CNS Drugs

, Volume 20, Issue 6, pp 443–464 | Cite as

The Mitochondrial Myopathy Encephalopathy, Lactic Acidosis with Stroke-Like Episodes (MELAS) Syndrome

A Review of Treatment Options
Therapy in Practice


Mitochondrial encephalomyopathies are a multisystemic group of disorders that are characterised by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Among this group of disorders, the mitochondrial myopathy, encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome is one of the most frequently occurring, maternally inherited mitochondrial disorders.

As the name implies, stroke-like episodes are the defining feature of the MELAS syndrome, often occurring before the age of 15 years. The clinical course of this disorder is highly variable, ranging from asymptomatic, with normal early development, to progressive muscle weakness, lactic acidosis, cognitive dysfunction, seizures, stroke-like episodes, encephalopathy and premature death.

This syndrome is associated with a number of point mutations in the mitochondrial DNA, with over 80% of the mutations occurring in the dihydrouridine loop of the mitochondrial transfer RNALeu(UUR) [tRNALeu(UUR)] gene. The pathophysiology of the disease is not completely understood; however, several different mechanisms are proposed to contribute to this disease. These include decreased aminoacylation of mitochondrial tRNA, resulting in decreased mitochondrial protein synthesis; changes in calcium homeostasis; and alterations in nitric oxide metabolism.

Currently, no consensus criteria exist for treating the MELAS syndrome or mitochondrial dysfunction in other diseases. Many of the therapeutic strategies used have been adopted as the result of isolated case reports or limited clinical studies that have included a heterogeneous population of patients with the MELAS syndrome, other defects in oxidative phosphorylation or lactic acidosis due to disorders of pyruvate metabolism. Current approaches to the treatment of the MELAS syndrome are based on the use of antioxidants, respiratory chain substrates and cofactors in the form of vitamins; however, no consistent benefits have been observed with these treatments.


Lactic Acidosis CoQ10 Creatine Supplementation Idebenone Leigh Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to acknowledge Drs Lee-Jun C. Wong and William J. Craigen for critically reviewing the manuscript.

No sources of funding were used to assist in the preparation of this review. The authors have no potential conflicts of interest to disclose that are directly relevant to the content of this review.


  1. 1.
    Tritschler HJ, Medori R. Mitochondrial DNA alterations as a source of human disorders. Neurology 1993; 43(2): 280–8PubMedCrossRefGoogle Scholar
  2. 2.
    Schon EA, Bonilla E, DiMauro S. Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr 1997; 29(2): 131–49PubMedCrossRefGoogle Scholar
  3. 3.
    Majamaa K, Moilanen JS, Uimonen S, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet 1998; 63(2): 447–54PubMedCrossRefGoogle Scholar
  4. 4.
    Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 2000; 48(2): 188–93PubMedCrossRefGoogle Scholar
  5. 5.
    Thambisetty M, Newman NJ, Glass JD, et al. A practical approach to the diagnosis and management of MELAS: case report and review. Neurologist 2002; 8(5): 302–12PubMedCrossRefGoogle Scholar
  6. 6.
    Rahman S, Poulton J, Marchington D, et al. Decrease of 3243 A->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet 2001; 68(1): 238–40PubMedCrossRefGoogle Scholar
  7. 7.
    Sue CM, Quigley A, Katsabanis S, et al. Detection of MELAS A3243G point mutation in muscle, blood and hair follicles. J Neurol Sci 1998; 161(1): 36–9PubMedCrossRefGoogle Scholar
  8. 8.
    Shanske S, Pancrudo J, Kaufmann P, et al. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A 2004; 130(2): 134–7CrossRefGoogle Scholar
  9. 9.
    Goto Y, Horai S, Matsuoka T, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology 1992; 42 (3 Pt 1): 545–50PubMedCrossRefGoogle Scholar
  10. 10.
    Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem 1992; 61: 1175–212PubMedCrossRefGoogle Scholar
  11. 11.
    DiMauro S. Mitochondrial diseases. Biochim Biophys Acta 2004; 1658(1–2): 80–8PubMedGoogle Scholar
  12. 12.
    Zeviani M, Muntoni F, Savarese N, et al. A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA (Lys) gene. Eur J Hum Genet 1993; 1(1): 80–7PubMedGoogle Scholar
  13. 13.
