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

  • Amy Goldstein
  • Serenella Servidei


Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a well-recognized clinical mitochondrial disease which causes typical symptoms of short stature, failure to thrive, recurrent headaches and vomiting, stroke-like episodes causing hemiplegia or vision loss, epilepsy, hearing loss, and diabetes. Additional manifestations include other endocrinopathies and cardiac involvement. MELAS is typically caused by a mitochondrial DNA point mutation (m.3243A>G) and is therefore maternally inherited. It is not at all unusual to find additional family members who are also affected or may be oligosymptomatic with other clinical phenotypes caused by this pathogenic variant such as maternally inherited diabetes and deafness (MIDD). Recognition of MELAS is critically important to ensure proper long-term surveillance and potential therapies. MELAS leads to overall morbidity and mortality due to recurrent stroke-like episodes, cerebral atrophy, and physical and mental deterioration over time.


Mitochondrial encephalomyopathy Stroke-like episodes Strongly SDH-reactive vessels (SSVs) Cytochrome C oxidase (COX) negative fibers Lactic acidosis L-arginine 


  1. 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.PubMedCrossRefGoogle Scholar
  2. 2.
    Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651–3.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options. CNS Drugs. 2006;20(6):443–64. Review. Erratum in: CNS Drugs. 2008;22(1):81PubMedCrossRefGoogle Scholar
  4. 4.
    Kami K, Fujita Y, Igarashi S, Koike S, Sugawara S, Ikeda S, Sato N, Ito M, Tanaka M, Tomita M, Soga T. Metabolomic profiling rationalized pyruvate efficacy in cybrid cells harboring MELAS mitochondrial DNA mutations. Mitochondrion. 2012;12(6):644–53. Scholar
  5. 5.
    Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992;2(2):125–35. ReviewPubMedCrossRefGoogle Scholar
  6. 6.
    Yatsuga S, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T, Kakuma T, Koga Y, Taro Matsuoka for MELAS Study Group in Japan. MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta. 2012;1820(5):619–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Goodfellow JA, Dani K, Stewart W, Santosh C, McLean J, Mulhern S, Razvi S. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people. Postgrad Med J. 2012;88(1040):326–34.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Sproule DM, Battista V, Koenigsberger DY, Pascual JM, Shanske S, Sano M, Mao X, Hirano M, Shungu DC, Dimauro S, De Vivo DC. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011;77(22):1965–71.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    DiMauro S, Hirano M. MELAS. 2001 Feb 27 [Updated 2013 Nov 21] 2013. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2018.
  10. 10.
    Petruzzella V, Zoccolella S, Amati A, Torraco A, Lamberti P, Carnicella F, Serlenga L, Papa S. Cerebellar ataxia as atypical manifestation of the 3243A>G MELAS mutation. Clin Genet. 2004;65:64–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Anglin RE, Garside SL, Tarnopolsky MA, Mazurek MF, Rosebush PI. The psychiatric manifestations of mitochondrial disorders: a case and review of the literature. J Clin Psychiatry. 2012;73:506–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Kraya T, Neumann L, Paelecke-Habermann Y, Deschauer M, Stoevesandt D, Zierz S, Watzke S. Cognitive impairment, clinical severity and MRI changes in MELAS syndrome. Mitochondrion. 2019;44:53–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Miceli G, Conti G, Cianfoni A, Di Giacopo R, Zampetti P, Servidei S. Acute auditory agnosia as the presenting hearing disorder in MELAS. Neurol Sci. 2008;29(6):459–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Kolb SJ, Costello F, Lee AG, et al. Distinguishing ischemic stroke from the stroke-like lesions of MELAS using apparent diffusion coefficient mapping. J Neurol Sci. 2003;216:11–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Iizuka T, Sakai F, Kan S, Suzuki N. Slowly progressive spread of the stroke-like lesions in MELAS. Neurology. 2003;61:1238–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Ito H, Mori K, Kagami S. Neuroimaging of stroke-like episodes in MELAS. Brain and Development. 2011;33(4):283–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Malhotra K, Liebeskind DS. Imaging of MELAS. Curr Pain Headache Rep. 2016;20(9):54.PubMedCrossRefGoogle Scholar
  18. 18.
