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Stroke-Like Episodes in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

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Stroke Genetics

Abstract

The syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a disease marked by a clinical triad of (1) stroke-like episode (SLE) before age 40 years, (2) encephalopathy characterized by seizures and dementia, and (3) lactic acidosis and ragged red fibers. The development of SLEs, acute neurological deterioration marked by radiographic evidence of strokes that do not adhere to vascular territories, is a pathognomonic clinical feature of this disease. A wide array of other systemic features, including short stature, Wolff-Parkinson-White syndrome, and diabetes mellitus, and neurological symptoms, such as sensorineural hearing loss, depression, and migraines, are also frequent manifestations of the disorder. MELAS is caused by a mutation affecting the mitochondrial genome; more than 30 specific mutations have been recognized, although greater than 80% of cases result from a single adenine-to-guanine transition mutation affecting the mitochondrial tRNA(Leu) gene (m.3243A>G). In this review, we will discuss the mechanisms of mitochondrial inheritance, including concepts such as heteroplasmy and mitotic segregation that underlay the complex genetics of this disease. Clinical and radiographic features of SLEs will be discussed at length, as will hypotheses that attempt to explain the pathogenesis of these events. While current treatment is limited to cofactor supplementation, ongoing research into potential therapies such as idebenone and l-arginine will also be discussed.

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Notes

  1. 1.

    http://www.mitomap.org

  2. 2.

    ClinicalTrials.gov identifier NCT00887562

  3. 3.

    Japan Medical Association IIA00025, http://apps.who.int/trialsearch/trial.aspx?trialid=JPRN-JMA-IIA00025

  4. 4.

    ClinicalTrials.gov identifier NCT01339494

References

  1. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol. 1984;16(4):481–8.

    Article  CAS  Google Scholar 

  2. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci. 2008;1142:133–58.

    Article  CAS  Google Scholar 

  3. Schon EA. The mitochondrial genome. In: Rosenberg RPS, DiMauro S, Barchi R, Nestler E, editors. The molecular and genetic basis of neurologic and psychiatric disease. 3rd ed. Philadelphia: Butterworth-Heinemann; 2003. p. 179–88.

    Google Scholar 

  4. Anderson S, Bankier AT, Barrel BG. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457.

    Article  CAS  Google Scholar 

  5. Wong JL. Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve. 2007;36(3):279–93.

    Article  CAS  Google Scholar 

  6. Ruiz-Pesini E, Lott MT, Procaccio V, Poole J, Brandon MC, Mishmar D, et al. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res. 2007;35(Database issue):D823–8. http://www.mitomap.org.

    Article  CAS  Google Scholar 

  7. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med. 2002;347:576–80.

    Article  Google Scholar 

  8. Jenuth JP, Peterson AC, Fu K. Random genetic drift in the female germline explains the random segregation of mammalian mitochondrial DNA. Nat Genet. 1986;13:146.

    Google Scholar 

  9. Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992;2(2):125–35.

    Article  CAS  Google Scholar 

  10. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994;9(1):4–13.

    Article  CAS  Google Scholar 

  11. Chinnery PF, Turnbull DM. Epidemiology and treatment of mitochondrial disorders. Am J Med Genet. 2001;106(1):94–101.

    Article  CAS  Google Scholar 

  12. Gerbitz KD, van den Ouweland JM, Maassen JA, Jaksch M. Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta. 1995;1271(1):253–60.

    Article  Google Scholar 

  13. Uusimaa J, Moilanen JS, Vainionpää L. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol. 2007;62(3):278–87.

    Article  CAS  Google Scholar 

  14. Manwaring N, Jones MM, Wang JJ. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7(3):230–3.

    Article  CAS  Google Scholar 

  15. Sproule DM, Kaufmann P, Engelstad K, Starc TJ, Hordof AJ, De Vivo DC. Wolff-Parkinson-white syndrome in patients with MELAS. Arch Neurol. 2007;64(11):1625–7.

    Article  Google Scholar 

  16. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, et al. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001;344(24):1823–31.

    Article  CAS  Google Scholar 

  17. Bianchi MC, Sgandurra G, Tosetti M, Battini R, Cioni G. Brain magnetic resonance in the diagnostic evaluation of mitochondrial encephalopathies. Biosci Rep. 2007;27(1–3):69–85.