    Fabrizi GM, Cardaioli E, Grieco GS, et al. The A to G transition at nt 3243 of the mitochondrial tRNALeu (UUR) may cause an MERRF syndrome. J Neurol Neurosurg Psychiatry 1996; 61(1): 47–51PubMedCrossRefGoogle Scholar
  14. 14.
    Koga Y, Akita Y, Takane N, et al. Heterogeneous presentation in A3243G mutation in the mitochondrial tRNA (Leu (UUR)) gene. Arch Dis Child 2000; 82(5): 407–11PubMedCrossRefGoogle Scholar
  15. 15.
    Anan R, Nakagawa M, Miyata M, et al. Cardiac involvement in mitochondrial diseases: a study on 17 patients with documented mitochondrial DNA defects. Circulation 1995; 91(4): 955–61PubMedCrossRefGoogle Scholar
  16. 16.
    Moraes CT, Ciacci F, Silvestri G, et al. Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromuscul Disord 1993; 3(1): 43–50PubMedCrossRefGoogle Scholar
  17. 17.
    Shimomura T, Kitano A, Marukawa H, et al. Point mutation in platelet mitochondrial tRNA (Leu (UUR)) in patient with cluster headache. Lancet 1994; 344(8922): 625PubMedCrossRefGoogle Scholar
  18. 18.
    van den Ouweland JM, Lemkes HH, Trembath RC, et al. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA (Leu (UUR)) gene. Diabetes 1994; 43(6): 746–51PubMedCrossRefGoogle Scholar
  19. 19.
    Kishnani PS, Van Hove JL, Shoffner JS, et al. Acute pancreatitis in an infant with lactic acidosis and a mutation at nucleotide 3243 in the mitochondrial DNA tRNALeu (UUR) gene. Eur J Pediatr 1996; 155(10): 898–903PubMedCrossRefGoogle Scholar
  20. 20.
    Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 1992; 31(4): 391–8PubMedCrossRefGoogle Scholar
  21. 21.
    Hirano M, Ricci E, Koenigsberger MR, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord 1992; 2(2): 125–35PubMedCrossRefGoogle Scholar
  22. 22.
    Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol 1994; 9(1): 4–13PubMedCrossRefGoogle Scholar
  23. 23.
    Kadowaki T, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330(14): 962–8PubMedCrossRefGoogle Scholar
  24. 24.
    Morgan-Hughes JA, Sweeney MG, Cooper JM, et al. Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype. Biochim Biophys Acta 1995; 1271(1): 135–40PubMedCrossRefGoogle Scholar
  25. 25.
    Crimi M, Galbiati S, Moroni I, et al. A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome. Neurology 2003; 60(11): 1857–61PubMedCrossRefGoogle Scholar
  26. 26.
    Dougherty FE, Ernst SG, Aprille JR. Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr 1994; 125 (5 Pt 1): 758–61PubMedCrossRefGoogle Scholar
  27. 27.
    Ohkoshi N, Ishii A, Shiraiwa N, et al. Dysfunction of the hypothalamic-pituitary system in mitochondrial encephalomyopathies. J Med 1998; 29(1–2): 13–29PubMedGoogle Scholar
  28. 28.
    Yoneda M, Maeda M, Kimura H, et al. Vasogenic edema on MELAS: a serial study with diffusion-weighted MR imaging. Neurology 1999; 53(9): 2182–4PubMedCrossRefGoogle Scholar
  29. 29.
    Wilichowski E, Pouwels PJ, Frahm J, et al. Quantitative proton magnetic resonance spectroscopy of cerebral metabolic disturbances in patients with MELAS. Neuropediatrics 1999; 30(5): 256–63PubMedCrossRefGoogle Scholar
  30. 30.
    Taylor DE, Simonson SG. Use of near-infrared spectroscopy to monitor tissue oxygenation. New Horiz 1996; 4(4): 420–5PubMedGoogle Scholar
  31. 31.
    Bank W, Park J, Lech G, et al. Near-infrared spectroscopy in the diagnosis of mitochondrial disorders. Biofactors 1998; 7(3): 243–5PubMedCrossRefGoogle Scholar
  32. 32.
