A modern approach to the treatment of mitochondrial disease

  • Sumit ParikhEmail author
  • Russell Saneto
  • Marni J. Falk
  • Irina Anselm
  • Bruce H. Cohen
  • Richard Haas
  • The Mitochondrial Medicine Society

Opinion statement

The treatment of mitochondrial disease varies considerably. Most experts use a combination of vitamins, optimize patients’ nutrition and general health, and prevent worsening of symptoms during times of illness and physiologic stress. We agree with this approach, and we agree that therapies using vitamins and cofactors have value, though there is debate about the choice of these agents and the doses prescribed. Despite the paucity of high-quality scientific evidence, these therapies are relatively harmless, may alleviate select clinical symptoms, and theoretically may offer a means of staving off disease progression. Like many other mitochondrial medicine physicians, we have observed significant (and at times life-altering) clinical responses to such pharmacologic interventions. However, it is not yet proven that these therapies truly alter the course of the disease, and some experts may choose not to use these medications at all. At present, the evidence of their effectiveness does not rise to the level required for universal use.

Based on our clinical experience and judgment, however, we agree that a therapeutic trial of coenzyme Q10, along with other antioxidants, should be attempted. Although individual specialists differ as to the exact drug cocktail, a common approach involves combinations of antioxidants that may have a synergistic effect. Because almost all relevant therapies are classified as medical foods or over-the-counter supplements, most physicians also attempt to balance the apparent clinical benefit of mitochondrial cocktails with the cost burden that these supplements pose for the family.


Carnitine CoQ10 Main Side Effect Vagus Nerve Stimulation Main Drug Interaction 
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References and Recommended Reading

