicek L, Rouleau J, Coppard N, Meier T, Chinnery PF. Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy. Brain. 2013;136:e230.
20. Rudolph G, Dimitriadis K, Büchner B, Heck S, Al-Tamami J, Seidensticker F, Rummey C, Leinonen M, Meier T, Klopstock T. Effects of idebenone on color vision in patients with Leber hereditary optic neuropathy. J Neuroophthalmol. 2013;33:30–36.
21. Candiani g, Colombo c, Daghini R, et al. Methodological Handbook—How to Organize a Consensus Conference. Rome: Italian Institute of Health, 2013. Available at: http://http://www.snlg-iss.it
/en_CC_methodological_handbook. Accessed July 29, 2016.
22. Barboni P, Savini G, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, de Vivo A, Carelli V. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's hereditary optic neuropathy. Ophthalmology. 2005;112:120–126.
23. Barboni P, Savini G, Valentino ML, La Morgia C, Bellusci C, De Negri AM, Sadun F, Carta A, Carbonelli M, Sadun AA, Carelli V. Leber's hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci. 2006;47:5303–5309.
24. Dimitriadis K, Leonhardt M, Yu-Wai-Man P, Kirkman MA, Korsten A, De Coo IF, Chinnery PF, Klopstock T. Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients. Orphanet J Rare Dis. 2014;9:158.
25. Ramos Cdo V, Bellusci C, Savini G, Carbonelli M, Berezovsky A, Tamaki C, Cinoto R, Sacai PY, Moraes-Filho MN, Miura HM, Valentino ML, Iommarini L, De Negri AM, Sadun F, Cortelli P, Montagna P, Salomao SR, Sadun AA, Carelli V, Barboni P. Association of optic disc size with development and prognosis of Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2009;50:1666–1674.
26. Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros PA, Sadun F, DeNegri AM, Andrade R, Moraes M, Passos A, Kjaer P, Pereira J, Valentino ML, Schein S, Belfort R. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2003;136:231–238.
27. Kirkman MA, Yu-Wai-Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, Chinnery PF. Gene-environment interactions in Leber hereditary optic neuropathy. Brain. 2009;132:2317–2326.
28. Newman NJ. Leber hereditary optic neuropathy: bad habits, bad vision? Brain. 2009;132:2306–2308.
29. Carelli V, d'Adamo P, Valentino ML, La Morgia C, Ross-Cisneros FN, Caporali L, Maresca A, Loguercio Polosa P, Barboni P, De Negri A, Sadun F, Karanjia R, Salomao SR, Berezovsky A, Chicani F, Moraes M, Moraes Filho M, Belfort R Jr, Sadun AA. Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion. Brain. 2016;139:e17.
30. Yu-Wai-Man P, Hudson G, Klopstock T, Chinnery PF. Reply: Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion. Brain. 2016;139:e18.
31. 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. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain. 2011;134:220–234.
32. Maresca A, Caporali L, Strobbe D, Zanna C, Malavolta D, La Morgia C, Valentino ML, Carelli V. Genetic basis of mitochondrial optic neuropathies. Curr Mol Med. 2014;14:985–992.
33. Erickson RP. Leber's optic atrophy, a possible example of maternal inheritance. Am J Hum Genet. 1972;24:348–349.
34. McClelland CM, Van Stavern GP, Tselis AC. Leber hereditary optic neuropathy mimicking neuromyelitis optica. J Neuroophthalmol. 2011;31:265–268.
35. Hsu TK, Wang AG, Yen MY, Liu JH. Leber's hereditary optic neuropathy masquerading as optic neuritis with spontaneous visual recovery. Clin Exp Optom. 2014;97:84–86.
36. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber's hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Ophthalmol. 1993;111:1482–1485.
37. Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995;118:319–337.
38. Nikoskelainen EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K, Savontaus ML. Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology. 1996;103:504–514.
39. 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. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy. Brain. 2014;137:335–353.