    Xu W, Wen J, Sun C, Cao J, Li Y, Geng D. Conventional and diffusional magnetic resonance imaging. Features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in Chinese patients: a study of 40 cases. J Comput Assist Tomogr. 2018;42(4):510–6.PubMedGoogle Scholar
  19. 19.
    Ooiwa Y, Uematsu Y, Terada T, Nakai K, Itakura T, Komai N, et al. Cerebral blood flow in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Stroke. 1993;24:304–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Kim JH, Lim MK, Jeon TY, Rha JH, Eo H, Yoo SY, Shu CH. Diffusion and perfusion characteristics of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode) in thirteen patients. Korean J Radiol. 2011;12(1):15–24.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Walcott BP, Edlow BL, Xia Z, Kahle KT, Nahed BV, Schmahmann JD. Steroid responsive A3243G mutation MELAS. Clinical and radiographic evidence for regional hyperperfusion leading to neuronal loss. Neurologist. 2012;18:159–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Betts J, Jaros E, Perry RH, Schaefer AM, Taylor RW, Abdel-All Z, et al. Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol. 2006;32(4):359–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Iizuka T, Sakai F. Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res. 2005;2:29–45.PubMedCrossRefGoogle Scholar
  24. 24.
    Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Donati A, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Ienco EC, Filosto M, Lamperti C, Catteruccia M, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Valentino ML, Vercelli L, Zeviani M, Siciliano G. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol. 2014;261(3):504–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Pickett SJ, Grady JP, Ng YS, Gorman GS, Schaefer AM, Wilson IJ, Cordell HJ, Turnbull DM, Taylor RW, McFarland R. Phenotypic heterogeneity in m.3243A>G mitochondrial disease: the role of nuclear factors. Ann Clin Transl Neurol. 2018;5(3):333–45.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Tzoulis C, Neckelmann G, Mørk SJ, Engelsen BE, Viscomi C, Moen G, Ersland L, Zeviani M, Bindoff LA. Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes. Brain. 2010;133(Pt 5):1428–37.PubMedCrossRefGoogle Scholar
  27. 27.
    Demarest ST, Whitehead MT, Turnacioglu S, Pearl PL, Gropman AL. Phenotypic analysis of epilepsy in the mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes-associated mitochondrial DNA A3243G mutation. J Child Neurol. 2014;29(9):1249–56.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee HN, Eom S, Kim SH, Kang HC, Lee JS, Kim HD, Lee YM. Epilepsy characteristics and clinical outcome in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Pediatr Neurol. 2016;64:59–65.PubMedCrossRefGoogle Scholar
  29. 29.
    Nesbitt V, Pitceathly RD, Turnbull DM, Taylor RW, Sweeney MG, Mudanohwo EE, Rahman S, Hanna MG, McFarland R. The UK MRC mitochondrial disease patient cohort study: clinical phenotypes associated with the m.3243A>G mutation-implications for diagnosis and management. J Neurol Neurosurg Psychiatry. 2013;84(8):936–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Vollono C, Primiano G, Della Marca G, Losurdo A, Servidei S. Migraine in mitochondrial disorders: prevalence and characteristics. Cephalalgia. 2018;38(6):1093–106.PubMedCrossRefGoogle Scholar
  31. 31.
    Kärppä M, Herva R, Moslemi AR, Oldfors A, Kakko S, Majamaa K. Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA. Brain. 2005;128(Pt 8):1861–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Chinnery PF, Howell N, Lightowlers RN. Turnbull DM molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain. 1997;120(Pt 10):1713–21.PubMedCrossRefGoogle Scholar
  33. 33.
    El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116(1–2):4–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Luigetti M, Sauchelli D, Primiano G, Cuccagna C, Bernardo D, Monaco L, Servidei S. Eur J Neurol. 2016;23(6):1020–7.PubMedCrossRefGoogle Scholar
  35. 35.