    Article  CAS  Google Scholar 

  18. Matthews PM, Andermann F, Silver K. Proton MR spectroscopy characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology. 1993;43:2484–90.

    Article  Google Scholar 

  19. Kuwabara T, Watanabe H, Tanaka K. Mitochondrial encephalomyopathy: elevated visual cortex lactate unresponsive to photic stimulation-a localized 1H-MRS study. Neurology. 1994;44:557–9.

    Article  CAS  Google Scholar 

  20. Castillo M, Kwock L, Green C. MELAS syndrome: imaging and proton MR spectroscopic findings. AJNR Am J Neuroradiol. 1995;16:233–9.

    CAS  Google Scholar 

  21. Kapeller P, Fazekas F, Hoffenbacher H. Magnetic resonance imaging and spectroscopy of progressive cerebral involvement in Kearn Sayre syndrome. J Neurol Sci. 1996;135:126–30.

    Article  CAS  Google Scholar 

  22. Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, et al. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology. 2004;62:1297–302.

    Article  CAS  Google Scholar 

  23. Cross JH, Gadian DG, Connelly A. Proton magnetic resonance spectroscopy studies in lactic acidosis and mitochondrial disorders. J Inherit Metab Dis. 1993;16:800–11.

    Article  CAS  Google Scholar 

  24. Lin DDM, Crawford TO, Barker PB. Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. AJNR Am J Neuroradiol. 2003;24:33–41.

    Google Scholar 

  25. Iizuka T, Sakai F, Ide T, Miyakawa S, Sato M, Yoshii S. Regional cerebral blood flow and cerebrovascular reactivity during chronic stage of stroke-like episodes in MELAS – implication of neurovascular cellular mechanism. J Neurol Sci. 2007;257:126–38.

    Article  Google Scholar 

  26. Sakuta R, Nonaka I. Vascular involvement in mitochondrial myopathy. Ann Neurol. 1989;25(6):594–601.

    Article  CAS  Google Scholar 

  27. Hasegawa H, Matsuoka T, Goto Y. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Ann Neurol. 1991;13:1439–45.

    Google Scholar 

  28. Tokunaga M, Mita S, Sakuta R, Nonaka I, Araki S. Increased mitochondrial DNA in blood vessels and ragged-red fibers in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Ann Neurol. 1993;33:275–80.

    Article  CAS  Google Scholar 

  29. Koga Y, Akita Y, Junko N, Yatsuga S, Povalko N, Fukiyama R, et al. Endothelial dysfunction in MELAS improved by L-arginine supplementation. Neurology. 2006;66:1766–9.

    Article  CAS  Google Scholar 

  30. Naini A, Kaufmann P, Shanske S, Engelstad K, De Vivo DC, Schon EA. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J Neurol Sci. 2005;229–230:187–93.

    Article  Google Scholar 

  31. Ohama E, Ohara S, Ikuta K, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial angiopathy. Acta Neuropathol. 1987;74:226–33.

    Article  CAS  Google Scholar 

  32. Wu G, Morris SMJ. Arginine metabolism: nitric oxide and beyond. Biochem J. 1998;336:1–17.

    CAS  Google Scholar 

  33. Kobayashi Y, Momoi MY, Tominaga K, Shimoizumi H, Nihei K, Yanagisawa M, et al. Respiration-deficient cells are caused by a single point mutation in the mitochondrial tRNA-leu (UUR) gene in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Am J Hum Genet. 1991;49:590–9.

    CAS  Google Scholar 

  34. King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989;246(4929):500–3. Pubmed/2814477.

    Article  CAS  Google Scholar 

  35. King MP, Koga Y, Davidson M, Schon EA. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol Cell Biol. 1992;12(2):480–90.

    CAS  Google Scholar 

  36. Helm M, Florentz C, Chomyn A, Attardi G. Search for differences in post-transcriptional modification patterns of mitochondrial DNA-encoded wild-type and mutant human tRNALys and tRNALeu(UUR). Nucleic Acids Res. 1999;27(3):756–63.

    Article  CAS  Google Scholar 

  37. Börner GV, Zeviani M, Tiranti V, Carrara F, Hoffmann S, Gerbitz KD, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet. 2000;9(4):467–75.