40. Mashima Y, Hiida Y, Oguchi Y. Remission of Leber's hereditary optic neuropathy with idebenone. Lancet. 1992;340:368–369.
41. Cortelli P, Montagna P, Pierangeli G, Lodi R, Barboni P, Liguori R, Carelli V, Iotti S, Zaniol P, Lugaresi E, Barbiroli B. Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study. J Neurol Sci. 1997;148:25–31.
42. Carelli V, Barboni P, Zacchini A, Mancini R, Monari L, Cevoli S, Liguori R, Sensi M, Lugaresi E, Montagna P. Leber's hereditary optic neuropathy (LHON) with 14484/ND6 mutation in a North African patient. J Neurol Sci. 1998;160:183–188.
43. Mashima Y, Kigasawa K, Wakakura M, Oguchi Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000;20:166–170.
44. Quiros PA, Torres RJ, Salomao S, Berezovsky A, Carelli V, Sherman J, Sadun F, De Negri A, Belfort R, Sadun AA. Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study. Br J Ophthalmol. 2006;90:150–153.
45. Ventura DF, Gualtieri M, Oliveira AG, Costa MF, Quiros P, Sadun F, de Negri AM, Salomão SR, Berezovsky A, Sherman J, Sadun AA, Carelli V. Male prevalence of acquired color vision defects in asymptomatic carriers of Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2007;48:2362–2370.
46. Yee KM, Ross-Cisneros FN, Lee JG, Da Rosa AB, Salomao SR, Berezovsky A, Belfort R Jr, Chicani F, Moraes-Filho M, Sebag J, Carelli V, Sadun AA. Neuron-specific enolase is elevated in asymptomatic carriers of Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2012;53:6389–6392.
47. Barboni P, Savini G, Feuer WJ, Budenz DL, Carbonelli M, Chicani F, Ramos Cdo V, Salomao SR, Negri AD, Parisi V, Carelli V, Sadun AA. Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers. Eur J Ophthalmol. 2012;22:985–991.
48. Giordano L, Deceglie S, d'Adamo P, Valentino ML, La Morgia C, Fracasso F, Roberti M, Cappellari M, Petrosillo G, Ciaravolo S, Parente D, Giordano C, Maresca A, Iommarini L, Del Dotto V, Ghelli AM, Salomao SR, Berezovsky A, Belfort R Jr, Sadun AA, Carelli V, Loguercio Polosa P, Cantatore P. Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways. Cell Death Dis. 2015;6:e2021.
49. Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol. 2016;132:789–806.
50. Newman NJ, Biousse V, Newman SA, Bhatti MT, Hamilton SR, Farris BK, Lesser RL, Turbin RE. Progression of visual field defects in leber hereditary optic neuropathy: experience of the LHON treatment trial. Am J Ophthalmol. 2006;141:1061–1067.
51. Angebault C, Gueguen N, Desquiret-Dumas V, Chevrollier A, Guillet V, Verny C, Cassereau J, Ferre M, Milea D, Amati-Bonneau P, Bonneau D, Procaccio V, Reynier P, Loiseau D. Idebenone increases mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration. BMC Res Notes. 2011;4:557.
52. Erb M, Hoffmann-Enger B, Deppe H, Soeberdt M, Haefeli RH, Rummey C, Feurer A, Gueven N. Features of idebenone and related short-chain quinones that rescue ATP levels under conditions of impaired mitochondrial complex I. PLoS One. 2012;7:e36153.
53. Giorgio V, Petronilli V, Ghelli A, Carelli V, Rugolo M, Lenaz G, Bernardi P. The effects of idebenone on mitochondrial bioenergetics. Biochim Biophys Acta. 2012;1817:363–369.
54. Yu-Wai-Man P, Soiferman D, Moore DG, Burté F, Saada A. Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion. [published ahead of print January 16, 2017] doi: .
55. Heitz FD, Erb M, Anklin C, Robay D, Pernet V, Gueven N. Idebenone protects against retinal damage and loss of vision in a mouse model of Leber's hereditary optic neuropathy. PLoS One. 2012;7:e45182.