    Moraes CT, Ricci E, Bonilla E, et al. The mitochondrial tRNA (Leu (UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle. Am J Hum Genet 1992; 50(5): 934–49PubMedGoogle Scholar
  33. 33.
    Hasegawa H, Matsuoka T, Goto Y, et al. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann Neurol 1991; 29(6): 601–5PubMedCrossRefGoogle Scholar
  34. 34.
    Ohama E, Ohara S, Ikuta F, et al. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol (Berl) 1987; 74(3): 226–33CrossRefGoogle Scholar
  35. 35.
    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 U S A 2004; 101(42): 15070–5PubMedCrossRefGoogle Scholar
  36. 36.
    Kirino Y, Goto Y, Campos Y, et al. Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. Proc Natl Acad Sci U S A 2005; 102(20): 7127–32PubMedCrossRefGoogle Scholar
  37. 37.
    James AM, Sheard PW, Wei YH, et al. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem 1999; 259(1–2): 462–9PubMedCrossRefGoogle Scholar
  38. 38.
    Rusanen H, Majamaa K, Hassinen IE. Increased activities of antioxidant enzymes and decreased ATP concentration in cultured myoblasts with the 3243A->G mutation in mitochondrial DNA. Biochim Biophys Acta 2000; 1500(1): 10–6PubMedCrossRefGoogle Scholar
  39. 39.
    King MP, Koga Y, Davidson M, et al. 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): 480–90PubMedGoogle Scholar
  40. 40.
    Koga A, Koga Y, Akita Y, et al. Increased mitochondrial processing intermediates associated with three tRNA (Leu (UUR)) gene mutations. Neuromuscul Disord 2003; 13(3): 259–62PubMedCrossRefGoogle Scholar
  41. 41.
    Kaufmann P, Koga Y, Shanske S, et al. Mitochondrial DNA and RNA processing in MELAS. Ann Neurol 1996; 40(2): 172–80PubMedCrossRefGoogle Scholar
  42. 42.
    Koga Y, Yoshino M, Kato H. MELAS exhibits dominant negative effects on mitochondrial RNA processing. Ann Neurol 1998; 43(6): 835PubMedCrossRefGoogle Scholar
  43. 43.
    Lenaz G, Baracca A, Carelli V, et al. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta 2004; 1658(1–2): 89–94PubMedGoogle Scholar
  44. 44.
    Schanne FA, Kane AB, Young EE, et al. Calcium dependence of toxic cell death: a final common pathway. Science 1979; 206(4419): 700–2PubMedCrossRefGoogle Scholar
  45. 45.
    Moudy AM, Handran SD, Goldberg MP, et al. Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. Proc Natl Acad Sci U S A 1995; 92(3): 729–33PubMedCrossRefGoogle Scholar
  46. 46.
    Iizuka T, Sakai F, Suzuki N, et al. Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology 2002; 59(6): 816–24PubMedCrossRefGoogle Scholar
  47. 47.
    Iizuka T, Sakai F, Kan S, et al. Slowly progressive spread of the stroke-like lesions in MELAS. Neurology 2003; 61(9): 1238–44PubMedCrossRefGoogle Scholar
  48. 48.
    Naini A, Kaufmann P, Shanske S, et al. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J Neurol Sci 2005; 229-230: 187–93CrossRefGoogle Scholar
  49. 49.
    Toda N, Okamura T. The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacol Rev 2003; 55(2): 271–324PubMedCrossRefGoogle Scholar
  50. 50.
    Vos MH, Lipowski G, Lambry JC, et al. Dynamics of nitric oxide in the active site of reduced cytochrome c oxidase aa3. Biochemistry 2001; 40(26): 7806–11PubMedCrossRefGoogle Scholar
  51. 51.
    Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 2005; 64(4): 710–2PubMedCrossRefGoogle Scholar
  52. 52.
    Wu G, Morris Jr SM. Arginine metabolism: nitric oxide and beyond. Biochem J 1998; 336 (Pt 1): 1–17PubMedGoogle Scholar
  53. 53.
    DiMauro S. Mitochondrial encephalomyopathies: what next? J Inherit Metab Dis 1996; 19(4): 489–503PubMedCrossRefGoogle Scholar
  54. 54.