    Article  Google Scholar 

  38. Chomyn A, Enriquez JA, Micol V, Fernandez-Silva P, Attardi G. The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated human mitochondrial tRNALeu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes. J Biol Chem. 2000;275(25):19198–209.

    Article  CAS  Google Scholar 

  39. Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K. Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem. 2000;275(6):4251–7.

    Article  CAS  Google Scholar 

  40. Kirino Y, Yasukawa T, Ohta S, Akira S, Ishihara K, Watanabe K, et al. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc Natl Acad Sci USA. 2004;101(42):15070–5.

    Article  CAS  Google Scholar 

  41. Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008;17(23):3697–707.

    Article  CAS  Google Scholar 

  42. Shanske S, Pancrudo J, Kaufmann P, Engelstad K, Jhung S, Lu J, et al. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A. 2004;130(2):134–7.

    Article  Google Scholar 

  43. Mancuso M, Filosto M, Forli F. A non-syndromic hearing loss caused by very low levels of the mtDNA A3243G mutation. Acta Neurol Scand. 2004;110:72–4.

    Article  CAS  Google Scholar 

  44. Ciafaloni E, Ricci E, Shanske S. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 2002;31:391–8.

    Article  Google Scholar 

  45. Tatuch Y, Christodoulou J, Feigenbaum A. Heteroplasmic mtDNA mutation (T-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet. 1992;50:852–8.

    CAS  Google Scholar 

  46. Hancock DK, Schwarz FP, Song F, Wong LJ, Levin BC. Design and use of a peptide nucleic acid for detection of the heteroplasmic low-frequency mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation in human mitochondrial DNA. Clin Chem. 2002;48:2155–63.

    CAS  Google Scholar 

  47. Wong LJ, Senadheera D. Direct detection of multiple point mutations in mitochondrial DNA. Clin Chem. 1997;43:1857–61.

    CAS  Google Scholar 

  48. Bai RK, Wong LJ. Detection and quantification of heteroplasmic mutant mitochondrial DNA by real-time amplification refractory mutation system quantitative PCR analysis: a single-step approach. Clin Chem. 2004;50:996–1001.

    Article  CAS  Google Scholar 

  49. Gigarel N, Ray PF, Burlet P. Single cell quantification of the 8993 TNG NARP mitochondrial DNA mutation by fluorescent PCR. Mol Genet Metab. 2005;84:289–92.

    Article  CAS  Google Scholar 

  50. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;66(3):324–30.

    Article  CAS  Google Scholar 

  51. Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve. 1997;20(12):1502–9.

    Article  CAS  Google Scholar 

  52. Tarnopolsky MA, Mahoney DJ, Vajsar J, Rodriguez C, Doherty TJ, Roy BD, et al. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology. 2004;62(10):1771–7.

    Article  CAS  Google Scholar 

  53. Komura K, Hobbiebrunken E, Wilichowski EK, Hanefeld FA. Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies. Pediatr Neurol. 2003;28(1):53–8.

    Article  Google Scholar 

  54. Berbel-Garcia A, Barbera-Farre JR, Etessam JP, Salio AM, Cabello A, Gutierrez-Rivas E, et al. Coenzyme Q10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). Clin Neuropharmacol. 2004;27(4):187–91.

    Article  Google Scholar 

  55. Shinkai T, Nakashima M, Ohmori O, Terao T, Nakamura J, Hiramatsu N, et al. Coenzyme Q10 improves psychiatric symptoms in adult-onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: a case report. Aust N Z J Psychiatry. 2000;34(6):1034–5.

    Article  CAS  Google Scholar 

  56. Abe K, Matsuo Y, Kadekawa J, Inoue S, Yanagihara T. Effect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): valuation by noninvasive tissue oximetry. J Neurol Sci. 1999;162(1):65–8.

    Article  CAS  Google Scholar 

  57. Ihara Y, Namba R, Kuroda S, Sato T, Shirabe T. Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone. J Neurol Sci. 1989;90(3):263–71.

    Article  CAS  Google Scholar 

  58. Matthews PM, Ford B, Dandurand RJ, Eidelman DH, O’Connor D, Sherwin A, et al. Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology. 1993;43(5):884–90.