    García-Velasco A, Gómez-Escalonilla C, Guerra-Vales JM, Cabello A, Campos Y, Arenas J. Intestinal pseudo-obstruction and urinary retention: cardinal features of a mitochondrial DNA-related disease. J Intern Med. 2003;253(3):381–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Chang TM, Chi CS, Tsai CR, Lee HF, Li MC. Paralytic ileus in MELAS with phenotypic features of MNGIE. Pediatr Neurol. 2004;31(5):374–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Primiano G, Plantone D, Forte F, Sauchelli D, Scaldaferri F, Gasbarrini A, Servidei S. Acute refractory intestinal pseudo-obstruction in MELAS: efficacy of prucalopride. Neurology. 2014;82(21):1932–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Ng YS, Feeney C, Schaefer AM, Holmes CE, Hynd P, Alston CL, Grady JP, Roberts M, Maguire M, Bright A, Taylor RW, Yiannakou Y, McFarland R, Turnbull DM, Gorman GS. Pseudo-obstruction, stroke, and mitochondrial dysfunction: a lethal combination. Ann Neurol. 2016;80(5):686–92.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ng YS, Grady JP, Lax NZ, Bourke JP, Alston CL, Hardy SA, Falkous G, Schaefer AG, Radunovic A, Mohiddin SA, Ralph M, Alhakim A, Taylor RW, McFarland R, Turnbull DM, Gorman GS. Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults. Eur Heart J. 2016;37(32):2552–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Betts J, Barron MJ, Needham SJ, Schaefer AM, Taylor RW, Turnbull DM. Gastrointestinal tract involvement associated with the 3243A>G mitochondrial DNA mutation. Neurology. 2008;70(15):1290–2.PubMedCrossRefGoogle Scholar
  41. 41.
    Al-Gadi IS, Haas RH, Falk MJ, Goldstein A, McCormack SE. Endocrine disorders in primary mitochondrial disease. J Endocr Soc. 2018;2(4):361–73.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Menotti F, Brega A, Diegoli M, Grasso M, Modena MG, Arbustini E. A novel mtDNA point mutation in tRNA(Val) is associated with hypertrophic cardiomyopathy and MELAS. Ital Heart J. 2004;5(6):460–5.PubMedGoogle Scholar
  43. 43.
    Wortmann SB, Rodenburg RJ, Backx AP, Schmitt E, Smeitink JA, Morava E. Early cardiac involvement in children carrying the A3243G mtDNA mutation. Acta Paediatr. 2007;96(3):450–1.PubMedCrossRefGoogle Scholar
  44. 44.
    Hollingsworth KG, Gorman GS, Trenell MI, McFarland R, Taylor RW, Turnbull DM, MacGowan GA, Blamire AM, Chinnery PF. Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load. Neuromuscul Disord. 2012;22(7):592–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Bates MG, Bourke JP, Giordano C, d'Amati G, Turnbull DM, Taylor RW. Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management. Eur Heart J. 2012;33(24):3023–33.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Wahbi K, Bougouin W, Béhin A, Stojkovic T, Bécane HM, Jardel C, Berber N, Mochel F, Lombès A, Eymard B, Duboc D, Laforêt P. Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. Eur Heart J. 2015;36(42):2886–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Hotta O, Inoue CN, Miyabayashi S, Furuta T, Takeuchi A, Taguma Y. Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation. Kidney Int. 2001;59:1236–43.PubMedCrossRefGoogle Scholar
  48. 48.
    Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, Mao X, Shanske S, Hirano M, DiMauro S, De Vivo DC. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology. 2004;62(8):1297–302.PubMedCrossRefGoogle Scholar
  49. 49.
    DiMauro S, Bonilla E. Mitochondrial encephalomyopathies. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, editors. The molecular and genetic basis of neurological disease. Boston, MA: Butterworth-Heinemann; 1997. p. 201–35.Google Scholar
  50. 50.
    Filosto M, Tomelleri G, Tonin P, Scarpelli M, Vattemi G, Rizzuto N, Padovani A, Simonati A. Neuropathology of mitochondrial diseases. Biosci Rep. 2007;27:23–30.PubMedCrossRefGoogle Scholar
  51. 51.