    Gold DR, Cohen BH. Treatment of mitochondrial cytopathies. Semin Neurol 2001; 21(3): 309–25PubMedCrossRefGoogle Scholar
  55. 55.
    Cotariu D, Zaidman JL. Valproic acid and the liver. Clin Chem 1988; 34(5): 890–7PubMedGoogle Scholar
  56. 56.
    Rumbach L, Mutet C, Cremel G, et al. Effects of sodium valproate on mitochondrial membranes: electron paramagnetic resonance and transmembrane protein movement studies. Mol Pharmacol 1986; 30(3): 270–3PubMedGoogle Scholar
  57. 57.
    Ponchaut S, van Hoof F, Veitch K. Cytochrome aa3 depletion is the cause of the deficient mitochondrial respiration induced by chronic valproate administration. Biochem Pharmacol 1992; 43(3): 644–7PubMedCrossRefGoogle Scholar
  58. 58.
    Chabrol B, Mancini J, Chretien D, et al. Valproate-induced hepatic failure in a case of cytochrome c oxidase deficiency. Eur J Pediatr 1994; 153(2): 133–5PubMedGoogle Scholar
  59. 59.
    Lam CW, Lau CH, Williams JC, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate therapy. Eur J Pediatr 1997; 156(7): 562–4PubMedCrossRefGoogle Scholar
  60. 60.
    Ratnikova LA, Cheistiakov VV. Possible biochemical mechanism of the toxic effects of barbiturates [in Russian]. Biokhimiia 1978; 43(11): 1989–93PubMedGoogle Scholar
  61. 61.
    Vorobjev IA, Zorov DB. Diazepam inhibits cell respiration and induces fragmentation of mitochondrial reticulum. FEBS Lett 1983; 163(2): 311–4PubMedCrossRefGoogle Scholar
  62. 62.
    Morovvati S, Nakagawa M, Sato Y, et al. Phenotypes and mitochondrial DNA substitutions in families with A3243G mutation. Acta Neurol Scand 2002; 106(2): 104–8PubMedCrossRefGoogle Scholar
  63. 63.
    Kuroda Y, Ito M, Naito E, et al. Concomitant administration of sodium dichloroacetate and vitamin B1 for lactic acidemia in children with MELAS syndrome. J Pediatr 1997; 131(3): 450–2PubMedCrossRefGoogle Scholar
  64. 64.
    Majamaa K, Rusanen H, Remes A, et al. Metabolic interventions against complex I deficiency in MELAS syndrome. Mol Cell Biochem 1997; 174: 291–6PubMedCrossRefGoogle Scholar
  65. 65.
    Penn AM, Lee JW, Thuillier P, et al. MELAS syndrome with mitochondrial tRNA (Leu) (UUR) mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 1992; 42(11): 2147–52PubMedCrossRefGoogle Scholar
  66. 66.
    Napolitano A, Salvetti S, Vista M, et al. Long-term treatment with idebenone and riboflavin in a patient with MELAS. Neurol Sci 2000; 21(5 Suppl.): S981–2PubMedCrossRefGoogle Scholar
  67. 67.
    Majamaa K, Rusanen H, Remes AM, et al. Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. Life Sci 1996; 58(8): 691–9PubMedCrossRefGoogle Scholar
  68. 68.
    Remes AM, Liimatta EV, Winqvist S, et al. Ubiquinone and nicotinamide treatment of patients with the 3243A->G mtDNA mutation. Neurology 2002; 59(8): 1275–7PubMedCrossRefGoogle Scholar
  69. 69.
    Knip M, Douek IF, Moore WP, et al. Safety of high-dose nicotinamide: a review. Diabetologia 2000; 43(11): 1337–45PubMedCrossRefGoogle Scholar
  70. 70.
    Landi L, Cabrini L, Sechi AM, et al. Antioxidative effect of ubiquinones on mitochondrial membranes. Biochem J 1984; 222(2): 463–6PubMedGoogle Scholar
  71. 71.
    Bresolin N, Doriguzzi C, Ponzetto C, et al. Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center double-blind trial. J Neurol Sci 1990; 100(1–2): 70–8PubMedCrossRefGoogle Scholar
  72. 72.
    Chen RS, Huang CC, Chu NS. Coenzyme Q10 treatment in mitochondrial encephalomyopathies: short-term double-blind, crossover study. Eur Neurol 1997; 37(4): 212–8PubMedCrossRefGoogle Scholar
  73. 73.