  1. 1.
    Haas RH, Parikh S, Falk MJ, et al.: Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007, 120:1326–1333.CrossRefPubMedGoogle Scholar
  2. 2.
    Haas RH, Parikh S, Falk MJ, et al.: The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008, 94:16–37.CrossRefPubMedGoogle Scholar
  3. 3.
    Morava E, van den Heuvel L, Hol F, et al.: Mitochondrial disease criteria: diagnostic applications in children. Neurology 2006, 67:1823–1826.CrossRefPubMedGoogle Scholar
  4. 4.
    Wortmann SB, Zweers-van Essen H, Rodenburg RJ, et al.: Mitochondrial energy production correlates with the age-related BMI. Pediatr Res 2009, 65:103–108.CrossRefPubMedGoogle Scholar
  5. 5.
    Morava E, Rodenburg R, van Essen HZ, et al.: Dietary intervention and oxidative phosphorylation capacity. J Inherit Metab Dis 2006, 29:589.CrossRefPubMedGoogle Scholar
  6. 6.
    Cave SF: The history of vaccinations in the light of the autism epidemic. Altern Ther Health Med 2008, 14:54–57.PubMedGoogle Scholar
  7. 7.
    Freeman JM, Vining EP, Pillas DJ, et al.: The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Pediatrics 1998, 102:1358–1363.CrossRefPubMedGoogle Scholar
  8. 8.
    Freeman JM, Vining EP, Kossoff EH, et al.: A blinded, crossover study of the efficacy of the ketogenic diet. Epilepsia 2009, 50:322–325.CrossRefPubMedGoogle Scholar
  9. 9.
    Bough KJ, Wetherington J, Hassel B, et al.: Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 2006, 60:223–235.CrossRefPubMedGoogle Scholar
  10. 10.
    Kang HC, Lee YM, Kim HD, et al.: Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia 2007, 48:82–88.PubMedGoogle Scholar
  11. 11.
    Haas RH: The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease. Mitochondrion 2007, 7(Suppl):S136–S145.CrossRefGoogle Scholar
  12. 12.
    Quinzii C, Naini A, Salviati L, et al.: A mutation in parahydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 2006, 78:345–349.CrossRefPubMedGoogle Scholar
  13. 13.
    Lopez LC, Schuelke M, Quinzii CM, et al.: Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 2006, 79:1125–1129.CrossRefPubMedGoogle Scholar
  14. 14.
    Mollet J, Giurgea I, Schlemmer D, et al.: Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J Clin Invest 2007, 117:765–772.CrossRefPubMedGoogle Scholar
  15. 15.
    Lagier-Tourenne C, Tazir M, Lopez LC, et al.: ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 2008, 82:661–672.CrossRefPubMedGoogle Scholar
  16. 16.
    Shults CW, Flint Beal M, Song D, et al.: Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol 2004, 188:491–494.CrossRefPubMedGoogle Scholar
  17. 17.
    Bhagavan HN, Chopra RK: Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion 2007, 7(Suppl):S78–S88.CrossRefPubMedGoogle Scholar
  18. 18.
    Linnane AW, Kios M, Vitetta L: Coenzyme Q(10)—its role as a prooxidant in the formation of superoxide anion/hydrogen peroxide and the regulation of the metabolome. Mitochondrion 2007, 7(Suppl):S51–S61.CrossRefPubMedGoogle Scholar
  19. 19.
    Olsen RK, Olpin SE, Andresen BS, et al.: ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 2007, 130:2045–2054.CrossRefPubMedGoogle Scholar
  20. 20.
    Bugiani M, Lamantea E, Invernizzi F, et al.: Effects of riboflavin in children with complex II deficiency. Brain Dev 2006, 28:576–581.CrossRefPubMedGoogle Scholar
  21. 21.
    Tarnopolsky MA, Raha S: Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options. Med Sci Sports Exerc 2005, 37:2086–2093.CrossRefPubMedGoogle Scholar
  22. 22.
    Bernsen PL, Gabreels FJ, Ruitenbeek W, et al.: Treatment of complex I deficiency with riboflavin. J Neurol Sci 1993, 118:181–187.CrossRefPubMedGoogle Scholar
  23. 23.
    Tarnopolsky MA, Parise G: Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 1999, 22:1228–1233.CrossRefPubMedGoogle Scholar
  24. 24.
    Moroni I, Bugiani M, Bizzi A, et al.: Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics 2002, 33:79–85.CrossRefPubMedGoogle Scholar
  25. 25.
    Tarnopolsky MA, Roy BD, MacDonald JR: A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 1997, 20:1502–1509.CrossRefPubMedGoogle Scholar
  26. 26.
    Borchert A, Wilichowski E, Hanefeld F: Supplementation with creatine monohydrate in children with mitochondrial encephalomyopathies. Muscle Nerve 1999, 22:1299–1300.CrossRefPubMedGoogle Scholar
  27. 27.
    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, 58:827–828.PubMedGoogle Scholar
  28. 28.
    Koga Y, Akita Y, Nishioka J, et al.: L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 2005, 64:710–712.CrossRefPubMedGoogle Scholar
  29. 29.
    Tein I: Carnitine transport: pathophysiology and metabolism of known molecular defects. J Inherit Metab Dis 2003, 26:147–169.CrossRefPubMedGoogle Scholar
  30. 30.
    DiMauro S, Hirano M, Schon EA: Approaches to the treatment of mitochondrial diseases. Muscle Nerve 2006, 34:265–283.CrossRefPubMedGoogle Scholar
  31. 31.
    Marriage BJ, Clandinin MT, Macdonald IM, et al.: Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders. Mol Genet Metab 2004, 81:263–272.CrossRefPubMedGoogle Scholar
  32. 32.
    Bain MA, Faull R, Fornasini G, et al.: Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis. Nephrol Dial Transplant 2006, 21:1300–1304.CrossRefPubMedGoogle Scholar
  33. 33.
    Ramaekers VT, Weis J, Sequeira JM, et al.: Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency. Neuropediatrics 2007, 38:184–187.CrossRefPubMedGoogle Scholar
  34. 34.
    Garcia-Cazorla A, Serrano M, Perez-Duenas B, et al.: Secondary abnormalities of neurotransmitters in infants with neurological disorders. Dev Med Child Neurol 2007, 49:740–744.CrossRefPubMedGoogle Scholar