    Silvestri G, Rana M, Odoardi F, Modoni A, Paris E, Papacci M, Tonali P, Servidei S. Single-fiber PCR in MELAS(3243) patients: correlations between intratissue distribution and phenotypic expression of the mtDNA(A3243G) genotype. Am J Med Genet. 2000;94(3):201–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann Neurol. 1991;29:601–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Kaufmann P, Pascual JM, Anziska Y, Gooch CL, Engelstad K, Jhung S, DiMauro S, De Vivo DC. Nerve conduction abnormalities in patients with MELAS and the A3243G mutation. Arch Neurol. 2006;63:746–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Whitehead MT, Wien M, Lee B, Bass N, Gropman A. Black. Toenail sign in MELAS syndrome. Pediatr Neurol. 2017;75:61–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Finsterer J. Laminar cortical necrosis in mitochondrial disorders. Clin Neurol Neurosurg. 2009;111(8):655–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Tschampa HJ, Urbach H, Greschus S, Kunz WS, Kornblum C. Neuroimaging characteristics in mitochondrial encephalopathies associated with them.3243A>G MTTL1 mutation. J Neurol. 2013;260(4):1071–80.PubMedCrossRefGoogle Scholar
  57. 57.
    Primiano G, Servidei S. Intestinal pseudo-obstruction in mitochondrial diseases. Ann Neurol. 2017;81(1):158–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Tsujikawa K, Senda J, Yasui K, Hasegawa Y, Hoshiyama M, Katsuno M, Sobue G. Distinctive distribution of brain volume reductions in MELAS and mitochondrial DNA A3243G mutation carriers: a voxel-based morphometric study. Mitochondrion. 2016;30:229–35.PubMedCrossRefGoogle Scholar
  59. 59.
    Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017;241(2):236–50.PubMedCrossRefGoogle Scholar
  60. 60.
    Abe K, Yoshimura H, Tanaka H, Fujita N, Hikita T, Sakoda S. Comparison of conventional and diffusion-weighted MRI and proton MR spectroscopy in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like events. Neuroradiology. 2004;46(2):113–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Weiduschat N, Kaufmann P, Mao X, Engelstad KM, Hinton V, DiMauro S, De Vivo D, Shungu D. Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology. 2014;82(9):798–805.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    McDonnell MT, Schaefer AM, Blakely EL, McFarland R, Chinnery PF, Turnbull DM, Taylor RW. Noninvasive diagnosis of the 3243A > G mitochondrial DNA mutation using urinary epithelial cells. Eur J Hum Genet. 2004;12:778–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Shanske S, Pancrudo J, Kaufmann P, Engelstad K, Jhung S, Lu J, Naini A, DiMauro S, De Vivo DC. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A. 2004;130A:134–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Rahman S, Poulton J, Marchington D, Suomalainen A. Decrease of 3243 A->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet. 2001;68(1):238–40.PubMedCrossRefGoogle Scholar
  65. 65.
    Goto Y, Nonaka I, Horai S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta. 1991;1097:238–40.PubMedCrossRefGoogle Scholar
  66. 66.
    Morten KJ, Cooper JM, Brown GK, Lake BD, Pike D. Poulton J. a new point mutation associated with mitochondrial encephalomyopathy. Hum Mol Genet. 1993;2:2081–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Goto Y, Tsugane K, Tanabe Y, Nonaka I, Horai S. A new point mutation at nucleotide pair 3291 of the mitochondrial tRNA(Leu(UUR)) gene in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochem Biophys Res Commun. 1994;202:1624–30.PubMedCrossRefGoogle Scholar
  68. 68.
    Sato W, Hayasaka K, Shoji Y, Takahashi T, Takada G, Saito M, Fukawa O, Wachi E. A mitochondrial tRNA(Leu)(UUR) mutation at 3,256 associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochem Mol Biol Int. 1994;33:1055–61.PubMedGoogle Scholar
  69. 69.
    Nishino I, Komatsu M, Kodama S, Horai S, Nonaka I, Goto Y. The 3260 mutation in mitochondrial DNA can cause mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Muscle Nerve. 1996;19:1603–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Hanna MG, Nelson IP, Morgan-Hughes JA, Wood NW. MELAS: a new disease associated mitochondrial DNA mutation and evidence for further genetic heterogeneity. J Neurol Neurosurg Psychiatry. 1998;65:512–7.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Taylor RW, Chinnery PF, Haldane F, Morris AA, Bindoff LA, Wilson J, Turnbull DM. MELAS associated with a mutation in the valine transfer RNA gene of mitochondrial DNA. Ann Neurol. 1996;40:459–62.PubMedCrossRefGoogle Scholar
  72. 72.