    Abe K, Fujimura H, Nishikawa Y, et al. Marked reduction in CSF lactate and pyruvate levels after CoQ therapy in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Acta Neurol Scand 1991; 83(6): 356–9PubMedCrossRefGoogle Scholar
  74. 74.
    Ihara Y, Namba R, Kuroda S, et al. Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone. J Neurol Sci 1989; 90(3): 263–71PubMedCrossRefGoogle Scholar
  75. 75.
    Matthews PM, Ford B, Dandurand RJ, et al. Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 1993; 43(5): 884–90PubMedCrossRefGoogle Scholar
  76. 76.
    Shoffner JM. Oxidative phosphorylation disease. In: Johnston RT, editor. Current therapy in neurological disease. Chicago (IL): Mosby, 1997: 332–42Google Scholar
  77. 77.
    Torii H, Yoshida K, Kobayashi T, et al. Disposition of idebenone (CV-2619), a new cerebral metabolism improving agent, in rats and dogs. J Pharmacobiodyn 1985; 8(6): 457–67PubMedCrossRefGoogle Scholar
  78. 78.
    Imada I, Fujita T, Sugiyama Y, et al. Effects of idebenone and related compounds on respiratory activities of brain mitochondria, and on lipid peroxidation of their membranes. Arch Gerontol Geriatr 1989; 8(3): 323–41PubMedCrossRefGoogle Scholar
  79. 79.
    Frackowiak RS, Herold S, Petty RK, et al. The cerebral metabolism of glucose and oxygen measured with positron tomography in patients with mitochondrial diseases. Brain 1988; 111 (Pt 5): 1009–24PubMedCrossRefGoogle Scholar
  80. 80.
    Ikejiri Y, Mori E, Ishii K, et al. Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS. Neurology 1996; 47(2): 583–5PubMedCrossRefGoogle Scholar
  81. 81.
    Pisano P, Durand A, Autret E, et al. Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy. Eur J Clin Pharmacol 1996; 51(2): 167–9PubMedCrossRefGoogle Scholar
  82. 82.
    Ichiki T, Tanaka M, Nishikimi M, et al. Deficiency of subunits of complex I and mitochondrial encephalomyopathy. Ann Neurol 1988; 23(3): 287–94PubMedCrossRefGoogle Scholar
  83. 83.
    Oguro H, Iijima K, Takahashi K, et al. Successful treatment with succinate in a patient with MELAS. Intern Med 2004; 43(5): 427–31PubMedCrossRefGoogle Scholar
  84. 84.
    Matsuura S, Arpin M, Hannum C, et al. In vitro synthesis and posttranslational uptake of cytochrome c into isolated mitochondria: role of a specific addressing signal in the apocytochrome. Proc Natl Acad Sci U S A 1981; 78(7): 4368–72PubMedCrossRefGoogle Scholar
  85. 85.
    Tanaka J, Nagai T, Arai H, et al. Treatment of mitochondrial encephalomyopathy with a combination of cytochrome C and vitamins B1 and B2. Brain Dev 1997; 19(4): 262–7PubMedCrossRefGoogle Scholar
  86. 86.
    Barak Y, Arnon S, Wolach B, et al. MELAS syndrome: peripheral neuropathy and cytochrome C-oxidase deficiency: a case report and review of the literature. Isr J Med Sci 1995; 31(4): 224–9PubMedGoogle Scholar
  87. 87.
    Sampson V, Alleyne T. Cytochrome c/cytochrome c oxidase interaction: direct structural evidence for conformational changes during enzyme turnover. Eur J Biochem 2001; 268(24): 6534–44PubMedCrossRefGoogle Scholar
  88. 88.
    Cooper JM, Hayes DJ, Challiss RA, et al. Treatment of experimental NADH ubiquinone reductase deficiency with menadione. Brain 1992; 115 (Pt 4): 991–1000PubMedGoogle Scholar
  89. 89.
    Shoffner JM. Oxidative phosphorylation disease. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001: 2367–2534Google Scholar
  90. 90.
    Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J 1999; 13(2): 411–8PubMedGoogle Scholar
  91. 91.