  35. 35.
    Stacpoole PW, Kerr DS, Barnes C, et al.: Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children Pediatrics 2006, 117:1519–1531.CrossRefPubMedGoogle Scholar
  36. 36.
    Barshop BA, Naviaux RK, McGowan KA, et al.: Chronic treatment of mitochondrial disease patients with dichloroacetate. Mol Genet Metab 2004, 83:138–149.CrossRefPubMedGoogle Scholar
  37. 37.
    Kaufmann P, Engelstad K, Wei Y, et al.: Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006, 66:324–330.CrossRefPubMedGoogle Scholar
  38. 38.
    Prietsch V, Lindner M, Zschocke J, et al.: Emergency management of inherited metabolic diseases. J Inherit Metab Dis 2002, 25:531–546.CrossRefPubMedGoogle Scholar
  39. 39.
    Morgan PG, Hoppel CL, Sedensky MM: Mitochondrial defects and anesthetic sensitivity. Anesthesiology 2002, 96:1268–1270.CrossRefPubMedGoogle Scholar
  40. 40.
    Arthur TM, Saneto RP, de Menezes MS, et al.: Vagus nerve stimulation in children with mitochondrial electron transport chain deficiencies. Mitochondrion 2007, 7:279–283.CrossRefPubMedGoogle Scholar
  41. 41.
    Dimmock DP, Dunn JK, Feigenbaum A, et al.: Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency. Liver Transpl 2008, 14:1480–1485.CrossRefPubMedGoogle Scholar
  42. 42.
    Hirano M, Marti R, Casali C, et al.: Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 2006, 67:1458–1460.CrossRefPubMedGoogle Scholar
  43. 43.
    Sinnathuray AR, Raut V, Awa A, et al.: A review of cochlear implantation in mitochondrial sensorineural hearing loss. Otol Neurotol 2003, 24:418–426.CrossRefPubMedGoogle Scholar
  44. 44.
    Tono T, Ushisako Y, Kiyomizu K, et al.: Cochlear implantation in a patient with profound hearing loss with the A1555G mitochondrial mutation. Am J Otol 1998, 19:754–757.PubMedGoogle Scholar
  45. 45.
    Spencer CT, Byrne BJ, Gewitz MH, et al.: Ventricular arrhythmia in the X-linked cardiomyopathy Barth syndrome. Pediatr Cardiol 2005, 26:632–637.CrossRefPubMedGoogle Scholar
  46. 46.
    Murphy RT, Mogensen J, McGarry K, et al.: Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history. J Am Coll Cardiol 2005, 45:922–930.CrossRefPubMedGoogle Scholar
  47. 47.
    Sanders GD, Hlatky MA, Owens DK: Cost-effectiveness of implantable cardioverter-defibrillators. N Engl J Med 2005, 353:1471–1480.CrossRefPubMedGoogle Scholar
  48. 48.
    Tarnopolsky MA: Mitochondrial DNA shifting in older adults following resistance exercise training. Appl Physiol Nutr Metab 2009, 34:348–354.CrossRefPubMedGoogle Scholar
  49. 49.
    Taivassalo T, Haller RG: Exercise and training in mitochondrial myopathies. Med Sci Sports Exerc 2005, 37:2094–2101.CrossRefPubMedGoogle Scholar
  50. 50.
    Jeppesen TD, Schwartz M, Olsen DB, et al.: Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 2006, 129:3402–3412.CrossRefPubMedGoogle Scholar
  51. 51.
    Sterba JA, Rogers BT, France AP, et al.: Horseback riding in children with cerebral palsy: effect on gross motor function. Dev Med Child Neurol 2002, 44:301–308.CrossRefPubMedGoogle Scholar
  52. 52.
    Puigserver P, Spiegelman BM: Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 2003, 24:78–90.CrossRefPubMedGoogle Scholar
  53. 53.
    Wenz T, Diaz F, Spiegelman BM, et al.: Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab 2008, 8:249–256.CrossRefPubMedGoogle Scholar
  54. 54.
    Saiko P, Szakmary A, Jaeger W, Szekeres T: Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat Res 2008, 658:68–94.CrossRefPubMedGoogle Scholar
  55. 55.
    Silva MF, Aires CC, Luis PB, et al.: Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 2008, 31:205–216.CrossRefGoogle Scholar
  56. 56.
    Dalakas MC: Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 2001, 6:14–20.CrossRefPubMedGoogle Scholar
  57. 57.
    Scruggs ER, Dirks Naylor AJ: Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology 2008, 82:83–88.CrossRefPubMedGoogle Scholar
  58. 58.
    Pinti M, Salomoni P, Cossarizza A: Anti-HIV drugs and the mitochondria. Biochim Biophys Acta 2006, 1757:700–707.CrossRefPubMedGoogle Scholar
  59. 59.
    Littarru GP, Langsjoen P: Coenzyme Q10 and statins: biochemical and clinical implications. Mitochondrion 2007, 7(Suppl):S168–S174.CrossRefPubMedGoogle Scholar
  60. 60.
    Sirvent P, Mercier J, Lacampagne A: New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol 2008, 8:333–338.CrossRefPubMedGoogle Scholar
  61. 61.
    Wagner BK, Kitami T, Gilbert TJ, et al.: Large-scale chemical dissection of mitochondrial function. Nat Biotechnol 2008, 26:343–351.CrossRefPubMedGoogle Scholar
  62. 62.
    Bindu LH, Reddy PP: Genetics of aminoglycoside-induced and prelingual non-syndromic mitochondrial hearing impairment: a review. Int J Audiol 2008, 47:702–707.CrossRefPubMedGoogle Scholar
  63. 63.
    Fischel-Ghodsian N: Genetic factors in aminoglycoside toxicity. Ann NY Acad Sci 1999, 884:99–109.CrossRefPubMedGoogle Scholar
  64. 64.
    Kovacic P, Pozos RS, Somanathan R, et al.: Mechanism of mitochondrial uncouplers, inhibitors, and toxins: focus on electron transfer, free radicals, and structure-activity relationships. Curr Med Chem 2005, 12:2601–2623.CrossRefPubMedGoogle Scholar
  65. 65.
    Spiller HA, Sawyer TS: Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 2006, 63:929–938.CrossRefPubMedGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Sumit Parikh
    • 1
    Email author
  • Russell Saneto
  • Marni J. Falk
  • Irina Anselm
  • Bruce H. Cohen
  • Richard Haas
  • The Mitochondrial Medicine Society
  1. 1.Neurometabolism & NeurogeneticsCleveland ClinicClevelandUSA

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