    Tanji K, Kaufmann P, Naini AB, Lu J, Parsons TC, Wang D, Willey JZ, Shanske S, Hirano M, Bonilla E, Khandji A, DiMauro S, Rowland LP. A novel tRNA(Val) mitochondrial DNA mutation causing MELAS. J Neurol Sci. 2008;270:23–7.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Bataillard M, Chatzoglou E, Rumbach L, Sternberg D, Tournade A, Laforet P, Jardel C, Maisonobe T, Lombes A. Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation. Neurology. 2001;56:405–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Herrero-Martín MD, Ayuso T, Tuñón MT, Martín MA, Ruiz-Pesini E, Montoya JA. MELAS/MERRF phenotype associated with the mitochondrial DNA 5521G>A mutation. J Neurol Neurosurg Psychiatry. 2010;81:471–2.PubMedCrossRefGoogle Scholar
  75. 75.
    Manfredi G, Schon EA, Bonilla E, Moraes CT, Shanske S, DiMauro S. Identification of a mutation in the mitochondrial tRNA(Cys) gene associated with mitochondrial encephalopathy. Hum Mutat. 1996;7:158–63.PubMedCrossRefGoogle Scholar
  76. 76.
    Lindberg C, Moslemi AR, Oldfors A. MELAS syndrome in a patient with a point mutation in MTTS1. Acta Neurol Scand. 2008;117:128–32.PubMedGoogle Scholar
  77. 77.
    Calvaruso MA, Willemsen MA, Rodenburg RJ, van den Brand M, Smeitink JA, Nijtmans L. New mitochondrial tRNA HIS mutation in a family with lactic acidosis and stroke-like episodes (MELAS). Mitochondrion. 2011;11:778–82.PubMedCrossRefGoogle Scholar
  78. 78.
    Abu-Amero KK, Al-Dhalaan H, Bohlega S, Hellani A, Taylor RW. A patient with typical clinical features of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report. J Med Case Rep. 2009;3:77.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Campos Y, Lorenzo G, Martin MA, Torregrosa A, del Hoyo P, Rubio JC, Garcia A, Arenas J. A mitochondrial tRNA(Lys) gene mutation (T8316C) in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes. Neuromuscul Disord. 2000;10:493–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Sakuta R, Honzawa S, Murakami N, Goto Y, Nagai T. Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation. Pediatr Neurol. 2002;27:397–400.PubMedCrossRefGoogle Scholar
  81. 81.
    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. Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy. Brain. 2007;130:1894–904.PubMedCrossRefGoogle Scholar
  82. 82.
    Kirby DM, McFarland R, Ohtake A, Dunning C, Ryan MT, Wilson C, Ketteridge D, Turnbull DM, Thorburn DR, Taylor RW. Mutations of the mitochondrial ND1 gene as a cause of MELAS. J Med Genet. 2004;41:784–9.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Tam EW, Feigenbaum A, Addis JB, Blaser S, Mackay N, Al-Dosary M, Taylor RW, Ackerley C, Cameron JM. Robinson BH. A novel mitochondrial DNA mutation in COX1 leads to strokes, seizures, and lactic acidosis. Neuropediatrics. 2008;39:328–34.PubMedCrossRefGoogle Scholar
  84. 84.
    Manfredi G, Schon EA, Moraes CT, Bonilla E, Berry GT, Sladky JT, DiMauro S. A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromuscul Disord. 1995;5:391–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Santorelli FM, Tanji K, Kulikova R, Shanske S, Vilarinho L, Hays AP, DiMauro S. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun. 1997;238:326–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol. 2003;53:128–32.PubMedCrossRefGoogle Scholar
  87. 87.