    Jacob S, Henriksen EJ, Tritschler HJ, et al. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 1996; 104(3): 284–8PubMedCrossRefGoogle Scholar
  92. 92.
    Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 2001; 49(5): 561–74PubMedCrossRefGoogle Scholar
  93. 93.
    Barbiroli B, Medori R, Tritschler HJ, et al. Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. J Neurol 1995; 242(7): 472–7PubMedCrossRefGoogle Scholar
  94. 94.
    De Vivo DC, Tein I. Primary and secondary disorders of carnitine metabolism. Int Pediatr 1990; 5: 134–41Google Scholar
  95. 95.
    Enns GM, Bennett MJ, Hoppel CL, et al. Mitochondrial respiratory chain complex I deficiency with clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. J Pediatr 2000; 136(2): 147–8CrossRefGoogle Scholar
  96. 96.
    Campos Y, Garcia-Silva T, Barrionuevo CR, et al. Mitochondrial DNA deletion in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) and Fanconi’s syndrome. Pediatr Neurol 1995; 13(1): 69–72PubMedCrossRefGoogle Scholar
  97. 97.
    Hsu CC, Chuang YH, Tsai JL, et al. CPEO and carnitine deficiency overlapping in MELAS syndrome. Acta Neurol Scand 1995; 92(3): 252–5PubMedCrossRefGoogle Scholar
  98. 98.
    Marriage B, Clandinin MT, Glerum DM. Nutritional cofactor treatment in mitochondrial disorders. J Am Diet Assoc 2003; 103: 1029–38PubMedCrossRefGoogle Scholar
  99. 99.
    Shapira Y, Cederbaum SD, Cancilla PA, et al. Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia. Neurology 1975; 25(7): 614–21PubMedCrossRefGoogle Scholar
  100. 100.
    Skoglund RR. Reversible alexia, mitochondrial myopathy, and lactic acidemia. Neurology 1979; 29(5): 717–20PubMedCrossRefGoogle Scholar
  101. 101.
    Heiman-Patterson TD, Argov Z, Chavin JM, et al. Biochemical and genetic studies in a family with mitochondrial myopathy. Muscle Nerve 1997; 20(10): 1219–24PubMedCrossRefGoogle Scholar
  102. 102.
    Mastaglia FL, Thompson PL, Papadimitriou JM. Mitochondrial myopathy with cardiomyopathy, lactic acidosis and response to prednisone and thiamine. Aust N Z J Med 1980; 10(6): 660–4PubMedCrossRefGoogle Scholar
  103. 103.
    Gubbay SS, Hankey GJ, Tan NT, et al. Mitochondrial encephalomyopathy with corticosteroid dependence. Med J Aust 1989; 151(2): 100–3, 106, 108PubMedGoogle Scholar
  104. 104.
    Montagna P, Gallassi R, Medori R, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988; 38(5): 751–4PubMedCrossRefGoogle Scholar
  105. 105.
    Rossi FH, Okun M, Yachnis A, et al. Corticosteroid treatment of mitochondrial encephalomyopathies. Neurologist 2002; 8(5): 313–5PubMedCrossRefGoogle Scholar
  106. 106.
    Willmore LJ, Triggs WJ. Effect of phenytoin and corticosteroids on seizures and lipid peroxidation in experimental posttraumatic epilepsy. J Neurosurg 1984; 60(3): 467–72PubMedCrossRefGoogle Scholar
  107. 107.
    Saunders RD, Dugan LL, Demediuk P, et al. Effects of methylprednisolone and the combination of alpha-tocopherol and selenium on arachidonic acid metabolism and lipid peroxidation in traumatized spinal cord tissue. J Neurochem 1987; 49(1): 24–31PubMedCrossRefGoogle Scholar
  108. 108.
    Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond) 1992; 83(3): 367–74Google Scholar
  109. 109.
    Tarnopolsky MA, Parise G. Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 1999; 22(9): 1228–33PubMedCrossRefGoogle Scholar
  110. 110.
    Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 1997; 20(12): 1502–9PubMedCrossRefGoogle Scholar
  111. 111.
    Hagenfeldt L, von Dobeln U, Solders G, et al. Creatine treatment in MELAS. Muscle Nerve 1994; 17(10): 1236–7PubMedGoogle Scholar
  112. 112.