    Article  CAS  Google Scholar 

  59. Bresolin N, Doriguzzi C, Ponzetto C, Angelini C, Moroni I, Castelli E, et al. Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center double-blind trial. J Neurol Sci. 1990;100(1–2):70–8.

    Article  CAS  Google Scholar 

  60. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007;35(2):235–42.

    Article  CAS  Google Scholar 

  61. Hirata K, Akita Y, Povalko N, Nishioka J, Yatsuga S, Matsuishi T, et al. Effect of l-arginine on synaptosomal mitochondrial function. Brain Dev. 2008;30(4):238–45.

    Article  Google Scholar 

  62. Koga Y, Ishibashi M, Ueki I, Yatsuga S, Fukiyama R, Akita Y, et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology. 2002;58(5):827–8.

    Article  CAS  Google Scholar 

  63. Kubota M, Sakakihara Y, Mori M, Yamagata T, Momoi-Yoshida M. Beneficial effect of L-arginine for stroke-like episode in MELAS. Brain Dev. 2004;26(7):481–3.

    Article  Google Scholar 

  64. Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Tanabe Y, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710–2.

    Article  CAS  Google Scholar 

Additional Reading

  • Borner GV, Zeviani M, Tiranti V, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet. 2000;9(4):467–75.

    Article  CAS  Google Scholar 

  • Chomyn A, Enriquez JA, Micol V, Fernandez-Silva P, Attardi G. The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke- like episode syndrome-associated human mitochondrial tRNALeu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes. J Biol Chem. 2000;275(25):19198–209.

    Article  CAS  Google Scholar 

  • Helm M, Florentz C, Chomyn A, Attardi G. Search for differences in post-transcriptional modification patterns of mitochondrial DNA-encoded wild-type and mutant human tRNALys and tRNALeu(UUR). Nucleic Acids Res. 1999;27(3):756–63.

    Article  CAS  Google Scholar 

  • King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989;246:500–3.

    Article  CAS  Google Scholar 

  • King MP, Koga Y, Davidson M, Schon EA. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu (UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol Cell Biol. 1992;12:480–90.

    CAS  Google Scholar 

  • Kirino Y, Yasukawa T, Ohta S, et al. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc Natl Acad Sci USA. 2004;101(42):15070–5.

    Article  CAS  Google Scholar 

  • Kobayashi Y, Momoi M, Tominaga K, et al. A point mutation in the mitochondrial tRNALeu (UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). Biochem Biophys Res Commun. 1990;173:816–22.

    Article  CAS  Google Scholar 

  • Park H, Davidson E, King MP. The pathogenic A3243G mutation in human mitochondrial tRNALeu(UUR) decreases the efficiency of aminoacylation. Biochemistry. 2003;42(4):958–64.

    Article  CAS  Google Scholar 

  • Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008;17:3697–707.

    Article  CAS  Google Scholar 

  • Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K. Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrialmyopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem. 2000;275(6):4251–7.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Columbia University, 180 Fort Washington Avenue, 5th Floor, New York, NY, 10032, USA

    Douglas M. Sproule M.D., M.Sc.

  2. Department of Pediatrics, Maimonides Medical Center, New York, NY, USA

    Linda Wong M.D.

  3. Department of Neurology, Columbia University Medical Center, New York, NY, USA

    Michio Hirano M.D.

  4. Department of Pediatric Neurology, Maimonides Medical Center, New York, NY, USA

    Steven G. Pavlakis M.D.

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  1. Douglas M. Sproule M.D., M.Sc.
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  2. Linda Wong M.D.
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  3. Michio Hirano M.D.
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  4. Steven G. Pavlakis M.D.
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Correspondence to Douglas M. Sproule M.D., M.Sc. .

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Editors and Affiliations

  1. Imperial College London & Hammersmith Ho, Fulham Palace Road, London, W6 8RF, United Kingdom

    Pankaj Sharma

  2. , Mayo Clinic Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, 32224, Florida, USA

    James F Meschia

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Sproule, D.M., Wong, L., Hirano, M., Pavlakis, S.G. (2013). Stroke-Like Episodes in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). In: Sharma, P., Meschia, J. (eds) Stroke Genetics. Springer, London. https://doi.org/10.1007/978-0-85729-209-4_8

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