    Naini AB, Lu J, Kaufmann P, Bernstein RA, Mancuso M, Bonilla E, Hirano M, DiMauro S. Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF. Arch Neurol. 2005;62:473–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Crimi M, Galbiati S, Moroni I, Bordoni A, Perini MP, Lamantea E, Sciacco M, Zeviani M, Biunno I, Moggio M, Scarlato G, Comi GP. A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome. Neurology. 2003;60:1857–61.PubMedCrossRefGoogle Scholar
  89. 89.
    Corona P, Antozzi C, Carrara F, D'Incerti L, Lamantea E, Tiranti V, Zeviani M. A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol. 2001;49:106–10.PubMedCrossRefGoogle Scholar
  90. 90.
    McKenzie M, Liolitsa D, Akinshina N, Campanella M, Sisodiya S, Hargreaves I, Nirmalananthan N, Sweeney MG, Abou-Sleiman PM, Wood NW, Hanna MG, Duchen MR. Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption. J Biol Chem. 2007;282:36845–52.PubMedCrossRefGoogle Scholar
  91. 91.
    Ravn K, Wibrand F, Hansen FJ, Horn N, Rosenberg T, Schwartz M. An mtDNA mutation, 14453G>A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Eur J Hum Genet. 2001;9:805–9.PubMedCrossRefGoogle Scholar
  92. 92.
    De Coo IF, Renier WO, Ruitenbeek W, Ter Laak HJ, Bakker M, Schagger H, Van Oost BA, Smeets HJ. A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann Neurol. 1999;1999(45):130–3.CrossRefGoogle Scholar
  93. 93.
    Emmanuele V, Sotiriou E, Rios PG, Ganesh J, Ichord R, Foley AR, Akman HO, DiMauro S. A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome. J Child Neurol. 2013;28:236–42.PubMedCrossRefGoogle Scholar
  94. 94.
    Manwaring N, Jones MM, Wang JJ, Rochtchina E, Howard C, Mitchell P, Sue CM. Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007;7(3):230–3.PubMedCrossRefGoogle Scholar
  95. 95.
    Grady JP, Pickett SJ, Ng YS, Alston CL, Blakely EL, Hardy SA, Feeney CL, Bright AA, Schaefer AM, Gorman GS, McNally RJ, Taylor RW, Turnbull DM, McFarland R. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med. 2018;Google Scholar
  96. 96.
    Majamaa-Voltti KA, Winqvist S, Remes AM, Tolonen U, Pyhtinen J, Uimonen S, Kärppä M, Sorri M, Peuhkurinen K, Majamaa K. A 3-year clinical follow-up of adult patients with 3243A>G in mitochondrial DNA. Neurology. 2006;66:1470–5.PubMedCrossRefGoogle Scholar
  97. 97.
    Malfatti E, Laforet P, Jardel C, Stojkovic T, Behin A, Eymard B, Lombes A, Benmalek A, Becane H-M, Berber N, Meune C, Duboc D, Wahbi K. High risk of severe cardiac adverse events in patients with mitochondrial m.3243A-G mutation. Neurology. 2013;80:100–5.PubMedCrossRefGoogle Scholar
  98. 98.
    Barends M, Verschuren L, Morava E, Nesbitt V, Turnbull D, McFarland R. Causes of death in adults with mitochondrial disease. JIMD Rep. 2016;26:103–13.PubMedCrossRefGoogle Scholar
  99. 99.
    Glover EI, Martin J, Maher A, Thornhill RE, Moran GR, Tarnopolsky MA. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve. 2010;42:739–48.PubMedCrossRefGoogle Scholar
  100. 100.
    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;35:235–42.PubMedCrossRefGoogle Scholar
  101. 101.
    Napolitano A, Salvetti S, Vista M, Lombardi V, Siciliano G, Giraldi C. Long-term treatment with idebenone and riboflavin in a patient with MELAS. Neurol Sci. 2000;21:S981–2.PubMedCrossRefGoogle Scholar
  102. 102.
    Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;66(3):324–30.PubMedCrossRefGoogle Scholar
  103. 103.
    Pfeffer G, Majamaa K, Turnbull DM, Thorburn D. Chinnery PFTreatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012;4:CD004426.Google Scholar
  104. 104.