    Barisic N, Bernert G, Ipsiroglu O, et al. Effects of oral creatine supplementation in a patient with MELAS phenotype and associated nephropathy. Neuropediatrics 2002; 33(3): 157–61PubMedCrossRefGoogle Scholar
  113. 113.
    Wallimann T, Dolder M, Schlattner U, et al. Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors 1998; 8(3–4): 229–34PubMedCrossRefGoogle Scholar
  114. 114.
    Radda GK, Odoom J, Kemp G, et al. Assessment of mitochondrial function and control in normal and diseased states. Biochim Biophys Acta 1995; 1271(1): 15–9PubMedCrossRefGoogle Scholar
  115. 115.
    Kurogouchi F, Oguchi T, Mawatari E, et al. A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol 1998; 18(6): 551–6PubMedCrossRefGoogle Scholar
  116. 116.
    Koga Y, Ishibashi M, Ueki I, et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology 2002; 58(5): 827–8PubMedCrossRefGoogle Scholar
  117. 117.
    Kubota M, Sakakihara Y, Mori M, et al. Beneficial effect of Larginine for stroke-like episode in MELAS. Brain Dev 2004; 26(7): 481–3PubMedCrossRefGoogle Scholar
  118. 118.
    Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329(27): 2002–12PubMedCrossRefGoogle Scholar
  119. 119.
    Nakaki T, Hishikawa K, Suzuki H, et al. L-arginine-induced hypotension [letter]. Lancet 1990; 336(8716): 696PubMedCrossRefGoogle Scholar
  120. 120.
    Stansbie D. Regulation of the human pyruvate dehydrogenase complex. Clin Sci Mol Med 1976; 51(5): 445–52PubMedGoogle Scholar
  121. 121.
    Clark AS, Mitch WE, Goodman MN, et al. Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle. J Clin Invest 1987; 79(2): 588–94PubMedCrossRefGoogle Scholar
  122. 122.
    Stacpoole PW, Henderson GN, Yan Z, et al. Clinical pharmacology and toxicology of dichloroacetate. Environ Health Perspect 1998; 106Suppl. 4: 989–94PubMedGoogle Scholar
  123. 123.
    Craigen WJ. Leigh disease with deficiency of lipoamide dehydrogenase: treatment failure with dichloroacetate. Pediatr Neurol 1996; 14(1): 69–71PubMedCrossRefGoogle Scholar
  124. 124.
    Takanashi J, Sugita K, Tanabe Y, et al. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. J Neurol Sci 1997; 145(1): 83–6PubMedCrossRefGoogle Scholar
  125. 125.
    Pavlakis SG, Kingsley PB, Kaplan GP, et al. Magnetic resonance spectroscopy: use in monitoring MELAS treatment. Arch Neurol 1998; 55(6): 849–52PubMedCrossRefGoogle Scholar
  126. 126.
    Mori M, Yamagata T, Goto T, et al. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev 2004; 26(7): 453–8PubMedCrossRefGoogle Scholar
  127. 127.
    Spruijt L, Naviaux RK, McGowan KA, et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve 2001; 24(7): 916–24PubMedCrossRefGoogle Scholar
  128. 128.
    Stacpoole PW, Harwood Jr HJ, Cameron DF, et al. Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats. Fundam Appl Toxicol 1990; 14(2): 327–37PubMedCrossRefGoogle Scholar
  129. 129.
    Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomised, controlled clinical trial. Neurology 2006; 66(3): 329–30CrossRefGoogle Scholar
  130. 130.
    Hashimoto Y, Niikura T, Tajima H, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A 2001; 98(11): 6336–41PubMedCrossRefGoogle Scholar
  131. 131.
    Kariya S, Takahashi N, Hirano M, et al. Humanin improves impaired metabolic activity and prolongs survival of serumdeprived human lymphocytes. Mol Cell Biochem 2003; 254(1–2): 83–9PubMedCrossRefGoogle Scholar
  132. 132.
    Kariya S, Hirano M, Furiya Y, et al. Effect of humanin on decreased ATP levels of human lymphocytes harboring A3243G mutant mitochondrial DNA. Neuropeptides 2005; 39(2): 97–101PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of Molecular and Human GeneticsBaylor College of Medicine and Texas Children’s Hospital, Clinical Care CenterHoustonUSA

Personalised recommendations