    Camp KM, Krotoski D, Parisi MA, Gwinn KA, Cohen BH, Cox CS, Enns GM, Falk MJ, Goldstein AC, Gopal-Srivastava R, Gorman GS, Hersh SP, Hirano M, Hoffman FA, Karaa A, MacLeod EL, McFarland R, Mohan C, Mulberg AE, Odenkirchen JC, Parikh S, Rutherford PJ, Suggs-Anderson SK, Tang WH, Vockley J, Wolfe LA, Yannicelli S, Yeske PE, Coates PM. Nutritional interventions in primary mitochondrial disorders: developing an evidence base. Mol Genet Metab. 2016;119(3):187–206.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Tanabe Y, Fujimoto S, Matsuishi T. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710–2.PubMedCrossRefGoogle Scholar
  106. 106.
    Koga Y, Akita Y, Junko N, Yatsuga S, Povalko N, Fukiyama R, Ishii M, Matsuishi T. Endothelial dysfunction in MELAS improved by L-arginine supplementation. Neurology. 2006;66(11):1766–9.PubMedCrossRefGoogle Scholar
  107. 107.
    El-Hattab AW, Hsu JW, Emrick LT, Wong LJ, Craigen WJ, Jahoor F, Scaglia F. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol Genet Metab. 2012;105(4):607–14.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    El-Hattab AW, Emrick LT, Hsu JW, Chanprasert S, Almannai M, Craigen WJ, Jahoor F, Scaglia F. Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. Mol Genet Metab. 2016;117(4):407–12.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Ohsawa Y, Hagiwara H, Nishimatsu SI, Hirakawa A, Kamimura N, Ohtsubo H, Fukai Y, Murakami T, Koga Y, Goto YI, Ohta S, Sunada Y, KN01 Study Group. Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial. J Neurol Neurosurg Psychiatry. 2018;Google Scholar
  110. 110.
    Koenig MK, Emrick L, Karaa A, Korson M, Scaglia F, Parikh S, Goldstein A. Recommendations for the management of strokelike episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. JAMA Neurol. 2016;73(5):591–4.PubMedCrossRefGoogle Scholar
  111. 111.
    Rodan LH, Wells GD, Banks L, Thompson S, Schneiderman JE, Tein I. Cerebral hyperperfusion and decreased cerebrovascular reactivity correlate with neurologic disease severity in MELAS. Mitochondrion. 2015;22:66–74.PubMedCrossRefGoogle Scholar
  112. 112.
    Fryer RH, Bain JM, De Vivo DC. Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS): a case report and critical reappraisal of treatment options. Pediatr Neurol. 2016;56:59–61.PubMedCrossRefGoogle Scholar
  113. 113.
    Primiano G, Vollono C, Dono F, Servidei S. Drug-resistant epilepsy in MELAS: safety and potential efficacy of lacosamide. Epilepsy Res. 2018;139:135–6.PubMedCrossRefGoogle Scholar
  114. 114.
    Karaa A, Goldstein A. The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes. Pediatr Diabetes. 2015;16(1):1–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Scarpelli M, Zappini F, Filosto M, Russignan A, Tonin P, Tomelleri G. Mitochondrial sensorineural hearing loss: a retrospective study and a description of cochlear implantation in a MELAS patient. Genet Res Int. 2012;2012:287432.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Karaa A, Elsharkawi I, Clapp MA, Balcells C. Effects of mitochondrial disease/dysfunction on pregnancy: a retrospective study. Mitochondrion. 2018; Scholar
  117. 117.
    Kang E, Wu J, Gutierrez NM, Koski A, Tippner-Hedges R, Agaronyan K, Platero-Luengo A, Martinez-Redondo P, Ma H, Lee Y, Hayama T, Van Dyken C, Wang X, Luo S, Ahmed R, Li Y, Ji D, Kayali R, Cinnioglu C, Olson S, Jensen J, Battaglia D, Lee D, Wu D, Huang T, Wolf DP, Temiakov D, Belmonte JC, Amato P, Mitalipov S. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 2016;540(7632):270–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Amy Goldstein
    • 1
  • Serenella Servidei
    • 2
  1. 1.Division of Human Genetics, Department of PediatricsChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Institute of NeurologyCatholic University of the Sacred HeartRomeItaly

Personalised recommendations